BioPAX pathway converted from "Immune System" in the Reactome database. Immune System Signaling in Immune system Immune System signaling Humans are exposed to millions of potential pathogens daily, through contact, ingestion, and inhalation. Our ability to avoid infection depends on the adaptive immune system and during the first critical hours and days of exposure to a new pathogen, our innate immune system. Authored: de Bono, B, Gillespie, ME, Luo, F, Ouwehand, W.H., 2006-03-30 04:06:59 Reviewed: D'Eustachio, P, Gay, NJ, Gale M, Jr, Zwaginga, JJ, 2006-04-19 04:09:58 Adaptive Immune System Adaptive immunity refers to antigen-specific immune response efficiently involved in clearing the pathogens. The adaptive immune system is comprised of B and T lymphocytes that express receptors with remarkable diversity tailored to recognize aspects of particular pathogens or antigens. During infection, dendritic cells (DC) which act as sentinels in the peripheral tissues recognize and pick up the pathogen in the form of antigenic determinants and then process these antigens and present them to T cells. These T cells of appropriate specificity respond to the antigen, and either kill the pathogen directly or secrete cytokines that will stimulate B lymphocyte response. B cells provide humoral immunity by secreting antibodies specific for the pathogen or antigen. Authored: de Bono, B, Garapati, P V, Jupe, S, May, B, 2011-05-22 Reviewed: Trowsdale, J, Bluestone, JA, Elliott, T, Esensten, J, Heemskerk, JW, 2011-05-28 Edited: de Bono, B, Garapati, P V, Jupe, S, May, B, 2011-05-22 TCR signaling The TCR is a multisubunit complex that consists of clonotypic alpha/beta chains noncovalently associated with the invariant CD3 delta/epsilon/gamma and TCR zeta chains. T cell activation by antigen presenting cells (APCs) results in the activation of protein tyrosine kinases (PTKs) that associate with CD3 and TCR zeta subunits and the co-receptor CD4. Members of the Src kinases (Lck), Syk kinases (ZAP-70), Tec (Itk) and Csk families of nonreceptor PTKs play a crucial role in T cell activation. Activation of PTKs following TCR engagement results in the recruitment and tyrosine phosphorylation of enzymes such as phospholipase C gamma1 and Vav as well as critical adaptor proteins such as LAT, SLP-76 and Gads. These proximal activation leads to reorganization of the cytoskeleton as well as transcription activation of multiple genes leading to T lymphocyte proliferation, differentiation and/or effector function. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Phosphorylation of CD3 and TCR zeta chains Prior to T cell receptor (TCR) stimulation, CD4/CD8 associated LCK remains seperated from the TCR and is maintained in an inactive state by the action of CSK. PAG bound CSK phosphorylates the negative regulatory tyrosine of LCK and inactivates the LCK kinase domain (step 1). CSK also inhibits PTPN22 by sequestering it via binding (step 2). Upon TCR stimulation, CSK dissociates from PAG1 (step 3) and PTPN22 (step4) and is unable to inhibit LCK. Furthermore, LCK becomes activated via PTPRC-mediated dephosphorylation of negative regulatory tyrosine residues (step 5). CD4/CD8 binds MHCII receptor in APC and the associated LCK co-localizes with the TCR. LCK is further activated by trans-autophosphorylation on the tyrosine residue on its activation loop (step 6). Active LCK further phosphorylates the tyrosine residues on CD3 chains. The signal-transducing CD3 delta/epsilon/gamma and TCR zeta chains contain a critical signaling motif known as the immunoreceptor tyrosine-based activation motif (ITAM). The two critical tyrosines of each ITAM motif are phosphorylated by LCK (step 7). Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 LEFT-TO-RIGHT Interaction of Csk with PAG Csk is a tyrosine kinase that phosphorylates the negative regulatory C-terminal tyrosine residue Y505 of Lck to maintain Lck in an inactive state. In resting T cells, Csk is targeted to lipid rafts through engagement of its SH2 domain with phosphotyrosine residue pY317 of PAG. PAG is expressed as a tyrosine phosphorylated protein in nonstimulated T-cells. This interaction of Csk and PAG allows activation of Csk and inhibition of Lck. Given that PAG-1 T cell knock out show a weak phenotype, some other protein may substitute in activating Csk. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 p-CBP p-Y317-PAG1 p-PAG1 Reactome DB_ID: 180494 plasma membrane GENE ONTOLOGY GO:0005886 UniProt:Q9NWQ8 PAG1 PAG1 CBP PAG FUNCTION Negatively regulates TCR (T-cell antigen receptor)-mediated signaling in T-cells and FCER1 (high affinity immunoglobulin epsilon receptor)-mediated signaling in mast cells. Promotes CSK activation and recruitment to lipid rafts, which results in LCK inhibition. Inhibits immunological synapse formation by preventing dynamic arrangement of lipid raft proteins. May be involved in cell adhesion signaling.SUBUNIT Interacts with FYN. When phosphorylated, interacts with CSK. Interacts with SLC9A3R1/EBP50. In resting T-cells, part of a PAG1-SLC9A3R1-MSN complex which is disrupted upon TCR activation. Interacts with LYN on plasma membrane lipid rafts. Identified in a complex with LYN and STAT3.TISSUE SPECIFICITY Ubiquitously expressed. Present in germinal center B-cells, plasma cells, T-cells, monocytes and platelets (at protein level).PTM Palmitoylated.PTM Phosphorylated by FYN on Tyr-317 in resting T-cells; which promotes interaction with CSK. Dephosphorylated by PTPRC/CD45 upon TCR activation; which leads to CSK dissociation. May also be dephosphorylated by PTPN11. Hyperphosphorylated in mast cells upon FCER1 activation. Phosphorylated by LYN. Homo sapiens NCBI Taxonomy 9606 UniProt Q9NWQ8 317 EQUAL O4'-phospho-L-tyrosine MOD MOD:00048 1 EQUAL 432 EQUAL Reactome Database ID Release 78 180494 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=180494 Reactome R-HSA-180494 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-180494.1 Reactome http://www.reactome.org CSK Tyrosine-protein kinase CSK C-Src kinase Reactome DB_ID: 203776 cytosol GENE ONTOLOGY GO:0005829 UniProt:P41240 CSK CSK FUNCTION Non-receptor tyrosine-protein kinase that plays an important role in the regulation of cell growth, differentiation, migration and immune response. Phosphorylates tyrosine residues located in the C-terminal tails of Src-family kinases (SFKs) including LCK, SRC, HCK, FYN, LYN, CSK or YES1. Upon tail phosphorylation, Src-family members engage in intramolecular interactions between the phosphotyrosine tail and the SH2 domain that result in an inactive conformation. To inhibit SFKs, CSK is recruited to the plasma membrane via binding to transmembrane proteins or adapter proteins located near the plasma membrane. Suppresses signaling by various surface receptors, including T-cell receptor (TCR) and B-cell receptor (BCR) by phosphorylating and maintaining inactive several positive effectors such as FYN or LCK.SUBUNIT Homodimer (via SH3-domain) (PubMed:19888460). Interacts with PTPN22 (PubMed:15208781). Interacts with phosphorylated SIT1, PAG1, LIME1 and TGFB1I1; these interactions serve to recruit CSK to the membrane where it can phosphorylate and inhibit Src-family kinases (PubMed:11433379, PubMed:10790433, PubMed:14610046, PubMed:10838081). Interacts with SRCIN1 (PubMed:17525734). Interacts with RHOH (PubMed:20851766). Interacts (via SH2 domain) with SCIMP; this interaction is dependent on phosphorylation of SCIMP 'Tyr-107' (PubMed:21930792). Interacts (via SH2 domain) with PRAG1 (when phosphorylated at 'Tyr-391'); this interaction prevents translocation of CSK from the cytoplasm to the membrane leading to increased activity of CSK (By similarity).TISSUE SPECIFICITY Expressed in lung and macrophages.DOMAIN The architecture of this protein is similar to that of Src-family kinases (SFKs) with one N-terminal SH3 domain, one SH2 domain, and a C-terminal kinase domain.PTM Phosphorylated at Ser-364 by PKA, leading to increased activity. Autophosphorylated.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. CSK subfamily. UniProt P41240 1 EQUAL 450 EQUAL Reactome Database ID Release 78 203776 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=203776 Reactome R-HSA-203776 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-203776.1 Csk:p-PAG Reactome DB_ID: 202297 1 1 Reactome Database ID Release 78 202297 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202297 Reactome R-HSA-202297 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202297.1 Reactome Database ID Release 78 203774 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=203774 Reactome R-HSA-203774 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-203774.1 12938237 Pubmed 2003 The activation of Csk by CD4 interferes with TCR-mediated activatory signaling Marinari, B Simeoni, L Schraven, B Piccolella, E Tuosto, L Eur J Immunol 33:2609-18 11827988 Pubmed 2002 Adapters in lymphocyte signaling Leo, A Wienands, J Baier, G Horejsi, V Schraven, B J Clin Invest 109:301-9 10790433 Pubmed 2000 Phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG), a novel ubiquitously expressed transmembrane adaptor protein, binds the protein tyrosine kinase csk and is involved in regulation of T cell activation Brdicka, T Pavlistova, D Leo, A Bruyns, E Korinek, V Angelisova, P Scherer, J Shevchenko, A Hilgert, I Cerny, J Drbal, K Kuramitsu, Y Kornacker, B Horejsi, V Schraven, B J Exp Med 191:1591-604 LEFT-TO-RIGHT 2.7.10 Inactivation of Lck by Csk Lck is a member of the Src family tyrosine kinases and these members have the following domains in common: N-terminal Myristoylation site for saturated fatty acid addition, a unique region, a Src-homology 3 (SH3) domain, an SH2 domain, a tyrosine kinase domain (SH1), and a C-terminal negative regulatory domain. Myristoylation engenders Lck with the ability to attach to cellular membranes. This interaction is mediated by both myristic acid and palmitic acid that are bound to the amino terminal glycine and Cys-3 and/or Cys-5. <br><br>The unique region of Lck is thought to be involved in the interaction with the cytoplasmic tails of coreceptors CD4 and CD8. The Lck/CD4 interaction require conserved cysteine motifs: a CxCP motif in CD4 and a CxxC motif in the Lck unique domain. The SH3 and SH2 domains of Lck are involved in intramolecular and intermolecular regulation by mediating protein-protein interactions via poly-proline and phosphotyrosine-specific interactions, respectively. <br><br>Lck adopts specific conformation that largely dictate its level of activity. The C-ter tail has an autoinhibitory phosphorylation site (tyr 505). When the Y505 is phosphorylated, Lck adopts a closed conformation, where the pY505 residue creates an intramolecular binding motif for the SH2 domain, effectively inactivating the kinase domain. The inactivating phosphorylation on Y505 is carried out by the Src-specific kinase Csk. Protein tyrosine phosphatase CD45 (PTPRC) and CD148 (PTPRJ) have dual function in TCR signaling. They act both in activation as well as inactivation of Src family kinases (SFKs) which are involved in the initiation of TCR signal transduction (Stepanek et al. 2011). The activator role is to dephosphorylate an inhibitory site tyrosine 505 (Y505) at the C-terminal end of Lck, which is needed to enable Lck to an open conformation and expose the activation loop (A-loop) containing the activating tyrosine 394 (Y394) (Xu et al. 1993. McNeill et al. 2007, Zikherman et al. 2010, Stepanek et al. 2011, Salmond et al. 2009). Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 113592 ATP(4-) [ChEBI:30616] ATP(4-) ATP atp Adenosine 5'-triphosphate ChEBI CHEBI:30616 Reactome Database ID Release 78 113592 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113592 Reactome R-ALL-113592 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113592.5 COMPOUND C00002 additional information MI MI:0361 Antigen-bearing MHC Class II : TCR complex:CD4:Lck Reactome DB_ID: 202157 T-cell receptor complex Reactome DB_ID: 198901 T-cell receptor Reactome DB_ID: 198183 Converted from EntitySet in Reactome TCR chain alpha Reactome DB_ID: 198184 TRAC T-cell receptor alpha chain C region TCA_HUMAN Reactome DB_ID: 198175 UniProt:P01848 TRAC TRAC TCRA FUNCTION Constant region of T cell receptor (TR) alpha chain (PubMed:24600447). Alpha-beta T cell receptors are antigen specific receptors which are essential to the immune response and are present on the cell surface of T lymphocytes. Recognize peptide-major histocompatibility (MH) (pMH) complexes that are displayed by antigen presenting cells (APC), a prerequisite for efficient T cell adaptive immunity against pathogens (PubMed:25493333). Binding of alpha-beta TR to pMH complex initiates TR-CD3 clustering on the cell surface and intracellular activation of LCK that phosphorylates the ITAM motifs of CD3G, CD3D, CD3E and CD247 enabling the recruitment of ZAP70. In turn, ZAP70 phosphorylates LAT, which recruits numerous signaling molecules to form the LAT signalosome. The LAT signalosome propagates signal branching to three major signaling pathways, the calcium, the mitogen-activated protein kinase (MAPK) kinase and the nuclear factor NF-kappa-B (NF-kB) pathways, leading to the mobilization of transcription factors that are critical for gene expression and essential for T cell growth and differentiation (PubMed:23524462). The T cell repertoire is generated in the thymus, by V-(D)-J rearrangement. This repertoire is then shaped by intrathymic selection events to generate a peripheral T cell pool of self-MH restricted, non-autoaggressive T cells. Post-thymic interaction of alpha-beta TR with the pMH complexes shapes TR structural and functional avidity (PubMed:15040585).SUBUNIT Alpha-beta TR is a heterodimer composed of an alpha and beta chain; disulfide-linked. The alpha-beta TR is associated with the transmembrane signaling CD3 coreceptor proteins to form the TR-CD3 (TcR or TCR). The assembly of alpha-beta TR heterodimers with CD3 occurs in the endoplasmic reticulum where a single alpha-beta TR heterodimer associates with one CD3D-CD3E heterodimer, one CD3G-CD3E heterodimer and one CD247 homodimer forming a stable octomeric structure. CD3D-CD3E and CD3G-CD3E heterodimers preferentially associate with TR alpha and TR beta chains, respectively. The association of the CD247 homodimer is the last step of TcR assembly in the endoplasmic reticulum and is required for transport to the cell surface.DOMAIN The connecting peptide (CP) domain contributes to the TR-CD3 assembly and signal transduction.DOMAIN The TM domain mediates the interaction with the CD3 subunits.POLYMORPHISM There are several alleles. The sequence shown is that of IMGT allele TRAC*01. UniProt P01848 1 EQUAL 142 EQUAL Reactome Database ID Release 78 198175 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198175 Reactome R-HSA-198175 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198175.1 TCRA T-cell receptor alpha chain V region CTL-L17 precursor TVA2_HUMAN Reactome DB_ID: 198180 UniProt:P04437 TRAV29DV5 TRAV29DV5 FUNCTION V region of the variable domain of T cell receptor (TR) alpha chain that participates in the antigen recognition (PubMed:24600447). Alpha-beta T cell receptors are antigen specific receptors which are essential to the immune response and are present on the cell surface of T lymphocytes. Recognize peptide-major histocompatibility (MH) (pMH) complexes that are displayed by antigen presenting cells (APC), a prerequisite for efficient T cell adaptive immunity against pathogens (PubMed:25493333). Binding of alpha-beta TR to pMH complex initiates TR-CD3 clustering on the cell surface and intracellular activation of LCK that phosphorylates the ITAM motifs of CD3G, CD3D, CD3E and CD247 enabling the recruitment of ZAP70. In turn ZAP70 phosphorylates LAT, which recruits numerous signaling molecules to form the LAT signalosome. The LAT signalosome propagates signal branching to three major signaling pathways, the calcium, the mitogen-activated protein kinase (MAPK) kinase and the nuclear factor NF-kappa-B (NF-kB) pathways, leading to the mobilization of transcription factors that are critical for gene expression and essential for T cell growth and differentiation (PubMed:23524462). The T cell repertoire is generated in the thymus, by V-(D)-J rearrangement. This repertoire is then shaped by intrathymic selection events to generate a peripheral T cell pool of self-MH restricted, non-autoaggressive T cells. Post-thymic interaction of alpha-beta TR with the pMH complexes shapes TR structural and functional avidity (PubMed:15040585).SUBUNIT Alpha-beta TR is a heterodimer composed of an alpha and beta chain; disulfide-linked. The alpha-beta TR is associated with the transmembrane signaling CD3 coreceptor proteins to form the TR-CD3 (TcR or TCR). The assembly of alpha-beta TR heterodimers with CD3 occurs in the endoplasmic reticulum where a single alpha-beta TR heterodimer associates with one CD3D-CD3E heterodimer, one CD3G-CD3E heterodimer and one CD247 homodimer forming a stable octomeric structure. CD3D-CD3E and CD3G-CD3E heterodimers preferentially associate with TR alpha and TR beta chains, respectively. The association of the CD247 homodimer is the last step of TcR assembly in the endoplasmic reticulum and is required for transport to the cell surface.POLYMORPHISM There are several alleles. The sequence shown is that of IMGT allele TRAV29/DV5*01. UniProt P04437 28 EQUAL 139 EQUAL Reactome Database ID Release 78 198180 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198180 Reactome R-HSA-198180 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198180.1 TVA3_HUMAN T-cell receptor alpha chain V region PY14 precursor Reactome DB_ID: 198176 UniProt:P01737 TRAV8-4 TRAV8-4 FUNCTION V region of the variable domain of T cell receptor (TR) alpha chain that participates in the antigen recognition (PubMed:24600447). Alpha-beta T cell receptors are antigen specific receptors which are essential to the immune response and are present on the cell surface of T lymphocytes. Recognize peptide-major histocompatibility (MH) (pMH) complexes that are displayed by antigen presenting cells (APC), a prerequisite for efficient T cell adaptive immunity against pathogens (PubMed:25493333). Binding of alpha-beta TR to pMH complex initiates TR-CD3 clustering on the cell surface and intracellular activation of LCK that phosphorylates the ITAM motifs of CD3G, CD3D, CD3E and CD247 enabling the recruitment of ZAP70. In turn ZAP70 phosphorylates LAT, which recruits numerous signaling molecules to form the LAT signalosome. The LAT signalosome propagates signal branching to three major signaling pathways, the calcium, the mitogen-activated protein kinase (MAPK) kinase and the nuclear factor-kappa-B (NF-kB) pathways, leading to the mobilization of transcription factors that are critical for gene expression and essential for T cell growth and differentiation (PubMed:23524462). The T cell repertoire is generated in the thymus, by V-(D)-J rearrangement. This repertoire is then shaped by intrathymic selection events to generate a peripheral T cell pool of self-MH restricted, non-autoaggressive T cells. Post-thymic interaction of alpha-beta TR with the pMH complexes shapes TR structural and functional avidity (PubMed:15040585).SUBUNIT Alpha-beta TR is a heterodimer composed of an alpha and beta chain; disulfide-linked. The alpha-beta TR is associated with the transmembrane signaling CD3 coreceptor proteins to form the TR-CD3 (TcR or TCR). The assembly of alpha-beta TR heterodimers with CD3 occurs in the endoplasmic reticulum where a single alpha-beta TR heterodimer associates with one CD3D-CD3E heterodimer, one CD3G-CD3E heterodimer and one CD247 homodimer forming a stable octomeric structure. CD3D-CD3E and CD3G-CD3E heterodimers preferentially associate with TR alpha and TR beta chains, respectively. The association of the CD247 homodimer is the last step of TcR assembly in the endoplasmic reticulum and is required for transport to the cell surface.POLYMORPHISM There are several alleles. The sequence shown is that of IMGT allele TRAV8-4*01. UniProt P01737 21 EQUAL 135 EQUAL Reactome Database ID Release 78 198176 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198176 Reactome R-HSA-198176 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198176.2 TRAV19 fullName evidence="9"T cell receptor alpha variable 19 TVA19_HUMAN Reactome DB_ID: 9608264 UniProt:A0A0A6YYK7 TRAV19 TRAV19 FUNCTION V region of the variable domain of T cell receptor (TR) alpha chain that participates in the antigen recognition (PubMed:24600447). Alpha-beta T cell receptors are antigen specific receptors which are essential to the immune response and are present on the cell surface of T lymphocytes. Recognize peptide-major histocompatibility (MH) (pMH) complexes that are displayed by antigen presenting cells (APC), a prerequisite for efficient T cell adaptive immunity against pathogens (PubMed:25493333). Binding of alpha-beta TR to pMH complex initiates TR-CD3 clustering on the cell surface and intracellular activation of LCK that phosphorylates the ITAM motifs of CD3G, CD3D, CD3E and CD247 enabling the recruitment of ZAP70. In turn ZAP70 phosphorylates LAT, which recruits numerous signaling molecules to form the LAT signalosome. The LAT signalosome propagates signal branching to three major signaling pathways, the calcium, the mitogen-activated protein kinase (MAPK) kinase and the nuclear factor NF-kappa-B (NF-kB) pathways, leading to the mobilization of transcription factors that are critical for gene expression and essential for T cell growth and differentiation (PubMed:23524462). The T cell repertoire is generated in the thymus, by V-(D)-J rearrangement. This repertoire is then shaped by intrathymic selection events to generate a peripheral T cell pool of self-MH restricted, non-autoaggressive T cells. Post-thymic interaction of alpha-beta TR with the pMH complexes shapes TR structural and functional avidity (PubMed:15040585).SUBUNIT Alpha-beta TR is a heterodimer composed of an alpha and beta chain; disulfide-linked. The alpha-beta TR is associated with the transmembrane signaling CD3 coreceptor proteins to form the TR-CD3 (TcR or TCR). The assembly of alpha-beta TR heterodimers with CD3 occurs in the endoplasmic reticulum where a single alpha-beta TR heterodimer associates with one CD3D-CD3E heterodimer, one CD3G-CD3E heterodimer and one CD247 homodimer forming a stable octomeric structure. CD3D-CD3E and CD3G-CD3E heterodimers preferentially associate with TR alpha and TR beta chains, respectively. The association of the CD247 homodimer is the last step of TcR assembly in the endoplasmic reticulum and is required for transport to the cell surface.POLYMORPHISM There are several alleles. The sequence shown is that of IMGT allele TRAV19*01. UniProt A0A0A6YYK7 22 EQUAL 116 EQUAL Reactome Database ID Release 78 9608264 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9608264 Reactome R-HSA-9608264 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9608264.1 Reactome Database ID Release 78 198184 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198184 Reactome R-HSA-198184 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198184.2 1 Converted from EntitySet in Reactome TCR chain beta Reactome DB_ID: 198177 TRBC1 T-cell receptor beta chain C region TCB_HUMAN Reactome DB_ID: 198188 UniProt:P01850 TRBC1 TRBC1 FUNCTION Constant region of T cell receptor (TR) beta chain (PubMed:24600447). Alpha-beta T cell receptors are antigen specific receptors which are essential to the immune response and are present on the cell surface of T lymphocytes. Recognize peptide-major histocompatibility (MH) (pMH) complexes that are displayed by antigen presenting cells (APC), a prerequisite for efficient T cell adaptive immunity against pathogens (PubMed:25493333). Binding of alpha-beta TR to pMH complex initiates TR-CD3 clustering on the cell surface and intracellular activation of LCK that phosphorylates the ITAM motifs of CD3G, CD3D, CD3E and CD247 enabling the recruitment of ZAP70. In turn, ZAP70 phosphorylates LAT, which recruits numerous signaling molecules to form the LAT signalosome. The LAT signalosome propagates signal branching to three major signaling pathways, the calcium, the mitogen-activated protein kinase (MAPK) kinase and the nuclear factor NF-kappa-B (NF-kB) pathways, leading to the mobilization of transcription factors that are critical for gene expression and essential for T cell growth and differentiation (PubMed:9382891, PubMed:23524462). The T cell repertoire is generated in the thymus, by V-(D)-J rearrangement. This repertoire is then shaped by intrathymic selection events to generate a peripheral T cell pool of self-MH restricted, non-autoaggressive T cells. Post-thymic interaction of alpha-beta TR with the pMH complexes shapes TR structural and functional avidity (PubMed:15040585).SUBUNIT Alpha-beta TR is a heterodimer composed of an alpha and beta chain; disulfide-linked. The alpha-beta TR is associated with the transmembrane signaling CD3 coreceptor proteins to form the TR-CD3 (TcR or TCR). The assembly of alpha-beta TR heterodimers with CD3 occurs in the endoplasmic reticulum where a single alpha-beta TR heterodimer associates with one CD3D-CD3E heterodimer, one CD3G-CD3E heterodimer and one CD247 homodimer forming a stable octomeric structure. CD3D-CD3E and CD3G-CD3E heterodimers preferentially associate with TR alpha and TR beta chains, respectively. The association of the CD247 homodimer is the last step of TcR assembly in the endoplasmic reticulum and is required for transport to the cell surface.DOMAIN The connecting peptide (CP) domain is essential for signal transmission in response to antigenic stimulation, likely downstream from ZAP70 recruitment.DOMAIN The TM domain mediates the interaction with the CD3 subunits.POLYMORPHISM There are several alleles. The sequence shown is that of IMGT allele TRBC1*01. UniProt P01850 1 EQUAL 177 EQUAL Reactome Database ID Release 78 198188 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198188 Reactome R-HSA-198188 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198188.1 TCRB T-cell receptor beta chain V region CTL-L17 precursor TVB2_HUMAN Reactome DB_ID: 198187 UniProt:P04435 TRBV7-9 TRBV7-9 FUNCTION V region of the variable domain of T cell receptor (TR) beta chain that participates in the antigen recognition (PubMed:24600447). Alpha-beta T cell receptors are antigen specific receptors which are essential to the immune response and are present on the cell surface of T lymphocytes. Recognize peptide-major histocompatibility (MH) (pMH) complexes that are displayed by antigen presenting cells (APC), a prerequisite for efficient T cell adaptive immunity against pathogens (PubMed:25493333). Binding of alpha-beta TR to pMH complex initiates TR-CD3 clustering on the cell surface and intracellular activation of LCK that phosphorylates the ITAM motifs of CD3G, CD3D, CD3E and CD247 enabling the recruitment of ZAP70. In turn ZAP70 phosphorylates LAT, which recruits numerous signaling molecules to form the LAT signalosome. The LAT signalosome propagates signal branching to three major signaling pathways, the calcium, the mitogen-activated protein kinase (MAPK) kinase and the nuclear factor NF-kappa-B (NF-kB) pathways, leading to the mobilization of transcription factors that are critical for gene expression and essential for T cell growth and differentiation (PubMed:23524462). The T cell repertoire is generated in the thymus, by V-(D)-J rearrangement. This repertoire is then shaped by intrathymic selection events to generate a peripheral T cell pool of self-MH restricted, non-autoaggressive T cells. Post-thymic interaction of alpha-beta TR with the pMH complexes shapes TR structural and functional avidity (PubMed:15040585).SUBUNIT Alpha-beta TR is a heterodimer composed of an alpha and beta chain; disulfide-linked. The alpha-beta TR is associated with the transmembrane signaling CD3 coreceptor proteins to form the TR-CD3 (TcR or TCR). The assembly of alpha-beta TR heterodimers with CD3 occurs in the endoplasmic reticulum where a single alpha-beta TR heterodimer associates with one CD3D-CD3E heterodimer, one CD3G-CD3E heterodimer and one CD247 homodimer forming a stable octomeric structure. CD3D-CD3E and CD3G-CD3E heterodimers preferentially associate with TR alpha and TR beta chains, respectively. The association of the CD247 homodimer is the last step of TcR assembly in the endoplasmic reticulum and is required for transport to the cell surface.SUBUNIT (Microbial infection) Interacts with Staphylococcus aureus enterotoxins A/entA and H/entH.POLYMORPHISM There are several alleles. The sequence shown is that of IMGT allele TRBV7-9*01. UniProt P04435 22 EQUAL 133 EQUAL Reactome Database ID Release 78 198187 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198187 Reactome R-HSA-198187 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198187.1 TRBV12-3 T-cell receptor beta chain V region YT35 precursor TVB1_HUMAN Reactome DB_ID: 198181 UniProt:P01733 TRBV12-3 TRBV12-3 TCRBV12S3 TCRBV8S1 FUNCTION V region of the variable domain of T cell receptor (TR) beta chain that participates in the antigen recognition (PubMed:24600447). Alpha-beta T cell receptors are antigen specific receptors which are essential to the immune response and are present on the cell surface of T lymphocytes. Recognize peptide-major histocompatibility (MH) (pMH) complexes that are displayed by antigen presenting cells (APC), a prerequisite for efficient T cell adaptive immunity against pathogens (PubMed:25493333). Binding of alpha-beta TR to pMH complex initiates TR-CD3 clustering on the cell surface and intracellular activation of LCK that phosphorylates the ITAM motifs of CD3G, CD3D, CD3E and CD247 enabling the recruitment of ZAP70. In turn ZAP70 phosphorylates LAT, which recruits numerous signaling molecules to form the LAT signalosome. The LAT signalosome propagates signal branching to three major signaling pathways, the calcium, the mitogen-activated protein kinase (MAPK) kinase and the nuclear factor NF-kappa-B (NF-kB) pathways, leading to the mobilization of transcription factors that are critical for gene expression and essential for T cell growth and differentiation (PubMed:23524462). The T cell repertoire is generated in the thymus, by V-(D)-J rearrangement. This repertoire is then shaped by intrathymic selection events to generate a peripheral T cell pool of self-MH restricted, non-autoaggressive T cells. Post-thymic interaction of alpha-beta TR with the pMH complexes shapes TR structural and functional avidity (PubMed:15040585).SUBUNIT Alpha-beta TR is a heterodimer composed of an alpha and beta chain; disulfide-linked. The alpha-beta TR is associated with the transmembrane signaling CD3 coreceptor proteins to form the TR-CD3 (TcR or TCR). The assembly of alpha-beta TR heterodimers with CD3 occurs in the endoplasmic reticulum where a single alpha-beta TR heterodimer associates with one CD3D-CD3E heterodimer, one CD3G-CD3E heterodimer and one CD247 homodimer forming a stable octomeric structure. CD3D-CD3E and CD3G-CD3E heterodimers preferentially associate with TR alpha and TR beta chains, respectively. The association of the CD247 homodimer is the last step of TcR assembly in the endoplasmic reticulum and is required for transport to the cell surface.POLYMORPHISM There are several alleles. The sequence shown is that of IMGT allele TRBV12-3*01. UniProt P01733 22 EQUAL 135 EQUAL Reactome Database ID Release 78 198181 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198181 Reactome R-HSA-198181 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198181.1 Reactome Database ID Release 78 198177 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198177 Reactome R-HSA-198177 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198177.1 1 Reactome Database ID Release 78 198183 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198183 Reactome R-HSA-198183 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198183.1 1 CD3 epsilon gamma Reactome DB_ID: 198902 CD3G T-cell surface glycoprotein CD3 gamma chain precursor CD3G_HUMAN CD3 gamma Reactome DB_ID: 197917 UniProt:P09693 CD3G CD3G T3G FUNCTION Part of the TCR-CD3 complex present on T-lymphocyte cell surface that plays an essential role in adaptive immune response. When antigen presenting cells (APCs) activate T-cell receptor (TCR), TCR-mediated signals are transmitted across the cell membrane by the CD3 chains CD3D, CD3E, CD3G and CD3Z. All CD3 chains contain immunoreceptor tyrosine-based activation motifs (ITAMs) in their cytoplasmic domain. Upon TCR engagement, these motifs become phosphorylated by Src family protein tyrosine kinases LCK and FYN, resulting in the activation of downstream signaling pathways (PubMed:2470098). In addition to this role of signal transduction in T-cell activation, CD3G plays an essential role in the dynamic regulation of TCR expression at the cell surface (PubMed:8187769). Indeed, constitutive TCR cycling is dependent on the di-leucine-based (diL) receptor-sorting motif present in CD3G.SUBUNIT The TCR-CD3 complex is composed of a CD3D/CD3E and a CD3G/CD3E heterodimers that preferentially associate with TCRalpha and TCRbeta, respectively, to form TCRalpha/CD3E/CD3G and TCRbeta/CD3G/CD3E trimers. In turn, the hexamer interacts with CD3Z homodimer to form the TCR-CD3 complex. Alternatively, TCRalpha and TCRbeta can be replaced by TCRgamma and TCRdelta.DOMAIN A di-leucine motif and a tyrosine-based motif are individually sufficient to induce both endocytosis and delivery to lysosomes.PTM Phosphorylated on Tyr residues after T-cell receptor triggering by LCK in association with CD4/CD8 (PubMed:2470098). Phosphorylated also by PKC; leading to the TCR complex down-regulation (PubMed:8187769).PTM Phosphorylated on Tyr residues after T-cell receptor triggering by LCK in association with CD4/CD8. UniProt P09693 23 EQUAL 182 EQUAL Reactome Database ID Release 78 197917 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=197917 Reactome R-HSA-197917 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-197917.1 1 CD3E T-cell surface glycoprotein CD3 epsilon chain precursor CD3E_HUMAN Reactome DB_ID: 197906 UniProt:P07766 CD3E CD3E T3E FUNCTION Part of the TCR-CD3 complex present on T-lymphocyte cell surface that plays an essential role in adaptive immune response. When antigen presenting cells (APCs) activate T-cell receptor (TCR), TCR-mediated signals are transmitted across the cell membrane by the CD3 chains CD3D, CD3E, CD3G and CD3Z. All CD3 chains contain immunoreceptor tyrosine-based activation motifs (ITAMs) in their cytoplasmic domain. Upon TCR engagement, these motifs become phosphorylated by Src family protein tyrosine kinases LCK and FYN, resulting in the activation of downstream signaling pathways (PubMed:2470098). In addition of this role of signal transduction in T-cell activation, CD3E plays an essential role in correct T-cell development. Initiates the TCR-CD3 complex assembly by forming the two heterodimers CD3D/CD3E and CD3G/CD3E. Participates also in internalization and cell surface down-regulation of TCR-CD3 complexes via endocytosis sequences present in CD3E cytosolic region (PubMed:10384095, PubMed:26507128).SUBUNIT The TCR-CD3 complex is composed of a CD3D/CD3E and a CD3G/CD3E heterodimers that preferentially associate with TCRalpha and TCRbeta, respectively, to form TCRalpha/CD3E/CD3G and TCRbeta/CD3G/CD3E trimers. In turn, the hexamer interacts with CD3Z homodimer to form the TCR-CD3 complex. Alternatively, TCRalpha and TCRbeta can be replaced by TCRgamma and TCRdelta. Interacts with CD6 (PubMed:15294938). Interacts with NCK1 (PubMed:15972658). Interacts with NUMB; this interaction is important for TCR-CD3 internalization and subsequent degradation (PubMed:26507128).PTM Phosphorylated on Tyr residues after T-cell receptor triggering by LCK in association with CD4/CD8. UniProt P07766 23 EQUAL 207 EQUAL Reactome Database ID Release 78 197906 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=197906 Reactome R-HSA-197906 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-197906.1 1 Reactome Database ID Release 78 198902 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198902 Reactome R-HSA-198902 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198902.1 1 CD3 epsilon delta Reactome DB_ID: 198900 1 CD3D T-cell surface glycoprotein CD3 delta chain CD3D_HUMAN Reactome DB_ID: 198171 UniProt:P04234 CD3D CD3D T3D FUNCTION Part of the TCR-CD3 complex present on T-lymphocyte cell surface that plays an essential role in adaptive immune response. When antigen presenting cells (APCs) activate T-cell receptor (TCR), TCR-mediated signals are transmitted across the cell membrane by the CD3 chains CD3D, CD3E, CD3G and CD3Z. All CD3 chains contain immunoreceptor tyrosine-based activation motifs (ITAMs) in their cytoplasmic domain. Upon TCR engagement, these motifs become phosphorylated by Src family protein tyrosine kinases LCK and FYN, resulting in the activation of downstream signaling pathways (PubMed:2470098). In addition of this role of signal transduction in T-cell activation, CD3D plays an essential role in thymocyte differentiation. Indeed, participates in correct intracellular TCR-CD3 complex assembly and surface expression. In absence of a functional TCR-CD3 complex, thymocytes are unable to differentiate properly. Interacts with CD4 and CD8 and thus serves to establish a functional link between the TCR and coreceptors CD4 and CD8, which is needed for activation and positive selection of CD4 or CD8 T-cells(PubMed:12215456).SUBUNIT The TCR-CD3 complex is composed of a CD3D/CD3E and a CD3G/CD3E heterodimers that preferentially associate with TCRalpha and TCRbeta, respectively, to form TCRalpha/CD3E/CD3G and TCRbeta/CD3G/CD3E trimers. In turn, the hexamer interacts with CD3Z homodimer to form the TCR-CD3 complex. Alternatively, TCRalpha and TCRbeta can be replaced by TCRgamma and TCRdelta. Interacts with coreceptors CD4 and CD8 (PubMed:1396954, PubMed:12215456).TISSUE SPECIFICITY CD3D is mostly present on T-lymphocytes with its TCR-CD3 partners. Present also in fetal NK-cells.PTM Phosphorylated on Tyr residues after T-cell receptor triggering by LCK in association with CD4/CD8. UniProt P04234 22 EQUAL 171 EQUAL Reactome Database ID Release 78 198171 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198171 Reactome R-HSA-198171 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198171.1 1 Reactome Database ID Release 78 198900 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198900 Reactome R-HSA-198900 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198900.1 1 CD247-1 CD3 zeta (CD3 zeta isoform 1) T-cell surface glycoprotein CD3 zeta chain CD3Z_HUMAN T Cell Receptor zeta chain CD247 isoform 1 Reactome DB_ID: 198166 UniProt:P20963-1 CD247 CD247 CD3Z T3Z TCRZ FUNCTION Part of the TCR-CD3 complex present on T-lymphocyte cell surface that plays an essential role in adaptive immune response. When antigen presenting cells (APCs) activate T-cell receptor (TCR), TCR-mediated signals are transmitted across the cell membrane by the CD3 chains CD3D, CD3E, CD3G and CD3Z. All CD3 chains contain immunoreceptor tyrosine-based activation motifs (ITAMs) in their cytoplasmic domain. Upon TCR engagement, these motifs become phosphorylated by Src family protein tyrosine kinases LCK and FYN, resulting in the activation of downstream signaling pathways (PubMed:2470098, PubMed:7509083). CD3Z ITAMs phosphorylation creates multiple docking sites for the protein kinase ZAP70 leading to ZAP70 phosphorylation and its conversion into a catalytically active enzyme (PubMed:7509083). Plays an important role in intrathymic T-cell differentiation. Additionally, participates in the activity-dependent synapse formation of retinal ganglion cells (RGCs) in both the retina and dorsal lateral geniculate nucleus (dLGN) (By similarity).SUBUNIT The TCR-CD3 complex is composed of a CD3D/CD3E and a CD3G/CD3E heterodimers that preferentially associate with TCRalpha and TCRbeta, respectively, to form TCRalpha/CD3E/CD3G and TCRbeta/CD3G/CD3E trimers. In turn, the hexamer interacts with CD3Z homodimer to form the TCR-CD3 complex. Alternatively, TCRalpha and TCRbeta can be replaced by TCRgamma and TCRdelta (PubMed:17055436). Interacts with SLA (PubMed:10449770). Interacts with TRAT1 (PubMed:11390434). Interacts with DOCK2 (PubMed:12176041). Interacts with SLA2. Interacts with SHB (PubMed:9484780). Interacts with ZAP70 (PubMed:26783323, PubMed:7659156). Interacts (tyrosine phosphorylated) with SHC1 (via SH2 domain) (PubMed:7544002). Interacts with PTPRC (PubMed:15684325). Interacts with CRK; this interaction regulates CD3Z phosphorylation (PubMed:28465009). Interacts (on T cell side) with CD81, ICAM1 and CD9 at immunological synapses between antigen-presenting cells and T cells (PubMed:23858057). Interacts with CD160 (PubMed:11978774). Interacts with LY6E (By similarity).SUBUNIT (Microbial infection) Interacts with HIV-1 Nef; this interaction up-regulates the expression of the Fas ligand (FASLG) at the cell surface.SUBUNIT (Microbial infection) Interacts with HIV-2 Nef protein; this interaction induces down-regulation of cell surface TCR/CD3 complexes.TISSUE SPECIFICITY CD3Z is expressed in normal lymphoid tissue and in peripheral blood mononuclear cells (PBMCs) (PubMed:11722641).DOMAIN The ITAM domains mediate interaction with SHB.PTM Phosphorylated on Tyr residues after T-cell receptor triggering by LCK in association with CD4/CD8.SIMILARITY Belongs to the CD3Z/FCER1G family. UniProt Isoform P20963-1 22 EQUAL 164 EQUAL Reactome Database ID Release 78 198166 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198166 Reactome R-HSA-198166 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198166.1 2 Reactome Database ID Release 78 198901 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198901 Reactome R-HSA-198901 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198901.1 1 CD4 Reactome DB_ID: 167542 UniProt:P01730 CD4 CD4 FUNCTION Integral membrane glycoprotein that plays an essential role in the immune response and serves multiple functions in responses against both external and internal offenses. In T-cells, functions primarily as a coreceptor for MHC class II molecule:peptide complex. The antigens presented by class II peptides are derived from extracellular proteins while class I peptides are derived from cytosolic proteins. Interacts simultaneously with the T-cell receptor (TCR) and the MHC class II presented by antigen presenting cells (APCs). In turn, recruits the Src kinase LCK to the vicinity of the TCR-CD3 complex. LCK then initiates different intracellular signaling pathways by phosphorylating various substrates ultimately leading to lymphokine production, motility, adhesion and activation of T-helper cells. In other cells such as macrophages or NK cells, plays a role in differentiation/activation, cytokine expression and cell migration in a TCR/LCK-independent pathway. Participates in the development of T-helper cells in the thymus and triggers the differentiation of monocytes into functional mature macrophages.FUNCTION (Microbial infection) Primary receptor for human immunodeficiency virus-1 (HIV-1) (PubMed:2214026, PubMed:16331979, PubMed:9641677, PubMed:12089508). Down-regulated by HIV-1 Vpu (PubMed:17346169). Acts as a receptor for Human Herpes virus 7/HHV-7 (PubMed:7909607).SUBUNIT Forms disulfide-linked homodimers at the cell surface. Interacts with LCK (PubMed:16888650). Interacts with PTK2/FAK1 (PubMed:18078954). Binds to P4HB/PDI. Interacts with IL16; this interaction induces a CD4-dependent signaling in lymphocytes (PubMed:1673145). Interacts (via Ig-like V-type domain) with MHCII alpha chain (via alpha-2 domain) and beta chain (via beta-2 domain); this interaction increases the affinity of TCR for peptide-MHCII. CD4 oligomerization via Ig-like C2-type 2 and 3 domains appears to be required for stable binding to MHCII and adhesion between T cells and APCs (PubMed:27114505, PubMed:21900604, PubMed:7604010).SUBUNIT (Microbial infection) Interacts with HIV-1 Envelope polyprotein gp160 and protein Vpu (PubMed:2214026, PubMed:16331979, PubMed:9641677, PubMed:7604010).SUBUNIT (Microbial infection) Interacts with Human Herpes virus 7 surface proteins.TISSUE SPECIFICITY Highly expressed in T-helper cells. The presence of CD4 is a hallmark of T-helper cells which are specialized in the activation and growth of cytotoxic T-cells, regulation of B cells, or activation of phagocytes. CD4 is also present in other immune cells such as macrophages, dendritic cells or NK cells.DOMAIN The Ig-like V-type domain mediates the interaction with MHCII.PTM Palmitoylation and association with LCK contribute to the enrichment of CD4 in lipid rafts.PTM Phosphorylated by PKC; phosphorylation at Ser-433 plays an important role for CD4 internalization.POLYMORPHISM The OKT monoclonal antibodies are widely used for the analysis of human peripheral blood T-lymphocytes. OKT4 reacts with T-helper/inducer lymphocytes. The OKT4 epitope of the CD4 cell-surface protein is polymorphic in white, black, and Japanese populations. The variable phenotypic expression is due a CD4 polymorphism. OKT4 positive individuals carry Arg-265 and OKT4 negative individuals carry Trp-265 [MIM:613949]. UniProt P01730 26 EQUAL 458 EQUAL Reactome Database ID Release 78 167542 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=167542 Reactome R-HSA-167542 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-167542.1 1 MHC Class II bearing antigen peptide Reactome DB_ID: 203463 Antigen Reactome DB_ID: 173548 Reactome Database ID Release 78 173548 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=173548 Reactome R-ALL-173548 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-173548.2 ChEBI 36080 1 MHC class II alpha/beta dimer Reactome DB_ID: 2213189 Converted from EntitySet in Reactome HLA II beta chain Reactome DB_ID: 2130476 HLA-DPB1 HLA class II histocompatibility antigen, DP HB2P_HUMAN Reactome DB_ID: 197648 UniProt:P04440 HLA-DPB1 HLA-DPB1 HLA-DP1B FUNCTION Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route, where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules, and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments, exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides, autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs, other cells of the gastrointestinal tract, such as epithelial cells, express MHC class II molecules and CD74 and act as APCs, which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen, three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs, CD74 undergoes a sequential degradation by various proteases, including CTSS and CTSL, leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells, the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal microenvironment has been implicated in the regulation of antigen loading into MHC II molecules, increased acidification produces increased proteolysis and efficient peptide loading.SUBUNIT Heterodimer of an alpha and a beta subunit; also referred as MHC class II molecule. In the endoplasmic reticulum (ER) it forms a heterononamer; 3 MHC class II molecules bind to a CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system; CD74 undergoes sequential degradation by various proteases; leaving a small fragment termed CLIP on each MHC class II molecule. MHC class II molecule interacts with HLA_DM, and HLA_DO in B-cells, in order to release CLIP and facilitate the binding of antigenic peptides.POLYMORPHISM The following alleles of HLA-DPB1 are known: DPB1*01:01, DPB1*01:02, DPB1*02:01, DPB1*02:02, DPB1*02:03, DPB1*03:01, DPB1*03:02, DPB1*04:01, DPB1*04:02, DPB1*04:03, DPB1*05:01, DPB1*05:02, DPB1*06:01, DPB1*06:02, DPB1*08:01, DPB1*08:02, DPB1*09:01, DPB1*09:02, DPB1*10:01, DPB1*10:02, DPB1*11:01, DPB1*11:02, DPB1*13:01, DPB1*13:02, DPB1*14:01, DPB1*14:02, DPB1*15:01, DPB1*15:02, DPB1*16:01, DPB1*16:02, DPB1*17:01, DPB1*17:02, DPB1*18:01, DPB1*18:02, DPB1*19:01, DPB1*19:02, DPB1*20:01, DPB1*20:02, DPB1*21:01, DPB1*21:02, DPB1*22:01, DPB1*22:02, DPB1*23:01, DPB1*24:01, DPB1*24:02, DPB1*25:01, DPB1*25:02, DPB1*26:01, DPB1*26:02, DPB1*27:01, DPB1*28:01, DPB1*29:01, DPB1*30:01, DPB1*31:01, DPB1*32:01, DPB1*33:01, DPB1*34:01, DPB1*35:01, DPB1*36:01, DPB1*37:01, DPB1*38:01, DPB1*39:01, DPB1*40:01, DPB1*41:01, DPB1*44:01, DPB1*45:01, DPB1*46:01, DPB1*47:01, DPB1*48:01, DPB1*49:01, DPB1*50:01, DPB1*51:01, DPB1*52:01, DPB1*53:01, DPB1*54:01, DPB1*55:01, DPB1*56:01, DPB1*57:01, DPB1*58:01, DPB1*59:01, DPB1*60:01, DPB1*62:01, DPB1*63:01, DPB1*65:01, DPB1*66:01, DPB1*67:01, DPB1*68:01, DPB1*69:01, DPB1*70:01, DPB1*71:01, DPB1*72:01, DPB1*73:01, DPB1*74:01, DPB1*75:01, DPB1*76:01, DPB1*77:01, DPB1*78:01, DPB1*79:01, DPB1*80:01, DPB1*81:01, DPB1*82:01, DPB1*83:01, DPB1*84:01, DPB1*85:01, DPB1*86:01, DPB1*87:01, DPB1*88:01, DPB1*89:01, DPB1*90:01, DPB1*91:01, DPB1*92:01, DPB1*93:01, DPB1*94:01, DPB1*95:01, DPB1*96:01, DPB1*97:01, DPB1*98:01 and DPB1*99:01. The sequence shown is that of DPB1*04:01.SIMILARITY Belongs to the MHC class II family. UniProt P04440 30 EQUAL 258 EQUAL Reactome Database ID Release 78 197648 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=197648 Reactome R-HSA-197648 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-197648.1 HLA-DQB HLA class II histocompatibility antigen, DQ HB21_HUMAN Reactome DB_ID: 197578 UniProt:P01920 HLA-DQB1 HLA-DQB1 HLA-DQB FUNCTION Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route, where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules, and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments, exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides, autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs, other cells of the gastrointestinal tract, such as epithelial cells, express MHC class II molecules and CD74 and act as APCs, which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen, three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs, CD74 undergoes a sequential degradation by various proteases, including CTSS and CTSL, leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells, the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal microenvironment has been implicated in the regulation of antigen loading into MHC II molecules, increased acidification produces increased proteolysis and efficient peptide loading.SUBUNIT Heterodimer of an alpha and a beta subunit; also referred as MHC class II molecule. In the endoplasmic reticulum (ER) it forms a heterononamer; 3 MHC class II molecules bind to a CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system; CD74 undergoes sequential degradation by various proteases; leaving a small fragment termed CLIP on each MHC class II molecule. MHC class II molecule interacts with HLA_DM, and HLA_DO in B-cells, in order to release CLIP and facilitate the binding of antigenic peptides.POLYMORPHISM The following alleles of HLA-DQB1 are known: DQB1*02:01, DQB1*02:02, DQB1*02:03, DQB1*02:04, DQB1*02:05, DQB1*03:01, DQB1*03:02, DQB1*03:03, DQB1*03:04, DQB1*03:05, DQB1*03:06, DQB1*03:07, DQB1*03:08, DQB1*03:09, DQB1*03:10, DQB1*03:11, DQB1*03:12, DQB1*03:13, DQB1*03:14, DQB1*03:15, DQB1*03:16, DQB1*03:17, DQB1*03:18, DQB1*03:19, DQB1*03:20, DQB1*03:21, DQB1*03:22, DQB1*03:23, DQB1*03:24, DQB1*03:25, DQB1*03:26, DQB1*04:01, DQB1*04:02, DQB1*04:03, DQB1*05:01, DQB1*05:02, DQB1*05:03, DQB1*05:04, DQB1*05:05, DQB1*06:01, DQB1*06:02, DQB1*06:03, DQB1*06:04, DQB1*06:05, DQB1*06:06, DQB1*06:07, DQB1*06:08, DQB1*06:09, DQB1*06:10, DQB1*06:11, DQB1*06:12, DQB1*06:13, DQB1*06:14, DQB1*06:15, DQB1*06:16, DQB1*06:17, DQB1*06:18, DQB1*06:19, DQB1*06:20, DQB1*06:21, DQB1*06:22, DQB1*06:23, DQB1*06:24, DQB1*06:25, DQB1*06:27, DQB1*06:28, DQB1*06:29, DQB1*06:30, DQB1*06:31, DQB1*06:32, DQB1*06:33, DQB1*06:34, DQB1*06:35, DQB1*06:36, DQB1*06:37, DQB1*06:38, and DQB1*06:39. The sequence shown is that of DQB1*03:01.POLYMORPHISM DQ2 (heterodimer of DQA1*05:01/DQB1*02:01) is associated with more than 90% of celiac disease patients. A minority displays DQ8 (heterodimer of DQA1*03/DQB1*03:02).POLYMORPHISM DQ0602 (heterodimer of DQA1*01:02/DQB1*06:02) confers dominant protection against type 1 diabetes (T1D) and strong susceptibility to narcolepsy. DQB1*06:02 has been found to be present in most of the narcolepsy patients. As well 98% of the patients with an HCRT deficiency are positive for DQB1*06:02.SIMILARITY Belongs to the MHC class II family. UniProt P01920 33 EQUAL 261 EQUAL Reactome Database ID Release 78 197578 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=197578 Reactome R-HSA-197578 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-197578.1 HLA-DQB2 HLA class II histocompatibility antigen, DQ beta 2 chain HLA class II histocompatibility antigen, DX beta chain precursor HB2X_HUMAN Reactome DB_ID: 197649 UniProt:P05538 HLA-DQB2 HLA-DQB2 HLA-DXB FUNCTION Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route, where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules, and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments, exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides, autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs, other cells of the gastrointestinal tract, such as epithelial cells, express MHC class II molecules and CD74 and act as APCs, which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen, three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs, CD74 undergoes a sequential degradation by various proteases, including CTSS and CTSL, leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells, the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal microenvironment has been implicated in the regulation of antigen loading into MHC II molecules, increased acidification produces increased proteolysis and efficient peptide loading.SUBUNIT Heterodimer of an alpha and a beta subunit; also referred as MHC class II molecule. Dimer formation with HLA-DQA2, but not with HLA-DQA1, is required for efficient exit from the endoplasmic reticulum (ER). In the ER, forms a heterononamer; 3 MHC class II molecules bind to a CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system; CD74 undergoes sequential degradation by various proteases; leaving a small fragment termed CLIP on each MHC class II molecule. MHC class II molecule interacts with HLA_DM, and HLA_DO in B-cells, in order to release CLIP and facilitate the binding of antigenic peptides. Association with HLA-DMA also occurs in skin Langerhans cells, in post-Golgi compartments.TISSUE SPECIFICITY Restricted to skin Langerhans cells (at protein level).SIMILARITY Belongs to the MHC class II family. UniProt P05538 33 EQUAL 268 EQUAL Reactome Database ID Release 78 197649 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=197649 Reactome R-HSA-197649 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-197649.1 HLA-DQB1 HLA class II histocompatibility antigen, DQB1*0602 beta chain precursor HB25_HUMAN Reactome DB_ID: 197647 33 EQUAL 261 EQUAL Reactome Database ID Release 78 197647 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=197647 Reactome R-HSA-197647 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-197647.1 HLA-DRB4 HLA class II histocompatibility antigen, DR beta 4 chain DRB4_HUMAN Reactome DB_ID: 882032 UniProt:P13762 HLA-DRB4 HLA-DRB4 FUNCTION Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route, where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules, and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments, exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides, autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs, other cells of the gastrointestinal tract, such as epithelial cells, express MHC class II molecules and CD74 and act as APCs, which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen, three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs, CD74 undergoes a sequential degradation by various proteases, including CTSS and CTSL, leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells, the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal microenvironment has been implicated in the regulation of antigen loading into MHC II molecules, increased acidification produces increased proteolysis and efficient peptide loading.SUBUNIT Heterodimer of an alpha and a beta subunit; also referred as MHC class II molecule. In the endoplasmic reticulum (ER) it forms a heterononamer; 3 MHC class II molecules bind to a CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system; CD74 undergoes sequential degradation by various proteases; leaving a small fragment termed CLIP on each MHC class II molecule. MHC class II molecule interacts with HLA_DM, and HLA_DO in B-cells, in order to release CLIP and facilitate the binding of antigenic peptides.PTM Ubiquitinated by MARCH1 and MARCH8 at Lys-254 leading to sorting into the endosome system and down-regulation of MHC class II. When associated with ubiquitination of the alpha subunit of HLA-DR: HLA-DRA 'Lys-244', the down-regulation of MHC class II may be highly effective.POLYMORPHISM The following alleles of DRB4 are known: DRB4*01:01, DRB4*01:02, DRB4*01:03, DRB4*01:04, DRB4*01:05, DRB4*01:06 and DRB4*01:07. The sequence shown is that of DRB4*01:03.SIMILARITY Belongs to the MHC class II family.CAUTION HLA-DRB3, HLA-DRB4 and HLA-DRB5 may represent a unique gene. UniProt P13762 30 EQUAL 266 EQUAL Reactome Database ID Release 78 882032 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=882032 Reactome R-HSA-882032 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-882032.1 HLA-DRB5 HLA class II histocompatibility antigen, DR beta 5 chain DRB5_HUMAN Reactome DB_ID: 1235083 UniProt:Q30154 HLA-DRB5 HLA-DRB5 FUNCTION Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route, where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules, and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments, exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides, autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs, other cells of the gastrointestinal tract, such as epithelial cells, express MHC class II molecules and CD74 and act as APCs, which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen, three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs, CD74 undergoes a sequential degradation by various proteases, including CTSS and CTSL, leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells, the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal microenvironment has been implicated in the regulation of antigen loading into MHC II molecules, increased acidification produces increased proteolysis and efficient peptide loading.SUBUNIT Heterodimer of an alpha and a beta subunit; also referred as MHC class II molecule. In the endoplasmic reticulum (ER) it forms a heterononamer; 3 MHC class II molecules bind to a CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system; CD74 undergoes sequential degradation by various proteases; leaving a small fragment termed CLIP on each MHC class II molecule. MHC class II molecule interacts with HLA_DM, and HLA_DO in B-cells, in order to release CLIP and facilitate the binding of antigenic peptides.PTM Ubiquitinated by MARCH1 and MARCH8 at Lys-254 leading to down-regulation of MHC class II.POLYMORPHISM The following alleles of DRB5 are known: DRB5*01:01, DRB5*01:02, DRB5*01:03, DRB5*01:04, DRB5*01:05, DRB5*01:06, DRB5*01:07, DRB5*01:09, DRB5*01:11, DRB5*01:12 DRB5*01:13, DRB5*01:14, DRB5*02:02, DRB5*02:03, DRB5*02:04, DRB5*02:05. The sequence shown is that of DRB5*01:01.SIMILARITY Belongs to the MHC class II family.CAUTION HLA-DRB3, HLA-DRB4 and HLA-DRB5 may represent a unique gene. UniProt Q30154 30 EQUAL 266 EQUAL Reactome Database ID Release 78 1235083 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1235083 Reactome R-HSA-1235083 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1235083.1 HB2B_HUMAN HLA class II histocompatibility antigen, DR-1 beta chain precursor Reactome DB_ID: 197573 UniProt:P01912 HLA-DRB1 HLA-DRB1 FUNCTION Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route; where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules; and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments; exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides; autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs; other cells of the gastrointestinal tract; such as epithelial cells; express MHC class II molecules and CD74 and act as APCs; which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen; three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs; CD74 undergoes a sequential degradation by various proteases; including CTSS and CTSL; leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells; the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal microenvironment has been implicated in the regulation of antigen loading into MHC II molecules; increased acidification produces increased proteolysis and efficient peptide loading.SUBUNIT Heterodimer of an alpha and a beta subunit; also referred as MHC class II molecule. In the endoplasmic reticulum (ER) it forms a heterononamer; 3 MHC class II molecules bind to a CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system; CD74 undergoes sequential degradation by various proteases; leaving a small fragment termed CLIP on each MHC class II molecule. MHC class II molecule interacts with HLA_DM, and HLA_DO in B-cells, in order to release CLIP and facilitate the binding of antigenic peptides.PTM Ubiquitinated by MARCH1 and MARCH8 at Lys-254 leading to sorting into the endosome system and down-regulation of MHC class II.POLYMORPHISM The following alleles of DRB1-3 are known: DRB1*03:01; DRB1*03:02; DRB1*03:03; DRB1*03:04; DRB1*03:05; DRB1*03:06; DRB1*03:07; DRB1*03:08; DRB1*03:09; DRB1*03:10; DRB1*03:11; DRB1*03:12; DRB1*03:13; DRB1*03:14; DRB1*03:15; DRB1*03:16; DRB1*03:17; DRB1*03:18; DRB1*03:19; DRB1*03:20; DRB1*03:21; DRB1*03:22; DRB1*03:23; DRB1*03:24; DRB1*03:25; DRB1*03:26; DRB1*03:27; DRB1*03:28; DRB1*03:29; DRB1*03:30; DRB1*03:31; DRB1*03:32; DRB1*03:33; DRB1*03:34; DRB1*03:35; DRB1*03:36; DRB1*03:37; DRB1*03:38; DRB1*03:39; DRB1*03:40 and DRB1*03:41. The sequence shown is that of DRB1*03:01.SIMILARITY Belongs to the MHC class II family. UniProt P01912 30 EQUAL 266 EQUAL Reactome Database ID Release 78 197573 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=197573 Reactome R-HSA-197573 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-197573.1 HLA-DRB1 HLA class II histocompatibility antigen, DRB1-1 beta chain 2B11_HUMAN Reactome DB_ID: 882034 UniProt:P04229 HLA-DRB1 HLA-DRB1 FUNCTION Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route; where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules; and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments; exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides; autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs; other cells of the gastrointestinal tract; such as epithelial cells; express MHC class II molecules and CD74 and act as APCs; which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen; three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs; CD74 undergoes a sequential degradation by various proteases; including CTSS and CTSL; leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells; the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal microenvironment has been implicated in the regulation of antigen loading into MHC II molecules; increased acidification produces increased proteolysis and efficient peptide loading.FUNCTION (Microbial infection) Acts as a receptor for Epstein-Barr virus on lymphocytes.SUBUNIT Heterodimer of an alpha and a beta subunit; also referred as MHC class II molecule. In the endoplasmic reticulum (ER) it forms a heterononamer; 3 MHC class II molecules bind to a CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system; CD74 undergoes sequential degradation by various proteases; leaving a small fragment termed CLIP on each MHC class II molecule. MHC class II molecule interacts with HLA_DM, and HLA_DO in B-cells, in order to release CLIP and facilitate the binding of antigenic peptides.SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus gp42 protein (PubMed:11864610, PubMed:9151859).SUBUNIT (Microbial infection) Interacts with Staphylococcus aureus enterotoxin A/entA, enterotoxin B/entB, enterotoxin C1/entC1, entertoxin D/entD and enterotoxin H/entH.PTM Ubiquitinated by MARCH1 and MARCH8 at Lys-254 leading to sorting into the endosome system and down-regulation of MHC class II.POLYMORPHISM The following alleles of DRB1-1 are known: DRB1*01:01; DRB1*01:02; DRB1*01:03; DRB1*01:04; DRB1*01:05; DRB1*01:06; DRB1*01:07; DRB1*01:08; DRB1*01:09; DRB1*01:10; DRB1*01:11; DRB1*01:12; DRB1*01:13; DRB1*01:14; DRB1*01:15; DRB1*01:16; DRB1*01:17; DRB1*01:18; DRB1*01:19; DRB1*01:20 and DRB1*01:21. The sequence shown is that of DRB1*01:01.SIMILARITY Belongs to the MHC class II family. UniProt P04229 30 EQUAL 266 EQUAL Reactome Database ID Release 78 882034 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=882034 Reactome R-HSA-882034 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-882034.1 HLA-DRB1 HLA class II histocompatibility antigen, DRB1-10 beta chain 2B1A_HUMAN Reactome DB_ID: 1235082 UniProt:Q30167 HLA-DRB1 HLA-DRB1 FUNCTION Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route; where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules; and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments; exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides; autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs; other cells of the gastrointestinal tract; such as epithelial cells; express MHC class II molecules and CD74 and act as APCs; which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen; three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs; CD74 undergoes a sequential degradation by various proteases; including CTSS and CTSL; leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells; the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal microenvironment has been implicated in the regulation of antigen loading into MHC II molecules; increased acidification produces increased proteolysis and efficient peptide loading.SUBUNIT Heterodimer of an alpha and a beta subunit; also referred as MHC class II molecule. In the endoplasmic reticulum (ER) it forms a heterononamer; 3 MHC class II molecules bind to a CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system; CD74 undergoes sequential degradation by various proteases; leaving a small fragment termed CLIP on each MHC class II molecule. MHC class II molecule interacts with HLA_DM, and HLA_DO in B-cells, in order to release CLIP and facilitate the binding of antigenic peptides.PTM Ubiquitinated by MARCH1 and MARCH8 at Lys-254 leading to sorting into the endosome system and down-regulation of MHC class II.POLYMORPHISM The following alleles of DRB1-10 are known: DRB1*10:01; DRB1*10:02 and DRB1*10:03. The sequence shown is that of DRB1*10:01.SIMILARITY Belongs to the MHC class II family. UniProt Q30167 30 EQUAL 266 EQUAL Reactome Database ID Release 78 1235082 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1235082 Reactome R-HSA-1235082 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1235082.1 HLA-DRB1 HLA class II histocompatibility antigen, DRB1-11 beta chain 2B1B_HUMAN Reactome DB_ID: 1235089 UniProt:P20039 HLA-DRB1 HLA-DRB1 FUNCTION Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route, where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules, and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments, exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides, autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs, other cells of the gastrointestinal tract, such as epithelial cells, express MHC class II molecules and CD74 and act as APCs, which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen, three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs, CD74 undergoes a sequential degradation by various proteases, including CTSS and CTSL, leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells, the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal microenvironment has been implicated in the regulation of antigen loading into MHC II molecules, increased acidification produces increased proteolysis and efficient peptide loading.SUBUNIT Heterodimer of an alpha and a beta subunit; also referred as MHC class II molecule. In the endoplasmic reticulum (ER) it forms a heterononamer; 3 MHC class II molecules bind to a CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system; CD74 undergoes sequential degradation by various proteases; leaving a small fragment termed CLIP on each MHC class II molecule. MHC class II molecule interacts with HLA_DM, and HLA_DO in B-cells, in order to release CLIP and facilitate the binding of antigenic peptides.PTM Ubiquitinated by MARCH1 and MARCH8 at Lys-254 leading to sorting into the endosome system and down-regulation of MHC class II.POLYMORPHISM The following alleles of DRB1-11 are known: DRB1*11:01, DRB1*11:03, DRB1*11:04, DRB1*11:05, DRB1*11:06, DRB1*11:07, DRB1*11:08, DRB1*11:09, DRB1*11:10, DRB1*11:11, DRB1*11:12, DRB1*11:13, DRB1*11:14, DRB1*11:15, DRB1*11:16, DRB1*11:17, DRB1*11:18, DRB1*11:19, DRB1*11:20, DRB1*11:21, DRB1*11:22, DRB1*11:23, DRB1*11:24, DRB1*11:25, DRB1*11:26, DRB1*11:27, DRB1*11:28, DRB1*11:29, DRB1*11:30, DRB1*11:31, DRB1*11:32, DRB1*11:33, DRB1*11:34, DRB1*11:35, DRB1*11:36, DRB1*11:37, DRB1*11:38, DRB1*11:39, DRB1*11:40, DRB1*11:41, DRB1*11:42, DRB1*11:43, DRB1*11:44, DRB1*11:45, DRB1*11:46, DRB1*11:47, DRB1*11:48, DRB1*11:49, DRB1*11:50, DRB1*11:51, DRB1*11:52, DRB1*11:53, DRB1*11:54, DRB1*11:55, DRB1*11:56, DRB1*11:57, DRB1*11:58, DRB1*11:59, DRB1*11:60, DRB1*11:61, DRB1*11:62, DRB1*11:63, DRB1*11:64, DRB1*11:65, DRB1*11:66, DRB1*11:67, DRB1*11:68, DRB1*11:69, DRB1*11:70 and DRB1*11:72. The sequence shown is that of DRB1*11:01.POLYMORPHISM Allele DRB1*11:01 is associated with self-limiting hepatitis C virus (HCV) infections [MIM:609532].SIMILARITY Belongs to the MHC class II family. UniProt P20039 30 EQUAL 266 EQUAL Reactome Database ID Release 78 1235089 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1235089 Reactome R-HSA-1235089 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1235089.1 HLA-DRB1 HLA class II histocompatibility antigen, DRB1-12 beta chain 2B1C_HUMAN Reactome DB_ID: 1235084 UniProt:Q95IE3 HLA-DRB1 HLA-DRB1 FUNCTION Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route, where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules, and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments, exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides, autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs, other cells of the gastrointestinal tract, such as epithelial cells, express MHC class II molecules and CD74 and act as APCs, which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen, three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs, CD74 undergoes a sequential degradation by various proteases, including CTSS and CTSL, leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells, the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal microenvironment has been implicated in the regulation of antigen loading into MHC II molecules, increased acidification produces increased proteolysis and efficient peptide loading.SUBUNIT Heterodimer of an alpha and a beta subunit; also referred as MHC class II molecule. In the endoplasmic reticulum (ER) it forms a heterononamer; 3 MHC class II molecules bind to a CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system; CD74 undergoes sequential degradation by various proteases; leaving a small fragment termed CLIP on each MHC class II molecule. MHC class II molecule interacts with HLA_DM, and HLA_DO in B-cells, in order to release CLIP and facilitate the binding of antigenic peptides.PTM Ubiquitinated by MARCH1 and MARCH8 at Lys-254 leading to sorting into the endosome system and down-regulation of MHC class II.POLYMORPHISM The following alleles of DRB1-12 are known: DRB1*12:01, DRB1*12:02, DRB1*12:03, DRB1*12:04, DRB1*12:05, DRB1*12:06, DRB1*12:07, DRB1*12:08, DRB1*12:09, DRB1*12:10, DRB1*12:11, DRB1*12:12, DRB1*12:13, DRB1*12:14, DRB1*12:15, DRB1*12:16, DRB1*12:17, DRB1*12:18 and DRB1*12:19. The sequence shown is that of DRB1*12:01.SIMILARITY Belongs to the MHC class II family. UniProt Q95IE3 30 EQUAL 266 EQUAL Reactome Database ID Release 78 1235084 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1235084 Reactome R-HSA-1235084 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1235084.1 HLA-DRB1 HLA class II histocompatibility antigen, DRB1-13 beta chain 2B1D_HUMAN Reactome DB_ID: 1235086 UniProt:Q5Y7A7 HLA-DRB1 HLA-DRB1 FUNCTION Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route, where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules, and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments, exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides, autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs, other cells of the gastrointestinal tract, such as epithelial cells, express MHC class II molecules and CD74 and act as APCs, which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen, three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs, CD74 undergoes a sequential degradation by various proteases, including CTSS and CTSL, leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells, the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal microenvironment has been implicated in the regulation of antigen loading into MHC II molecules, increased acidification produces increased proteolysis and efficient peptide loading.SUBUNIT Heterodimer of an alpha and a beta subunit; also referred as MHC class II molecule. In the endoplasmic reticulum (ER) it forms a heterononamer; 3 MHC class II molecules bind to a CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system; CD74 undergoes sequential degradation by various proteases; leaving a small fragment termed CLIP on each MHC class II molecule. MHC class II molecule interacts with HLA_DM, and HLA_DO in B-cells, in order to release CLIP and facilitate the binding of antigenic peptides.PTM Ubiquitinated by MARCH1 and MARCH8 at Lys-254 leading to sorting into the endosome system and down-regulation of MHC class II.POLYMORPHISM The following alleles of DRB1-13 are known: DRB1*13:01, DRB1*13:02, DRB1*13:03, DRB1*13:04, DRB1*13:05, DRB1*13:06, DRB1*13:07, DRB1*13:08, DRB1*13:09, DRB1*13:10, DRB1*13:11, DRB1*13:12, DRB1*13:13, DRB1*13:14, DRB1*13:15, DRB1*13:16, DRB1*13:17, DRB1*13:18, DRB1*13:19, DRB1*13:20, DRB1*13:21, DRB1*13:22, DRB1*13:23, DRB1*13:24, DRB1*13:25, DRB1*13:26, DRB1*13:27, DRB1*13:28, DRB1*13:29, DRB1*13:30, DRB1*13:31, DRB1*13:32, DRB1*13:33, DRB1*13:34, DRB1*13:35, DRB1*13:36, DRB1*13:37, DRB1*13:38, DRB1*13:39, DRB1*13:40, DRB1*13:41, DRB1*13:42, DRB1*13:43, DRB1*13:44, DRB1*13:45, DRB1*13:46, DRB1*13:47, DRB1*13:48, DRB1*13:49, DRB1*13:50, DRB1*13:51, DRB1*13:52, DRB1*13:53, DRB1*13:54, DRB1*13:55, DRB1*13:56, DRB1*13:57, DRB1*13:58, DRB1*13:59, DRB1*13:60, DRB1*13:61, DRB1*13:62, DRB1*13:63, DRB1*13:64, DRB1*13:65, DRB1*13:66, DRB1*13:67, DRB1*13:68, DRB1*13:69, DRB1*13:70, DRB1*13:71, DRB1*13:72, DRB1*13:73, DRB1*13:74, DRB1*13:75, DRB1*13:76, DRB1*13:77, DRB1*13:78, DRB1*13:79, DRB1*13:80, DRB1*13:81, DRB1*13:82, DRB1*13:83, DRB1*13:84, DRB1*13:85, DRB1*13:86, DRB1*13:87 and DRB1*13:88. The sequence shown is that of DRB1*13:01.SIMILARITY Belongs to the MHC class II family. UniProt Q5Y7A7 30 EQUAL 266 EQUAL Reactome Database ID Release 78 1235086 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1235086 Reactome R-HSA-1235086 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1235086.1 HLA-DRB1 HLA class II histocompatibility antigen, DRB1-14 beta chain 2B1E_HUMAN Reactome DB_ID: 1235087 UniProt:Q9GIY3 HLA-DRB1 HLA-DRB1 FUNCTION Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route, where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules, and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments, exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides, autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs, other cells of the gastrointestinal tract, such as epithelial cells, express MHC class II molecules and CD74 and act as APCs, which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen, three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs, CD74 undergoes a sequential degradation by various proteases, including CTSS and CTSL, leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells, the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal microenvironment has been implicated in the regulation of antigen loading into MHC II molecules, increased acidification produces increased proteolysis and efficient peptide loading.SUBUNIT Heterodimer of an alpha and a beta subunit; also referred as MHC class II molecule. In the endoplasmic reticulum (ER) it forms a heterononamer; 3 MHC class II molecules bind to a CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system; CD74 undergoes sequential degradation by various proteases; leaving a small fragment termed CLIP on each MHC class II molecule. MHC class II molecule interacts with HLA_DM, and HLA_DO in B-cells, in order to release CLIP and facilitate the binding of antigenic peptides.PTM Ubiquitinated by MARCH1 and MARCH8 at Lys-254 leading to sorting into the endosome system and down-regulation of MHC class II.POLYMORPHISM The following alleles of DRB1-14 are known: DRB1*14:01, DRB1*14:02, DRB1*14:03, DRB1*14:04, DRB1*14:05, DRB1*14:06, DRB1*14:07, DRB1*14:08, DRB1*14:09, DRB1*14:10, DRB1*14:11, DRB1*14:12, DRB1*14:13, DRB1*14:14, DRB1*14:15, DRB1*14:16, DRB1*14:17, DRB1*14:18, DRB1*14:19, DRB1*14:20, DRB1*14:21, DRB1*14:22, DRB1*14:23, DRB1*14:24, DRB1*14:25, DRB1*14:26, DRB1*14:27, DRB1*14:28, DRB1*14:29, DRB1*14:30, DRB1*14:31, DRB1*14:32, DRB1*14:33, DRB1*14:34, DRB1*14:35, DRB1*14:36, DRB1*14:37, DRB1*14:38, DRB1*14:39, DRB1*14:40, DRB1*14:41, DRB1*14:42, DRB1*14:43, DRB1*14:44, DRB1*14:45, DRB1*14:46, DRB1*14:47, DRB1*14:48, DRB1*14:49, DRB1*14:50, DRB1*14:51, DRB1*14:52, DRB1*14:53, DRB1*14:54, DRB1*14:55, DRB1*14:56, DRB1*14:57, DRB1*14:58, DRB1*14:59, DRB1*14:60, DRB1*14:61, DRB1*14:62, DRB1*14:63, DRB1*14:64, DRB1*14:65, DRB1*14:67, DRB1*14:68, DRB1*14:69, DRB1*14:70, DRB1*14:71, DRB1*14:72, DRB1*14:73, DRB1*14:74, DRB1*14:75, DRB1*14:76, DRB1*14:77, DRB1*14:78, DRB1*14:79, DRB1*14:80, DRB1*14:81, DRB1*14:82, DRB1*14:83, DRB1*14:84 and DRB1*14:85. The sequence shown is that of DRB1*14:01.SIMILARITY Belongs to the MHC class II family. UniProt Q9GIY3 30 EQUAL 266 EQUAL Reactome Database ID Release 78 1235087 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1235087 Reactome R-HSA-1235087 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1235087.1 HB2G_HUMAN HLA class II histocompatibility antigen, DRB1-15 beta chain HLA class II histocompatibility antigen, DW2.2/DR2.2 beta chain Reactome DB_ID: 197644 UniProt:P01911 HLA-DRB1 HLA-DRB1 FUNCTION A beta chain of antigen-presenting major histocompatibility complex class II (MHCII) molecule. In complex with the alpha chain HLA-DRA, displays antigenic peptides on professional antigen presenting cells (APCs) for recognition by alpha-beta T cell receptor (TCR) on HLA-DRB1-restricted CD4-positive T cells. This guides antigen-specific T-helper effector functions, both antibody-mediated immune response and macrophage activation, to ultimately eliminate the infectious agents and transformed cells (PubMed:29884618, PubMed:22327072, PubMed:27591323, PubMed:8642306, PubMed:15265931, PubMed:31495665, PubMed:16148104). Typically presents extracellular peptide antigens of 10 to 30 amino acids that arise from proteolysis of endocytosed antigens in lysosomes (PubMed:8145819). In the tumor microenvironment, presents antigenic peptides that are primarily generated in tumor-resident APCs likely via phagocytosis of apoptotic tumor cells or macropinocytosis of secreted tumor proteins (PubMed:31495665). Presents peptides derived from intracellular proteins that are trapped in autolysosomes after macroautophagy, a mechanism especially relevant for T cell selection in the thymus and central immune tolerance (PubMed:17182262, PubMed:23783831). The selection of the immunodominant epitopes follows two processing modes: 'bind first, cut/trim later' for pathogen-derived antigenic peptides and 'cut first, bind later' for autoantigens/self-peptides (PubMed:25413013). The anchor residue at position 1 of the peptide N-terminus, usually a large hydrophobic residue, is essential for high affinity interaction with MHCII molecules (PubMed:8145819).FUNCTION Allele DRB1*01:01: Displays an immunodominant epitope derived from Bacillus anthracis pagA/protective antigen, PA (KLPLYISNPNYKVNVYAVT), to both naive and PA-specific memory CD4-positive T cells (PubMed:22327072). Presents immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load (PubMed:29884618). May present to T-helper 1 cells several HRV-16 epitopes derived from capsid proteins VP1 (PRFSLPFLSIASAYYMFYDG) and VP2 (PHQFINLRSNNSATLIVPYV), contributing to viral clearance (PubMed:27591323). Displays commonly recognized peptides derived from IAV external protein HA (PKYVKQNTLKLAT and SNGNFIAPEYAYKIVK) and from internal proteins M, NP and PB1, with M-derived epitope (GLIYNRMGAVTTEV) being the most immunogenic (PubMed:8145819, PubMed:9075930, PubMed:25413013, PubMed:32668259). Presents a self-peptide derived from COL4A3 (GWISLWKGFSF) to TCR (TRAV14 biased) on CD4-positive, FOXP3-positive regulatory T cells and mediates immune tolerance to self (PubMed:28467828). May present peptides derived from oncofetal trophoblast glycoprotein TPBG 5T4, known to be recognized by both T-helper 1 and regulatory T cells (PubMed:31619516). Displays with low affinity a self-peptide derived from MBP (VHFFKNIVTPRTP) (PubMed:9075930).FUNCTION Allele DRB1*03:01: May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (NEKQPSDDNWLNFDGTLLGN), contributing to viral clearance (PubMed:27591323). Displays self-peptides derived from retinal SAG (NRERRGIALDGKIKHE) and thyroid TG (LSSVVVDPSIRHFDV) (PubMed:25413013). Presents viral epitopes derived from HHV-6B gH/U48 and U85 antigens to polyfunctional CD4-positive T cells with cytotoxic activity implicated in control of HHV-6B infection (PubMed:31020640). Presents several immunogenic epitopes derived from C. tetani neurotoxin tetX, playing a role in immune recognition and long-term protection (PubMed:19830726).FUNCTION Allele DRB1*04:01: Presents an immunodominant bacterial epitope derived from M. tuberculosis esxB/culture filtrate antigen CFP-10 (EISTNIRQAGVQYSR), eliciting CD4-positive T cell effector functions such as IFNG production and cytotoxic activity (PubMed:15265931). May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (NEKQPSDDNWLNFDGTLLGN), contributing to viral clearance (PubMed:27591323). Presents tumor epitopes derived from melanoma-associated TYR antigen (QNILLSNAPLGPQFP and DYSYLQDSDPDSFQD), triggering CD4-positive T cell effector functions such as GMCSF production (PubMed:8642306). Displays preferentially citrullinated self-peptides derived from VIM (GVYATR/citSSAVR and SAVRAR/citSSVPGVR) and ACAN (VVLLVATEGR/ CitVRVNSAYQDK) (PubMed:24190431). Displays self-peptides derived from COL2A1 (PubMed:9354468).FUNCTION Allele DRB1*04:02: Displays native or citrullinated self-peptides derived from VIM.FUNCTION Allele DRB1*04:04: May present to T-helper 1 cells several HRV-16 epitopes derived from capsid proteins VP1 (HIVMQYMYVPPGAPIPTTRN) and VP2 (RGDSTITSQDVANAVVGYGV), contributing to viral clearance (PubMed:27591323). Displays preferentially citrullinated self-peptides derived from VIM (SAVRAR/citSSVPGVR) (PubMed:24190431).FUNCTION Allele DRB1*04:05: May present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (KRYFKLSHLQMHSRKH), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies.FUNCTION Allele DRB1*05:01: Presents an immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load.FUNCTION Allele DRB1*07:01: Upon EBV infection, presents latent antigen EBNA2 peptide (PRSPTVFYNIPPMPLPPSQL) to CD4-positive T cells, driving oligoclonal expansion and selection of a dominant virus-specific memory T cell subset with cytotoxic potential to directly eliminate virus-infected B cells (PubMed:31308093). May present to T-helper 1 cells several HRV-16 epitopes derived from capsid proteins VP1 (PRFSLPFLSIASAYYMFYDG) and VP2 (VPYVNAVPMDSMVRHNNWSL), contributing to viral clearance (PubMed:27591323). In the context of tumor immunesurveillance, may present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (MTEYKLVVVGAVGVGKSALTIQLI), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies (PubMed:22929521). In metastatic epithelial tumors, presents to intratumoral CD4-positive T cells a KRAS neoantigen (MTEYKLVVVGAVGVGKSALTIQLI) carrying G12V hotspot driver mutation and may mediate tumor regression (PubMed:30282837).FUNCTION Allele DRB1*11:01: Displays an immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load (PubMed:29884618). May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (SDRIIQITRGDSTITSQDVA), contributing to viral clearance (PubMed:27591323). Presents several immunogenic epitopes derived from C. tetani neurotoxin tetX, playing a role in immune recognition and longterm protection (PubMed:19830726). In the context of tumor immunesurveillance, may present tumor-derived neoantigens to CD4-positive T cells and trigger anti-tumor helper functions (PubMed:31495665).FUNCTION Allele DRB1*13:01: Presents viral epitopes derived from HHV-6B antigens to polyfunctional CD4-positive T cells implicated in control of HHV-6B infection.FUNCTION Allele DRB1*15:01: May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (SNNSATLIVPYVNAVPMDSM), contributing to viral clearance (PubMed:27591323). Displays a self-peptide derived from MBP (ENPVVHFFKNIVTPR) (PubMed:9782128, PubMed:25413013). May present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (KRYFKLSHLQMHSRKH), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies.FUNCTION Allele DRB1*15:02: Displays an immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load (PubMed:29884618). May present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (KRYFKLSHLQMHSRKH), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies (PubMed:19120973).FUNCTION (Microbial infection) Acts as a receptor for Epstein-Barr virus on lymphocytes.SUBUNIT Heterotrimer that consists of an alpha chain HLA-DRA, a beta chain HLA-DRB1 and a peptide (peptide-MHCII) (PubMed:7477400, PubMed:9354468, PubMed:9782128, PubMed:31619516, PubMed:32668259). Newly synthesized alpha and beta chains forms a heterodimer (MHCII) that associates with the CD74/invariant chain (Ii) in the endoplasmic reticulum (ER). Ii is a trimer composed of three subunits and each subunit interacts with one MHCII dimer, blocking the peptide-binding cleft. As a result, MHCII molecules can not bind peptides present in the ER (PubMed:7479981). The complex of MHCII and CD74/Ii is transported in vesicles from ER to Golgi to lysosomes, where it encounters antigenic peptides generated via proteolysis of endocytosed antigens. MHCII dimers are dissociated from CD74/Ii by the combined action of proteolysis and HLA-DM (PubMed:25413013). Lysosomal enzymes such as cathepsin, degrade CD74/Ii leaving a 24 amino acid remnant called class II-associated Ii or CLIP. Interacts (via the peptide binding cleft) with CLIP; this interaction inhibits antigen peptide binding before entry in the endosomal compartment (PubMed:7477400, PubMed:9075930). The displacement of CLIP and replacement by a high affinity peptide in lysosomes is performed by HLA-DM heterodimer. HLA-DM catalyzes CLIP dissociation from MHCII, stabilizes empty MHCII and mediates the selection of high affinity peptides (PubMed:23260142, PubMed:11070170, PubMed:9075930). Interacts with HLA-DM heterodimer; this interaction is direct (PubMed:25413013). Interacts with TCR (via CDR3) (PubMed:29884618). Interacts (via beta-2 domain) with CD4 coreceptor (via Ig-like V-type domain); this interaction is of exceptionally low affinity yet necessary for optimal recognition of antigenic peptides (PubMed:21900604, PubMed:27114505).SUBUNIT (Microbial infection) Interacts with Staphylococcus aureus enterotoxin A/entA, enterotoxin B/entB, enterotoxin C1/entC1, enterotoxin D/entD and enterotoxin H/entH. Enterotoxins bind outside the peptide-binding cleft of MHCII: enterotoxin H/entH interacts via the beta-1 domain of MHCII and in a zinc-dependent way, whereas enterotoxin B/entB interacts primarily via the alpha-1 domain.SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus gp42 protein.TISSUE SPECIFICITY Expressed in professional APCs: monocyte/macrophages, dendritic cells and B cells (at protein level) (PubMed:31495665, PubMed:23783831, PubMed:19830726). Expressed in thymic epithelial cells (at protein level) (PubMed:23783831).DOMAIN The beta-1 domain is a structural part of the peptide-binding cleft. It contains one alpha helix and 4 beta sheets, respectively forming part of the wall and the floor of the peptide-binding cleft. The other 4 beta sheets of the floor and the second alpha helix wall is formed by the alpha-1 domain of HLA-DRA. Forms hydrogen bonds with the peptide main chain via conserved amino acid in most HLA-DRB molecules. The polymorphic residues accomodate the side chains of the peptide conferring peptide specificity to distinct HLA-DRB1 alleles (PubMed:8145819, PubMed:28467828, PubMed:9782128, PubMed:9354468). The peptide-bound beta-1 domain forms hydrogen bonds with CDR2 and CDR3 alpha-domains of TCR (PubMed:19303388).DOMAIN The beta-2 Ig-like domain mediates the interaction with CD4 coreceptor.PTM Ubiquitinated by MARCHF1 and MARCHF8 at Lys-254 leading to sorting into the endosome system and down-regulation of MHCII.POLYMORPHISM Highly polymorphic. Polymorphic residues encode for the beta-1 domain of the peptide-binding cleft, where they contribute to variations in peptide binding and TCR recognition among different alleles. The sequence shown is that of DRB1*15:01. The sequences of common representative alleles of serologically distinct allele groups as defined in the catalog of common and well-documented HLA alleles, are described as variants of DRB1*15:01 (PubMed:23510415). In the context of hematological malignancy and T cell transplantation, alleles DRB1*03:01 and DRB1*13:01 present minor histocompatibility antigens derived respectively from host MTHFD1 and LY75 proteins, contributing to T cell-mediated graft-versus-leukemia effect and complete remission (PubMed:19706888).DISEASE In populations of European descent, allele DRB1*01:03 is associated with increased susceptibility to Crohn disease and colonic ulcerative colitis. Decreased heterozygosity in individuals with colonic ulcerative colitis suggests that it acts as a recessive risk allele.DISEASE Allele DRB1*15:01 is associated with increased susceptibility to Goodpasture syndrome. Can present a self-peptide derived from COL4A3 (GWISLWKGFSF) on TCR (TRAV19 biased) in pathogenic CD4-positive T-helper 1 and T-helper 17 cells, triggering autoimmune inflammation. UniProt P01911 30 EQUAL 266 EQUAL Reactome Database ID Release 78 197644 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=197644 Reactome R-HSA-197644 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-197644.1 HLA-DRB1 HLA class II histocompatibility antigen, DRB1-16 beta chain 2B1G_HUMAN Reactome DB_ID: 882035 UniProt:Q29974 HLA-DRB1 HLA-DRB1 FUNCTION Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route, where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules, and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments, exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides, autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs, other cells of the gastrointestinal tract, such as epithelial cells, express MHC class II molecules and CD74 and act as APCs, which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen, three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs, CD74 undergoes a sequential degradation by various proteases, including CTSS and CTSL, leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells, the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal microenvironment has been implicated in the regulation of antigen loading into MHC II molecules, increased acidification produces increased proteolysis and efficient peptide loading.SUBUNIT Heterodimer of an alpha and a beta subunit; also referred as MHC class II molecule. In the endoplasmic reticulum (ER) it forms a heterononamer; 3 MHC class II molecules bind to a CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system; CD74 undergoes sequential degradation by various proteases; leaving a small fragment termed CLIP on each MHC class II molecule. MHC class II molecule interacts with HLA_DM, and HLA_DO in B-cells, in order to release CLIP and facilitate the binding of antigenic peptides.PTM Ubiquitinated by MARCH1 and MARCH8 at Lys-254 leading to sorting into the endosome system and down-regulation of MHC class II.POLYMORPHISM The following alleles of DRB1-16 are known: DRB1*16:01; DRB1*16:02; DRB1*16:03; DRB1*16:04; DRB1*16:05; DRB1*16:07; DRB1*16:08; DRB1*16:09; DRB1*16:10; DRB1*16:11 and DRB1*16:12. The sequence shown is that of DRB1*16:02.SIMILARITY Belongs to the MHC class II family. UniProt Q29974 30 EQUAL 266 EQUAL Reactome Database ID Release 78 882035 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=882035 Reactome R-HSA-882035 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-882035.1 HLA-DRB1 HLA class II histocompatibility antigen, DRB1-4 beta chain 2B14_HUMAN Reactome DB_ID: 882031 UniProt:P13760 HLA-DRB1 HLA-DRB1 FUNCTION Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route; where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules; and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments; exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides; autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs; other cells of the gastrointestinal tract; such as epithelial cells; express MHC class II molecules and CD74 and act as APCs; which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen; three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs; CD74 undergoes a sequential degradation by various proteases; including CTSS and CTSL; leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells; the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal microenvironment has been implicated in the regulation of antigen loading into MHC II molecules; increased acidification produces increased proteolysis and efficient peptide loading.SUBUNIT Heterodimer of an alpha and a beta subunit; also referred as MHC class II molecule. In the endoplasmic reticulum (ER) it forms a heterononamer; 3 MHC class II molecules bind to a CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system; CD74 undergoes sequential degradation by various proteases; leaving a small fragment termed CLIP on each MHC class II molecule. MHC class II molecule interacts with HLA_DM, and HLA_DO in B-cells, in order to release CLIP and facilitate the binding of antigenic peptides.PTM Ubiquitinated by MARCH1 and MARCH8 at Lys-254 leading to sorting into the endosome system and down-regulation of MHC class II.POLYMORPHISM The following alleles of DRB1-4 are known: DRB1*04:01, DRB1*04:02, DRB1*04:03, DRB1*04:04, DRB1*04:05, DRB1*04:06, DRB1*04:07, DRB1*04:08, DRB1*04:09, DRB1*04:10, DRB1*04:11, DRB1*04:12, DRB1*04:13, DRB1*04:14, DRB1*04:15, DRB1*04:16, DRB1*04:17, DRB1*04:18, DRB1*04:19, DRB1*04:20, DRB1*04:21, DRB1*04:22, DRB1*04:23, DRB1*04:24, DRB1*04:25, DRB1*04:26, DRB1*04:27, DRB1*04:28, DRB1*04:29, DRB1*04:30, DRB1*04:31, DRB1*04:32, DRB1*04:33, DRB1*04:34, DRB1*04:35, DRB1*04:36, DRB1*04:37, DRB1*04:38, DRB1*04:39, DRB1*04:40, DRB1*04:41, DRB1*04:42, DRB1*04:43, DRB1*04:44, DRB1*04:45, DRB1*04:46, DRB1*04:47, DRB1*04:48, DRB1*04:49, DRB1*04:50, DRB1*04:51, DRB1*04:52, DRB1*04:53, DRB1*04:54, DRB1*04:55, DRB1*04:56, DRB1*04:57, DRB1*04:58, DRB1*04:59, DRB1*04:60, DRB1*04:61, DRB1*04:62, DRB1*04:63, DRB1*04:64, DRB1*04:65, DRB1*04:66, DRB1*04:67, DRB1*04:68, DRB1*04:69, DRB1*04:70, DRB1*04:71, DRB1*04:72, DRB1*04:73, DRB1*04:74, DRB1*04:75, DRB1*04:76, DRB1*04:77 and DRB1*04:78. The sequence shown is that of DRB1*04:01.SIMILARITY Belongs to the MHC class II family. UniProt P13760 30 EQUAL 266 EQUAL Reactome Database ID Release 78 882031 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=882031 Reactome R-HSA-882031 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-882031.1 HLA-DRB1 HLA class II histocompatibility antigen, DRB1-7 beta chain 2B17_HUMAN Reactome DB_ID: 1235085 UniProt:P13761 HLA-DRB1 HLA-DRB1 FUNCTION Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route; where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules; and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments; exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides; autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs; other cells of the gastrointestinal tract; such as epithelial cells; express MHC class II molecules and CD74 and act as APCs; which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen; three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs; CD74 undergoes a sequential degradation by various proteases; including CTSS and CTSL; leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells; the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal microenvironment has been implicated in the regulation of antigen loading into MHC II molecules; increased acidification produces increased proteolysis and efficient peptide loading.SUBUNIT Heterodimer of an alpha and a beta subunit; also referred as MHC class II molecule. In the endoplasmic reticulum (ER) it forms a heterononamer; 3 MHC class II molecules bind to a CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system; CD74 undergoes sequential degradation by various proteases; leaving a small fragment termed CLIP on each MHC class II molecule. MHC class II molecule interacts with HLA_DM, and HLA_DO in B-cells, in order to release CLIP and facilitate the binding of antigenic peptides.PTM Ubiquitinated by MARCH1 and MARCH8 at Lys-254 leading to sorting into the endosome system and down-regulation of MHC class II.POLYMORPHISM The following alleles of DRB1-7 are known: DRB1*07:01, DRB1*07:03, DRB1*07:04, DRB1*07:05, DRB1*07:06, DRB1*07:07, DRB1*07:08, DRB1*07:09, DRB1*07:11, DRB1*07:12, DRB1*07:13, DRB1*07:14, DRB1*07:15, DRB1*07:16 and DRB1*07:17. The sequence shown is that of DRB1*07:01.POLYMORPHISM Allele DRB1*07:01 is associated with persistent hepatitis C virus (HCV) infections [MIM:609532].SIMILARITY Belongs to the MHC class II family. UniProt P13761 30 EQUAL 266 EQUAL Reactome Database ID Release 78 1235085 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1235085 Reactome R-HSA-1235085 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1235085.1 HLA-DRB1 HLA class II histocompatibility antigen, DRB1-8 beta chain 2B18_HUMAN Reactome DB_ID: 1235088 UniProt:Q30134 HLA-DRB1 HLA-DRB1 FUNCTION Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route; where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules; and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments; exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides; autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs; other cells of the gastrointestinal tract; such as epithelial cells; express MHC class II molecules and CD74 and act as APCs; which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen; three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs; CD74 undergoes a sequential degradation by various proteases; including CTSS and CTSL; leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells; the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal microenvironment has been implicated in the regulation of antigen loading into MHC II molecules; increased acidification produces increased proteolysis and efficient peptide loading.SUBUNIT Heterodimer of an alpha and a beta subunit; also referred as MHC class II molecule. In the endoplasmic reticulum (ER) it forms a heterononamer; 3 MHC class II molecules bind to a CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system; CD74 undergoes sequential degradation by various proteases; leaving a small fragment termed CLIP on each MHC class II molecule. MHC class II molecule interacts with HLA_DM, and HLA_DO in B-cells, in order to release CLIP and facilitate the binding of antigenic peptides.PTM Ubiquitinated by MARCH1 and MARCH8 at Lys-254 leading to sorting into the endosome system and down-regulation of MHC class II.POLYMORPHISM The following alleles of DRB1-8 are known: DRB1*08:01 (Dw8.1), DRB1*08:02 (Dw8.2; DRB1L), DRB1*08:03 (Dw8.3); DRB1*08:04; DRB1*08:05, DRB1*08:06, DRB1*08:07, DRB1*08:08, DRB1*08:09, DRB1*08:10, DRB1*08:11, DRB1*08:12, DRB1*08:13, DRB1*08:14, DRB1*08:15, DRB1*08:16, DRB1*08:17, DRB1*08:18, DRB1*08:19, DRB1*08:20, DRB1*08:21, DRB1*08:22, DRB1*08:23, DRB1*08:24, DRB1*08:25, DRB1*08:26, DRB1*08:27, DRB1*08:28, DRB1*08:29, DRB1*08:30, DRB1*08:31, DRB1*08:32, DRB1*08:33, DRB1*08:34, DRB1*08:35 and DRB1*08:36. The sequence shown is that of DRB1*08:01.SIMILARITY Belongs to the MHC class II family. UniProt Q30134 30 EQUAL 266 EQUAL Reactome Database ID Release 78 1235088 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1235088 Reactome R-HSA-1235088 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1235088.1 HLA-DRB1 HLA class II histocompatibility antigen, DRB1-9 beta chain precursor 2B19_HUMAN Reactome DB_ID: 197640 UniProt:Q9TQE0 HLA-DRB1 HLA-DRB1 FUNCTION Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route; where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules; and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments; exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides; autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs; other cells of the gastrointestinal tract; such as epithelial cells; express MHC class II molecules and CD74 and act as APCs; which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen; three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs; CD74 undergoes a sequential degradation by various proteases; including CTSS and CTSL; leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells; the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal microenvironment has been implicated in the regulation of antigen loading into MHC II molecules; increased acidification produces increased proteolysis and efficient peptide loading.SUBUNIT Heterodimer of an alpha and a beta subunit; also referred as MHC class II molecule. In the endoplasmic reticulum (ER) it forms a heterononamer; 3 MHC class II molecules bind to a CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system; CD74 undergoes sequential degradation by various proteases; leaving a small fragment termed CLIP on each MHC class II molecule. MHC class II molecule interacts with HLA_DM, and HLA_DO in B-cells, in order to release CLIP and facilitate the binding of antigenic peptides.PTM Ubiquitinated by MARCH1 and MARCH8 at Lys-254 leading to sorting into the endosome system and down-regulation of MHC class II.POLYMORPHISM The following alleles of DRB1-9 are known: DRB1*09:01, DRB1*09:02, DRB1*09:03, DRB1*09:04, DRB1*09:05, DRB1*09:06, DRB1*09:07 and DRB1*09:08. The sequence shown is that of DRB1*09:01.SIMILARITY Belongs to the MHC class II family. UniProt Q9TQE0 30 EQUAL 266 EQUAL Reactome Database ID Release 78 197640 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=197640 Reactome R-HSA-197640 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-197640.1 HLA-DRB3 HLA class II histocompatibility antigen, DRB3-1 beta chain precursor 2B31_HUMAN Reactome DB_ID: 197577 UniProt:P79483 HLA-DRB3 HLA-DRB3 FUNCTION A beta chain of antigen-presenting major histocompatibility complex class II (MHCII) molecule. In complex with the alpha chain HLA-DRA, displays antigenic peptides on professional antigen presenting cells (APCs) for recognition by alpha-beta T cell receptor (TCR) on HLA-DRB3-restricted CD4-positive T cells. This guides antigen-specific T-helper effector functions, both antibody-mediated immune response and macrophage activation, to ultimately eliminate the infectious agents and transformed cells. Typically presents extracellular peptide antigens of 10 to 30 amino acids that arise from proteolysis of endocytosed antigens in lysosomes (PubMed:2788702, PubMed:2463305, PubMed:16148104, PubMed:19531622, PubMed:20368442, PubMed:19830726, PubMed:23569328, PubMed:22929521, PubMed:30282837, PubMed:31020640, PubMed:31333679, PubMed:31308093). In the tumor microenvironment, presents antigenic peptides that are primarily generated in tumor-resident APCs likely via phagocytosis of apoptotic tumor cells or macropinocytosis of secreted tumor proteins (By similarity). Presents peptides derived from intracellular proteins that are trapped in autolysosomes after macroautophagy, a mechanism especially relevant for T cell selection in the thymus and central immune tolerance (By similarity). The selection of the immunodominant epitopes follows two processing modes: 'bind first, cut/trim later' for pathogen-derived antigenic peptides and 'cut first, bind later' for autoantigens/self-peptides. The anchor residue at position 1 of the peptide N-terminus, usually a large hydrophobic residue, is essential for high affinity interaction with MHCII molecules (By similarity).FUNCTION ALLELE DRB3*01:01: Exclusively presents several immunogenic epitopes derived from C. tetani neurotoxin tetX, playing a significant role in immune recognition and long-term protection (PubMed:19830726, PubMed:2788702, PubMed:2463305). Presents viral epitopes derived from HHV-6B U11, TRX2/U56 and U85 antigens to polyfunctional CD4-positive T cells with cytotoxic activity implicated in control of HHV-6B infection (PubMed:31020640).FUNCTION ALLELE DRB3*02:02 Exclusively presents several immunogenic epitopes derived from C. tetani neurotoxin tetX, playing a significant role in immune recognition and long-term protection (PubMed:19830726, PubMed:2788702). Upon EBV infection, presents to CD4-positive T cells latent antigen EBNA2 (PRSPTVFYNIPPMPLPPSQL) and lytic antigen BZLF1 (LTAYHVSTAPTGSWF) peptides, driving oligoclonal expansion and selection of virus-specific memory T cell subsets with cytotoxic potential to directly eliminate virus-infected B cells (PubMed:31308093, PubMed:23569328). Presents viral epitopes derived from HHV-6B U11, gB/U39 and gH/U48 antigens to polyfunctional CD4-positive T cells with cytotoxic activity implicated in control of HHV-6B infection (PubMed:31020640). Plays a minor role in CD4-positive T cell immune response against Dengue virus by presenting conserved peptides from capsid and non-structural NS3 proteins (PubMed:31333679). Displays peptides derived from IAV matrix protein M, implying a role in protection against IAV infection (PubMed:19830726). In the context of tumor immunesurveillance, may present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (KRYFKLSHLQMHSRKH), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies (PubMed:22929521). Presents to Vbeta2-positive T-helper 1 cells specifically an immunodominant peptide derived from tumor antigen CTAG1A/NY-ESO-1(PGVLLKEFTVSGNILTIRLTAADHR) and confers protective memory response (PubMed:19531622, PubMed:20368442). In metastatic epithelial tumors, presents to intratumoral CD4-positive T cells a TP53 neoantigen (HYNYMCNSSCMGSMNRRPILTIITL) carrying G245S hotspot driver mutation and may mediate tumor regression (PubMed:30282837).FUNCTION ALLELE DRB3*03:01: Presents a series of conserved peptides derived from the M. tuberculosis PPE family of proteins, in particular PPE29 and PPE33, known to be highly immunogenic (PubMed:32341563). Presents immunogenic epitopes derived from C. tetani neurotoxin tetX, playing a role in immune recognition and long-term protection (PubMed:2788702). Displays immunodominant viral peptides from HCV non-structural protein NS2, as part of a broad range T-helper response to resolve infection (PubMed:16148104).SUBUNIT Heterotrimer that consists of an alpha chain HLA-DRA, a beta chain HLA-DRB1 and a peptide (peptide-MHCII) (PubMed:17583734, PubMed:18697946). Newly synthesized alpha and beta chains forms a heterodimer (MHCII) that associates with the CD74/invariant chain (Ii) in the endoplasmic reticulum (ER). Ii is a trimer composed of three subunits and each subunit interacts with one MHCII dimer, blocking the peptide-binding cleft. As a result, MHCII molecules can not bind peptides present in the ER (By similarity). The complex of MHCII and CD74/Ii is transported in vesicles from ER to Golgi to lysosomes, where it encounters antigenic peptides generated via proteolysis of endocytosed antigens. MHCII dimers are dissociated from CD74/Ii by the combined action of proteolysis and HLA-DM (By similarity). Lysosomal enzymes such as cathepsin, degrade CD74/Ii leaving a 24 amino acid remnant called class II-associated Ii or CLIP. Interacts (via the peptide binding cleft) with CLIP; this interaction inhibits antigen peptide binding before entry in the endosomal compartment. The displacement of CLIP and replacement by a high affinity peptide in lysosomes is performed by HLA-DM heterodimer. HLA-DM catalyzes CLIP dissociation from MHCII, stabilizes empty MHCII and mediates the selection of high affinity peptides (By similarity). Interacts with HLA-DM heterodimer; this interaction is direct (By similarity). Interacts with TCR (via CDR3) (By similarity). Interacts (via beta-2 domain) with CD4 coreceptor (via Ig-like V-type domain); this interaction is of exceptionally low affinity yet necessary for optimal recognition of antigenic peptides (By similarity).TISSUE SPECIFICITY Expressed in professional APCs: monocyte/macrophages, dendritic cells and B cells (at protein level).DOMAIN The beta-1 domain is a structural part of the peptide-binding cleft. It contains one alpha helix and 4 beta sheets, respectively forming part of the wall and the floor of the peptide-binding cleft. The other 4 beta sheets of the floor and the second alpha helix wall is formed by the alpha-1 domain of HLA-DRA. Forms hydrogen bonds with the peptide main chain via conserved amino acid in most HLA-DRB molecules. The polymorphic residues accomodate the side chains of the peptide conferring peptide specificity to distinct HLA-DRB3 alleles (PubMed:17583734, PubMed:18697946). The peptide-bound beta-1 domain forms hydrogen bonds with CDR2 and CDR3 alpha-domains of TCR (By similarity).DOMAIN The beta-2 Ig-like domain mediates the interaction with CD4 coreceptor.PTM Ubiquitinated by MARCHF1 and MARCHF8 at Lys-254 leading to sorting into the endosome system and down-regulation of MHC class II.POLYMORPHISM Highly polymorphic. Polymorphic residues encode for the beta-1 domain of the peptide-binding cleft, where they contribute to variations in peptide binding and TCR recognition among different alleles. The sequence shown is that of DRB3*01:01. The sequences of common representative alleles of serologically distinct allele groups as defined in the catalog of common and well-documented HLA alleles, are described as variants of DRB3*01:01. The most frequent alleles in human population are DRB3*01:01 (DR52a), DRB3*02:02 (DR52b) and DRB3*03:01 (DR52c) (PubMed:23510415). Allele DRB3*01:01 belongs to an ancestral haplotype and is associated with autoimmune diseases that are linked to antigen presentation. It is found in more than 95% of the homozygous HPA-1B mothers that produce anti-HPA-1A antibodies, leading to neonatal alloimmune thrombocytopenia (NAIT) (PubMed:19494351, PubMed:19535639). In the context of hematological malignancy and T cell transplantation, alleles DRB3*01:01 and DRB3*02:02 present minor histocompatibility antigens derived respectively from host PTK2B and MR1 proteins, contributing to T cell-mediated graft-versus-leukemia effect and complete remission (PubMed:19706888). Allele DRB3*03:01 plays an important role in the outcome of HLA-identical sex-mismatched organ transplantation. Presents to T-helper cells a minor histocompatibility antigen encoded by the Y chromosome RPS4Y1 (VIKVNDTVQI), leading to the maturation of dendritic cells and expansion of antigen-specific cytotoxic T cells, ultimately triggering transplant rejection (PubMed:12944060).SIMILARITY Belongs to the MHC class II family.CAUTION HLA-DRB3, HLA-DRB4 and HLA-DRB5 may represent a unique gene. UniProt P79483 30 EQUAL 266 EQUAL Reactome Database ID Release 78 197577 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=197577 Reactome R-HSA-197577 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-197577.1 Reactome Database ID Release 78 2130476 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2130476 Reactome R-HSA-2130476 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2130476.1 1 Converted from EntitySet in Reactome HLA II alpha chain Reactome DB_ID: 2130597 HLA-DPA1 HLA class II histocompatibility antigen, DP alpha chain precursor HA2Q_HUMAN Reactome DB_ID: 197586 UniProt:P20036 HLA-DPA1 HLA-DPA1 HLA-DP1A HLASB FUNCTION Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route, where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules, and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments, exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides, autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs, other cells of the gastrointestinal tract, such as epithelial cells, express MHC class II molecules and CD74 and act as APCs, which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen, three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs, CD74 undergoes a sequential degradation by various proteases, including CTSS and CTSL, leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells, the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal microenvironment has been implicated in the regulation of antigen loading into MHC II molecules, increased acidification produces increased proteolysis and efficient peptide loading.SUBUNIT Heterodimer of an alpha and a beta subunit; also referred as MHC class II molecule. In the endoplasmic reticulum (ER) it forms a heterononamer; 3 MHC class II molecules bind to a CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system; CD74 undergoes sequential degradation by various proteases; leaving a small fragment termed CLIP on each MHC class II molecule. MHC class II molecule interacts with HLA_DM, and HLA_DO in B-cells, in order to release CLIP and facilitate the binding of antigenic peptides.POLYMORPHISM The following alleles of DPA1 are known: DPA1*01:03, DPA1*01:04, DPA1*01:05, DPA1*01:06, DPA1*01:07, DPA1*01:08, DPA1*01:09, DPA1*01:10, DPA1*02:01, DPA1*02:02, DPA1*02:03, DPA1*02:04, DPA1*03:01, DPA1*03:02, DPA1*03:03, DPA1*04:01 The sequence shown is that of DPA1*01:03.SIMILARITY Belongs to the MHC class II family. UniProt P20036 29 EQUAL 260 EQUAL Reactome Database ID Release 78 197586 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=197586 Reactome R-HSA-197586 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-197586.1 HLA-DQA2 HLA class II histocompatibility antigen, DQ HA26_HUMAN Reactome DB_ID: 197576 UniProt:P01906 HLA-DQA2 HLA-DQA2 HLA-DXA FUNCTION Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route, where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules, and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments, exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides, autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs, other cells of the gastrointestinal tract, such as epithelial cells, express MHC class II molecules and CD74 and act as APCs, which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen, three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs, CD74 undergoes a sequential degradation by various proteases, including CTSS and CTSL, leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells, the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal microenvironment has been implicated in the regulation of antigen loading into MHC II molecules, increased acidification produces increased proteolysis and efficient peptide loading.SUBUNIT Heterodimer of an alpha and a beta subunit; also referred as MHC class II molecule. Dimer formation with HLA-DQB2, but not with HLA-DQB1, is required for efficient exit from the endoplasmic reticulum (ER). In the ER, forms a heterononamer; 3 MHC class II molecules bind to a CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system; CD74 undergoes sequential degradation by various proteases; leaving a small fragment termed CLIP on each MHC class II molecule. MHC class II molecule interacts with HLA_DM, and HLA_DO in B-cells, in order to release CLIP and facilitate the binding of antigenic peptides. Association with HLA-DMA also occurs in skin Langerhans cells, in post-Golgi compartments.TISSUE SPECIFICITY Restricted to skin Langerhans cells, although some expression at low levels may occur at the surface of B lymphoblastoid cells.SIMILARITY Belongs to the MHC class II family. UniProt P01906 24 EQUAL 255 EQUAL Reactome Database ID Release 78 197576 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=197576 Reactome R-HSA-197576 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-197576.1 HLA-DQA1 HLA class II histocompatibility antigen, DQ HA23_HUMAN Reactome DB_ID: 197585 UniProt:P01909 HLA-DQA1 HLA-DQA1 FUNCTION Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route, where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules, and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments, exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides, autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs, other cells of the gastrointestinal tract, such as epithelial cells, express MHC class II molecules and CD74 and act as APCs, which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen, three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs, CD74 undergoes a sequential degradation by various proteases, including CTSS and CTSL, leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells, the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal microenvironment has been implicated in the regulation of antigen loading into MHC II molecules, increased acidification produces increased proteolysis and efficient peptide loading.SUBUNIT Heterodimer of an alpha and a beta subunit; also referred as MHC class II molecule. In the endoplasmic reticulum (ER) it forms a heterononamer; 3 MHC class II molecules bind to a CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system; CD74 undergoes sequential degradation by various proteases; leaving a small fragment termed CLIP on each MHC class II molecule. MHC class II molecule interacts with HLA_DM, and HLA_DO in B-cells, in order to release CLIP and facilitate the binding of antigenic peptides.POLYMORPHISM The following alleles of DQA1 are known: DQA1*01:01, DQA1*01:02, DQA1*01:03, DQA1*01:04, DQA1*01:05, DQA1*01:06, DQA1*01:07, DQA1*02:01, DQA1*03:01, DQA1*03:02, DQA1*03:03, DQA1*04:01, DQA1*04:02, DQA1*04:03, DQA1*04:04, DQA1*05:01, DQA1*05:02, DQA1*05:03, DQA1*05:04, DQA1*05:05, DQA1*05:06, DQA1*05:07, DQA1*05:08, DQA1*05:09, DQA1*06:01, DQA1*06:02. The sequence shown is that of DQA1*05:01.POLYMORPHISM DQ2 (heterodimer of DQA1*05:01/DQB1*02:01) is associated with more than 90% of celiac disease patients. A minority displays DQ8 (heterodimer of DQA1*03/DQB1*03:02). DQ0602 (heterodimer of DQA1*01:02/DQB1*06:02) confers dominant protection against type 1 diabetes (T1D) and strong susceptibility to narcolepsy.SIMILARITY Belongs to the MHC class II family. UniProt P01909 24 EQUAL 254 EQUAL Reactome Database ID Release 78 197585 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=197585 Reactome R-HSA-197585 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-197585.1 HLA-DRA HLA class II histocompatibility antigen, DR alpha chain precursor 2DRA_HUMAN Reactome DB_ID: 197588 UniProt:P01903 HLA-DRA HLA-DRA HLA-DRA1 FUNCTION An alpha chain of antigen-presenting major histocompatibility complex class II (MHCII) molecule. In complex with the beta chain HLA-DRB, displays antigenic peptides on professional antigen presenting cells (APCs) for recognition by alpha-beta T cell receptor (TCR) on HLA-DR-restricted CD4-positive T cells. This guides antigen-specific T-helper effector functions, both antibody-mediated immune response and macrophage activation, to ultimately eliminate the infectious agents and transformed cells (PubMed:29884618, PubMed:17334368, PubMed:8145819, PubMed:15322540, PubMed:22327072, PubMed:27591323, PubMed:31495665, PubMed:15265931, PubMed:9075930, PubMed:24190431). Typically presents extracellular peptide antigens of 10 to 30 amino acids that arise from proteolysis of endocytosed antigens in lysosomes (PubMed:8145819). In the tumor microenvironment, presents antigenic peptides that are primarily generated in tumor-resident APCs likely via phagocytosis of apoptotic tumor cells or macropinocytosis of secreted tumor proteins (PubMed:31495665). Presents peptides derived from intracellular proteins that are trapped in autolysosomes after macroautophagy, a mechanism especially relevant for T cell selection in the thymus and central immune tolerance (PubMed:17182262, PubMed:23783831). The selection of the immunodominant epitopes follows two processing modes: 'bind first, cut/trim later' for pathogen-derived antigenic peptides and 'cut first, bind later' for autoantigens/self-peptides (PubMed:25413013). The anchor residue at position 1 of the peptide N-terminus, usually a large hydrophobic residue, is essential for high affinity interaction with MHCII molecules (PubMed:8145819).SUBUNIT Heterotrimer that consists of an alpha chain HLA-DRA, a beta chain HLA-DRB and a peptide (peptide-MHCII) (PubMed:7477400, PubMed:9354468, PubMed:9782128, PubMed:31619516, PubMed:32668259, PubMed:11080454, PubMed:11163233, PubMed:12244309, PubMed:16079912, PubMed:17583734, PubMed:18697946). Newly synthesized alpha and beta chains forms a heterodimer (MHCII) that associates with the CD74/invariant chain (Ii) in the endoplasmic reticulum (ER). Ii is a trimer composed of three subunits and each subunit interacts with one MHCII dimer, blocking the peptide-binding cleft (PubMed:7479981). As a result, MHCII molecules can not bind peptides present in the ER (PubMed:7479981). The complex of MHCII and CD74/Ii is transported in vesicles from ER to Golgi to lysosomes, where it encounters antigenic peptides generated via proteolysis of endocytosed antigens. MHCII dimers are dissociated from CD74/Ii by the combined action of proteolysis and HLA-DM (PubMed:25413013, PubMed:23260142, PubMed:21115828). Lysosomal enzymes such as cathepsin, degrade CD74/Ii leaving a 24 amino acid remnant called class II-associated Ii or CLIP. Interacts (via the peptide binding cleft) with CLIP; this interaction inhibits antigen peptide binding before entry in the endosomal compartment (PubMed:9075930, PubMed:7477400). The displacement of CLIP and replacement by a high affinity peptide in lysosomes is performed by HLA-DM heterodimer. HLA-DM catalyzes CLIP dissociation from MHCII, stabilizes empty MHCII and mediates the selection of high affinity peptides (PubMed:23260142, PubMed:11070170, PubMed:9075930). Interacts with HLA-DM heterodimer; this interaction is direct (PubMed:25413013). Interacts (via alpha-1 domain) with TCR (via CDRs) (PubMed:17334368, PubMed:29884618). Interacts (via alpha-2 domain) with CD4 (via Ig-like V-type domain); this interaction increases the affinity of TCR for peptide-MHCII (PubMed:27114505).SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus BZLF2/gp42.SUBUNIT (Microbial infection) Interacts with Staphylococcus aureus enterotoxin A/entA, enterotoxin B/entB, enterotoxin C1/entC1, enterotoxin D/entD, and enterotoxin H/entH.TISSUE SPECIFICITY Expressed in professional APCs: macrophages, dendritic cells and B cells (at protein level) (PubMed:31495665, PubMed:15322540, PubMed:23783831). Expressed in thymic epithelial cells (at protein level) (PubMed:23783831).INDUCTION Up-regulated in dendritic cells upon maturation.DOMAIN The alpha-1 domain is a structural part of the peptide-binding cleft. It contains one alpha helix and 4 beta sheets, respectively forming part of the wall and the floor of the peptide-binding cleft. The other 4 beta sheets of the floor and the second alpha helix wall is formed by the beta-1 domain of HLA-DRB. Forms hydrogen bonds with the peptide main chain via conserved amino acids (PubMed:8145819, PubMed:9354468, PubMed:9782128, PubMed:17583734, PubMed:29884618). The peptide-bound alpha-1 domain forms hydrogen bonds with CDR2 and CDR3 alpha-domain of TCR (PubMed:29884618).DOMAIN The alpha-2 Ig-like domain mediates the interaction with CD4 coreceptor.PTM Ubiquitinated by MARCHF1 or MARCHF8 at Lys-244 leading to down-regulation of MHCII. When associated with ubiquitination of the beta chain at 'Lys-254', the down-regulation of MHCII may be highly effective.POLYMORPHISM The following alleles of DRA are known: DRA*01:01 and DRA*01:02. The sequence shown is that of DRA*01:02.SIMILARITY Belongs to the MHC class II family. UniProt P01903 26 EQUAL 254 EQUAL Reactome Database ID Release 78 197588 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=197588 Reactome R-HSA-197588 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-197588.1 Reactome Database ID Release 78 2130597 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2130597 Reactome R-HSA-2130597 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2130597.1 1 Reactome Database ID Release 78 2213189 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2213189 Reactome R-HSA-2213189 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2213189.1 1 Reactome Database ID Release 78 203463 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=203463 Reactome R-HSA-203463 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-203463.1 1 LCK Lymphocyte specific tyrosine kinase Reactome DB_ID: 167609 UniProt:P06239 LCK LCK FUNCTION Non-receptor tyrosine-protein kinase that plays an essential role in the selection and maturation of developing T-cells in the thymus and in the function of mature T-cells. Plays a key role in T-cell antigen receptor (TCR)-linked signal transduction pathways. Constitutively associated with the cytoplasmic portions of the CD4 and CD8 surface receptors. Association of the TCR with a peptide antigen-bound MHC complex facilitates the interaction of CD4 and CD8 with MHC class II and class I molecules, respectively, thereby recruiting the associated LCK protein to the vicinity of the TCR/CD3 complex. LCK then phosphorylates tyrosine residues within the immunoreceptor tyrosine-based activation motifs (ITAM) of the cytoplasmic tails of the TCR-gamma chains and CD3 subunits, initiating the TCR/CD3 signaling pathway. Once stimulated, the TCR recruits the tyrosine kinase ZAP70, that becomes phosphorylated and activated by LCK. Following this, a large number of signaling molecules are recruited, ultimately leading to lymphokine production. LCK also contributes to signaling by other receptor molecules. Associates directly with the cytoplasmic tail of CD2, which leads to hyperphosphorylation and activation of LCK. Also plays a role in the IL2 receptor-linked signaling pathway that controls the T-cell proliferative response. Binding of IL2 to its receptor results in increased activity of LCK. Is expressed at all stages of thymocyte development and is required for the regulation of maturation events that are governed by both pre-TCR and mature alpha beta TCR. Phosphorylates other substrates including RUNX3, PTK2B/PYK2, the microtubule-associated protein MAPT, RHOH or TYROBP. Interacts with FYB2 (PubMed:27335501).ACTIVITY REGULATION The relative activities of the inhibitory tyrosine-protein kinase CSK and the activating tyrosine-protein phosphatase PTPRC/CD45 determine the level of LCK activity. These interactions allow rapid and efficient activation of LCK in response to TCR stimulation.SUBUNIT Binds to the cytoplasmic domain of cell surface receptors, such as AXL, CD2, CD4, CD5, CD8, CD44, CD45 and CD122. Also binds to effector molecules, such as PI4K, VAV1, RASA1, FYB1 and to other protein kinases including CDK1, RAF1, ZAP70 and SYK. Binds to phosphatidylinositol 3'-kinase (PI3K) from T-lymphocytes through its SH3 domain and to the tyrosine phosphorylated form of KHDRBS1/p70 through its SH2 domain. This interaction inhibits its tyrosine-kinase activity. Interacts with SQSTM1. Interacts with phosphorylated LIME1. Interacts with CBLB and PTPRH. Interacts with RUNX3. Forms a signaling complex with EPHA1, PTK2B AND PI3-KINASE; upon activation by EFNA1 which may regulate T-lymphocyte migration. Associates with ZAP70 and RHOH; these interactions allow LCK-mediated RHOH and CD3 subunit phosphorylation in the presence of functional ZAP70. Interacts with UNC119; this interaction plays a crucial role in activation of LCK. Interacts with CEACAM1 (via cytoplasmic domain); mediates CEACAM1 phosphorylation resulting in PTPN6 recruitment that dephosphorylates TCR stimulation-induced CD247 and ZAP70 (PubMed:18424730). Interacts with CD160.SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 UL46; this interaction activates LCK.SUBUNIT (Microbial infection) Interacts with HIV-1 Nef through its SH3 domain.TISSUE SPECIFICITY Expressed specifically in lymphoid cells.DOMAIN The SH2 domain mediates interaction with SQSTM1. Interaction is regulated by Ser-59 phosphorylation.PTM Autophosphorylated on Tyr-394, increasing enzymatic activity, this site is dephosphorylated by PTN22. Phosphorylated on Tyr-505 by CSK, decreasing activity. Dephosphorylated by PTPRC/CD45. Dephosphorylation at Tyr-394 by PTPN2 negatively regulates T-cell receptor signaling.PTM Myristoylation is required prior to palmitoylation.PTM Palmitoylation regulates association with the plasma membrane and could be mediated by ZDHHC2.DISEASE A chromosomal aberration involving LCK is found in leukemias. Translocation t(1;7)(p34;q34) with TCRB.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. SRC subfamily. UniProt P06239 1 EQUAL 509 EQUAL Reactome Database ID Release 78 167609 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=167609 Reactome R-HSA-167609 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-167609.1 1 Reactome Database ID Release 78 202157 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202157 Reactome R-HSA-202157 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202157.1 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 29370 ADP(3-) [ChEBI:456216] ADP(3-) ADP 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP trianion ChEBI CHEBI:456216 Reactome Database ID Release 78 29370 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29370 Reactome R-ALL-29370 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29370.5 COMPOUND C00008 Antigen-bearing MHC Class II : TCR complex:CD4:p-Lck(Y505) Reactome DB_ID: 202154 p-Y505-LCK p-Lck (Y505) inactive Reactome DB_ID: 202159 505 EQUAL 1 EQUAL 509 EQUAL Reactome Database ID Release 78 202159 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202159 Reactome R-HSA-202159 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202159.1 1 1 1 1 Reactome Database ID Release 78 202154 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202154 Reactome R-HSA-202154 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202154.1 ACTIVATION activeUnit: #Protein45 GENE ONTOLOGY GO:0004713 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 78 202267 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202267 CSK Tyrosine-protein kinase CSK Reactome DB_ID: 180499 1 EQUAL 450 EQUAL Reactome Database ID Release 78 180499 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=180499 Reactome R-HSA-180499 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-180499.1 Reactome Database ID Release 78 202233 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202233 Reactome R-HSA-202233 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202233.3 21543337 Pubmed 2011 Regulation of Src family kinases involved in T cell receptor signaling by protein-tyrosine phosphatase CD148 Stepanek, Ondrej Kalina, Tomas Draber, Peter Skopcova, Tereza Svojgr, Karel Angelisová, Pavla Horejsí, Václav Weiss, Arthur Brdicka, Tomas J. Biol. Chem. 286:22101-12 15489910 Pubmed 2004 Structure and regulation of Src family kinases Boggon, TJ Eck, MJ Oncogene 23:7918-27 20346773 Pubmed 2010 CD45-Csk phosphatase-kinase titration uncouples basal and inducible T cell receptor signaling during thymic development Zikherman, Julie Jenne, Craig Watson, Susan Doan, Kristin Raschke, William Goodnow, Christopher C Weiss, Arthur Immunity 32:342-54 15489916 Pubmed 2004 Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation Palacios, EH Weiss, A Oncogene 23:7990-8000 19290918 Pubmed 2009 T-cell receptor proximal signaling via the Src-family kinases, Lck and Fyn, influences T-cell activation, differentiation, and tolerance Salmond, Robert J Filby, Andrew Qureshi, Ihjaaz Caserta, Stefano Zamoyska, Rose Immunol. Rev. 228:9-22 10360179 Pubmed 1999 Crystal structures of c-Src reveal features of its autoinhibitory mechanism Xu, W Doshi, A Lei, M Eck, M J Harrison, S C Mol. Cell 3:629-38 INHIBITION Reactome Database ID Release 78 6785250 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6785250 Reactome R-HSA-6785250 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6785250.1 Converted from EntitySet in Reactome CD45,CD148 PTPRC,PTPRJ Reactome DB_ID: 6785270 PTPRC Leukocyte common antigen precursor CD45_HUMAN Reactome DB_ID: 197931 UniProt:P08575 PTPRC PTPRC CD45 FUNCTION Protein tyrosine-protein phosphatase required for T-cell activation through the antigen receptor. Acts as a positive regulator of T-cell coactivation upon binding to DPP4. The first PTPase domain has enzymatic activity, while the second one seems to affect the substrate specificity of the first one. Upon T-cell activation, recruits and dephosphorylates SKAP1 and FYN. Dephosphorylates LYN, and thereby modulates LYN activity (By similarity).FUNCTION (Microbial infection) Acts as a receptor for human cytomegalovirus protein UL11 and mediates binding of UL11 to T-cells, leading to reduced induction of tyrosine phosphorylation of multiple signaling proteins upon T-cell receptor stimulation and impaired T-cell proliferation.SUBUNIT Binds GANAB and PRKCSH (By similarity). Interacts with SKAP1 (PubMed:11909961). Interacts with DPP4; the interaction is enhanced in an interleukin-12-dependent manner in activated lymphocytes (PubMed:12676959).SUBUNIT (Microbial infection) Interacts with human cytomegalovirus protein UL11; the interaction is required for binding of UL11 to T-cells.TISSUE SPECIFICITY Isoform 1: Detected in thymocytes. Isoform 2: Detected in thymocytes. Isoform 3: Detected in thymocytes. Isoform 4: Not detected in thymocytes. Isoform 5: Detected in thymocytes. Isoform 6: Not detected in thymocytes. Isoform 7: Detected in thymocytes. Isoform 8: Not detected in thymocytes.DEVELOPMENTAL STAGE Isoform 1: During T-cell development, expressed at the CD3-CD4-CD8- and CD3+CD4+CD8- stages but barely detectable at the CD3-CD4+CD8+ stage. Isoform 2: During T-cell development, expressed at low levels at the CD3-CD4-CD8- and CD3-CD4+CD8- stages but up-regulated at the CD3+CD4+CD8+ and CD3+CD4+CD8- stages. Isoform 3: During T-cell development, expressed at the CD3-CD4-CD8- and CD3+CD4+CD8- stages but barely detectable at the CD3-CD4+CD8+ stage. Isoform 5: During T-cell development, expressed at the CD3-CD4-CD8- and CD3+CD4+CD8- stages but barely detectable at the CD3-CD4+CD8+ stage. Isoform 7: Consistently expressed at high levels at all stages of T-cell development.DOMAIN The first PTPase domain interacts with SKAP1.PTM Heavily N- and O-glycosylated.SIMILARITY Belongs to the protein-tyrosine phosphatase family. Receptor class 1/6 subfamily.CAUTION It is uncertain whether Met-1 or Met-3 is the initiator. UniProt P08575 24 EQUAL 1304 EQUAL Reactome Database ID Release 78 197931 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=197931 Reactome R-HSA-197931 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-197931.1 PTPRJ Receptor-type tyrosine-protein phosphatase eta CD148 Reactome DB_ID: 6785269 UniProt:Q12913 PTPRJ PTPRJ DEP1 FUNCTION Tyrosine phosphatase which dephosphorylates or contributes to the dephosphorylation of CTNND1, FLT3, PDGFRB, MET, RET (variant MEN2A), KDR, LYN, SRC, MAPK1, MAPK3, EGFR, TJP1, OCLN, PIK3R1 and PIK3R2. Plays a role in cell adhesion, migration, proliferation and differentiation. Involved in vascular development. Regulator of macrophage adhesion and spreading. Positively affects cell-matrix adhesion. Positive regulator of platelet activation and thrombosis. Negative regulator of cell proliferation. Negative regulator of PDGF-stimulated cell migration; through dephosphorylation of PDGFR. Positive regulator of endothelial cell survival, as well as of VEGF-induced SRC and AKT activation; through KDR dephosphorylation. Negative regulator of EGFR signaling pathway; through EGFR dephosphorylation. Enhances the barrier function of epithelial junctions during reassembly. Negatively regulates T-cell receptor (TCR) signaling. Upon T-cell TCR activation, it is up-regulated and excluded from the immunological synapses, while upon T-cell-antigen presenting cells (APC) disengagement, it is no longer excluded and can dephosphorylate PLCG1 and LAT to down-regulate prolongation of signaling.SUBUNIT Monomer. Interacts with CTNNB1 (phosphorylated) and JUP (phosphorylated). Interacts with FLT3 (phosphorylated). Interacts with GAB1 and GRB2.TISSUE SPECIFICITY Expressed in the promyelocytic cell line HL-60, the granulocyte-macrophage colony-stimulating factor-dependent leukemic cell line F-36P, and the IL3 and erythropoietin-dependent leukemic cell line F-36E. Expressed predominantly in epithelial cells and lymphocytes. Enhanced expression at high cell density.PTM N- and O-glycosylated.SIMILARITY Belongs to the protein-tyrosine phosphatase family. Receptor class 3 subfamily. UniProt Q12913 36 EQUAL 1337 EQUAL Reactome Database ID Release 78 6785269 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6785269 Reactome R-HSA-6785269 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6785269.1 Reactome Database ID Release 78 6785270 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6785270 Reactome R-HSA-6785270 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6785270.1 LEFT-TO-RIGHT 3.1.3.48 Dephosphorylation of Lck-pY505 by CD45 TCR stimulation induce the transient dephosphorylation of PAG thereby release the Csk from its plasma membrane anchor. The release of Csk from its proximity with Lck may serve to facilitate the activation of Lck.Protein tyrosine phosphtase CD45 (PTPRC) and CD148 (PTPRJ) have dual function in TCR signalling. They act both in activation as well as inactivation of Src family kinases (SFKs) which are involved in the initiation of TCR signal transduction (Stepanek et al. 2011). The activatory role is to dephosphorylate an inhibitory site tyrosine 505 (Y505) at the C-terminal end of Lck, which is needed to enable Lck to an open conformation and expose the activation loop (A-loop) containing the activating tyrosine 394 (Y394) (Xu et al. 1993. McNeill et al. 2007, Zikherman et al. 2010, Stepanek et al. 2011, Salmond et al. 2009). Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 H2O water Reactome DB_ID: 29356 water [ChEBI:15377] water ChEBI CHEBI:15377 Reactome Database ID Release 78 29356 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29356 Reactome R-ALL-29356 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29356.5 COMPOUND C00001 Pi Orthophosphate hydrogenphosphate Phosphate Inorganic Phosphate Reactome DB_ID: 29372 hydrogenphosphate [ChEBI:43474] hydrogenphosphate hydrogen phosphate phosphate [PO3(OH)](2-) INORGANIC PHOSPHATE GROUP HYDROGENPHOSPHATE ION HPO4(2-) [P(OH)O3](2-) ChEBI CHEBI:43474 Reactome Database ID Release 78 29372 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29372 Reactome R-ALL-29372 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29372.4 COMPOUND C00009 ACTIVATION GENE ONTOLOGY GO:0004725 Reactome Database ID Release 78 202295 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202295 Reactome Database ID Release 78 202214 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202214 Reactome R-HSA-202214 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202214.2 2530588 Pubmed 1989 Expression of CD45 alters phosphorylation of the lck-encoded tyrosine protein kinase in murine lymphoma T-cell lines Ostergaard, H L Shackelford, D A Hurley, T R Johnson, P Hyman, R Sefton, B M Trowbridge, I S Proc. Natl. Acad. Sci. U.S.A. 86:8959-63 23580664 Pubmed 2013 The large ectodomains of CD45 and CD148 regulate their segregation from and inhibition of ligated T-cell receptor Cordoba, Shaun-Paul Choudhuri, Kaushik Zhang, Hao Bridge, Marcus Basat, Alp Bugra Dustin, Michael L van der Merwe, P Anton Blood 121:4295-302 LEFT-TO-RIGHT 2.7.10 Activation of Lck The binding of CD4/CD8 to non-polymorphic regions of MHC brings Lck in to proximity with TCR subunits phosphorylation. Lck is further phosphorylated to promote the active conformation and to increase their catalytic activity. The C-term domain contain a regulatory activation loop, which is the site of activating Tyr 394 phosphorylation. This tyrosine is auto-phosphorylated to attain an active conformation on TCR stimulation. Now Lck through its kinase activity phosphorylates the ITAMs in TCR zeta and CD3 members. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Antigen-bearing MHC Class II :TCR complex:CD4: Lck phosphorylated at Tyr394 Reactome DB_ID: 202266 1 p-Y394-LCK p-Y394-LCK(1-509) Lck phosphorylated at tyrosine 394 Reactome DB_ID: 202308 394 EQUAL 1 EQUAL 509 EQUAL Reactome Database ID Release 78 202308 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202308 Reactome R-HSA-202308 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202308.1 1 1 1 Reactome Database ID Release 78 202266 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202266 Reactome R-HSA-202266 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202266.1 ACTIVATION activeUnit: #Protein43 Reactome Database ID Release 78 202226 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202226 Reactome Database ID Release 78 202291 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202291 Reactome R-HSA-202291 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202291.1 LEFT-TO-RIGHT PTPN22 dissociates from CSK In unstimulated T-lymphocytes, protein tyrosine phosphatase PTPN22 (LYP, PEP) is associated with CSK, which inhibits the catalytic activity of PTPN22. In response to TCR-stimulation, the complex of CSK and PTPN22 dissociates through an unknown mechanism, which allows PTPN22 to be recruited to lipid rafts. The PTPN22 variant PTPN22 R620W, the result of a SNP associated with autoimmune diseases, does not bind to CSK and is constitutively active (Vang et al. 2012). Authored: Orlic-Milacic, Marija, 2016-02-03 Reviewed: Stanford, Stephanie, 2016-05-10 Reviewed: Bottini, Nunzio, 2016-05-10 Edited: Orlic-Milacic, Marija, 2016-02-03 PTPN22:CSK Reactome DB_ID: 8855376 LYP PTPN22 Tyrosine-protein phosphatase non-receptor type 22 Lymphoid phosphatase PEST-domain phosphatase PEP Hematopoietic cell protein-tyrosine phosphatase 70Z-PEP PTPN8 Reactome DB_ID: 8852205 UniProt:Q9Y2R2 PTPN22 PTPN22 PTPN8 FUNCTION Acts as negative regulator of T-cell receptor (TCR) signaling by direct dephosphorylation of the Src family kinases LCK and FYN, ITAMs of the TCRz/CD3 complex, as well as ZAP70, VAV, VCP and other key signaling molecules (PubMed:16461343, PubMed:18056643). Associates with and probably dephosphorylates CBL. Dephosphorylates LCK at its activating 'Tyr-394' residue (PubMed:21719704). Dephosphorylates ZAP70 at its activating 'Tyr-493' residue (PubMed:16461343). Dephosphorylates the immune system activator SKAP2 (PubMed:21719704). Positively regulates toll-like receptor (TLR)-induced type 1 interferon production (PubMed:23871208). Promotes host antiviral responses mediated by type 1 interferon (By similarity). Regulates NOD2-induced pro-inflammatory cytokine secretion and autophagy (PubMed:23991106). Dephosphorylates phospho-anandamide (p-AEA), an endocannabinoid to anandamide (also called N-arachidonoylethanolamide) (By similarity).ACTIVITY REGULATION Down-regulated by phosphorylation.SUBUNIT Interacts with CSK (PubMed:15208781). Interacts with LPXN (By similarity). Interacts with CBL (PubMed:10068674). Interacts with TRAF3 (via MATH domain); the interaction promotes TRAF3 polyubiquitination (PubMed:23871208).TISSUE SPECIFICITY Expressed in bone marrow, B and T-cells, PBMCs, natural killer cells, monocytes, dendritic cells and neutrophils (PubMed:15208781). Both isoform 1 and 4 are predominantly expressed in lymphoid tissues and cells. Isoform 1 is expressed in thymocytes and both mature B and T-cells.INDUCTION By muramyl-dipeptide and lipopolysaccharide.PTM Phosphorylation on Ser-35 by PKC/PRKCD abrogates its ability to dephosphorylate and inactivate the SRC family kinases.SIMILARITY Belongs to the protein-tyrosine phosphatase family. Non-receptor class 4 subfamily. UniProt Q9Y2R2 1 EQUAL 807 EQUAL Reactome Database ID Release 78 8852205 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8852205 Reactome R-HSA-8852205 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8852205.2 1 1 Reactome Database ID Release 78 8855376 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8855376 Reactome R-HSA-8855376 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8855376.2 Reactome Database ID Release 78 8855375 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8855375 Reactome R-HSA-8855375 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8855375.2 22426112 Pubmed 2012 LYP inhibits T-cell activation when dissociated from CSK Vang, Torkel Liu, Wallace H Delacroix, Laurence Wu, Shuangding Vasile, Stefan Dahl, Russell Yang, Li Musumeci, Lucia Francis, Dana Landskron, Johannes Tasken, Kjetil Tremblay, Michel L Lie, Benedicte A Page, Rebecca Mustelin, Tomas Rahmouni, Souad Rickert, Robert C Tautz, Lutz Nat. Chem. Biol. 8:437-46 LEFT-TO-RIGHT 3.1.3.48 Inactivation of LCK by LYP Inactivation of LCK by PTPN22 Protein tyrosine phosphatase PTPN22 (LYP, PEP) (Cohen et al. 1999) dephosphorylates tyrosine residue Y394 of LCK, thus inactivating LCK and down-regulating TCR signaling (Wu et al. 2006, Vang et al. 2012). Authored: Orlic-Milacic, Marija, 2016-02-03 Reviewed: Stanford, Stephanie, 2016-05-10 Reviewed: Bottini, Nunzio, 2016-05-10 Edited: Orlic-Milacic, Marija, 2016-02-03 ACTIVATION Reactome Database ID Release 78 8852203 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8852203 Reactome Database ID Release 78 8852200 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8852200 Reactome R-HSA-8852200 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8852200.2 10068674 Pubmed 1999 Cloning and characterization of a lymphoid-specific, inducible human protein tyrosine phosphatase, Lyp Cohen, S Dadi, H Shaoul, E Sharfe, N Roifman, C M Blood 93:2013-24 16461343 Pubmed 2006 Identification of substrates of human protein-tyrosine phosphatase PTPN22 Wu, Jiansheng Katrekar, Anjali Honigberg, Lee A Smith, Ashley M Conn, Marion T Tang, Jie Jeffery, Doug Mortara, Kyle Sampang, Jun Williams, Steve R Buggy, Joseph Clark, James M J. Biol. Chem. 281:11002-10 LEFT-TO-RIGHT 2.7.10 Phosphorylation of ITAM motifs in CD3 complexes The autophosphorylated, active Lck is now proximally positioned to phosphorylate specific tyrosine residues within ITAMs (immunoreceptor tyrosine-based activation motifs) located within the CD3 and the TCR zeta signaling chains of the TCR. ITAMs consist of evolutionarily conserved amino-acid sequence motifs of D/ExYxxLx(6-8)YxxL. Both the tyrosine residues in the motif are phosphorylated by Lck and the TCR complex include 10 ITAMs with one ITAM in each of the CD3 chains including the three tandem ITAMs in each zeta chains. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 20 20 Antigen-bearing MHC Class II: TCR with phosphorylated ITAMs:CD4 Reactome DB_ID: 203494 T-cell receptor complex with phosphorylated ITAMs Reactome DB_ID: 203493 1 CD3 epsilon: CD3 delta with phosphorylated ITAMs Reactome DB_ID: 202336 p-Y188,Y199-CD3E CD3 epsilon with phosphorylated ITAM Reactome DB_ID: 202228 188 EQUAL 199 EQUAL 23 EQUAL 207 EQUAL Reactome Database ID Release 78 202228 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202228 Reactome R-HSA-202228 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202228.1 1 p-Y149,Y160-CD3D CD3 delta with phosphorylated ITAMs Reactome DB_ID: 202329 149 EQUAL 160 EQUAL 22 EQUAL 171 EQUAL Reactome Database ID Release 78 202329 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202329 Reactome R-HSA-202329 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202329.1 1 Reactome Database ID Release 78 202336 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202336 Reactome R-HSA-202336 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202336.1 1 CD3 epsilon: CD3 gamma with phosphorylated ITAM Reactome DB_ID: 202167 1 p-Y160,Y171-CD3G CD3 gamma with phosphorylated ITAM Reactome DB_ID: 202362 160 EQUAL 171 EQUAL 23 EQUAL 182 EQUAL Reactome Database ID Release 78 202362 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202362 Reactome R-HSA-202362 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202362.2 1 Reactome Database ID Release 78 202167 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202167 Reactome R-HSA-202167 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202167.1 1 p-6Y-CD247 dimer CD3 zeta dimer with phosphorylated ITAMs Reactome DB_ID: 202303 p-6Y-CD3Z p-6Y-CD247 CD3 zeta with phosphorylated ITAMs Reactome DB_ID: 202166 72 EQUAL 83 EQUAL 111 EQUAL 123 EQUAL 142 EQUAL 153 EQUAL 22 EQUAL 164 EQUAL Reactome Database ID Release 78 202166 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202166 Reactome R-HSA-202166 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202166.3 2 Reactome Database ID Release 78 202303 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202303 Reactome R-HSA-202303 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202303.3 1 Reactome Database ID Release 78 203493 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=203493 Reactome R-HSA-203493 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-203493.1 ComplexPortal CPX-6482 ComplexPortal CPX-6581 1 1 1 1 Reactome Database ID Release 78 203494 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=203494 Reactome R-HSA-203494 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-203494.1 ACTIVATION activeUnit: #Protein49 Reactome Database ID Release 78 202294 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202294 Reactome Database ID Release 78 202165 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202165 Reactome R-HSA-202165 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202165.1 16364187 Pubmed 2005 T-cell signalling and immune system disorders Wilkinson, B Downey, JS Rudd, CE Expert Rev Mol Med 7:1-29 15084594 Pubmed 2004 T cell receptor signaling: beyond complex complexes Huang, Y Wange, RL J Biol Chem 279:28827-30 Reactome Database ID Release 78 202427 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202427 Reactome R-HSA-202427 6 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202427.6 10375551 Pubmed 1999 T cell antigen-receptor signal transduction van Leeuwen, JE Samelson, LE Curr Opin Immunol 11:242-8 Translocation of ZAP-70 to Immunological synapse The dual phosphorylated ITAMs recruit SYK kinase ZAP70 via their tandem SH2 domains (step 8). ZAP70 subsequently undergoes phosphorylation on multiple tyrosine residues for further activation. ZAP70 includes both positive and negative regulatory sites. Tyrosine 493 is a conserved regulatory site found within the activation loop of the kinase domain. This site has shown to be a positive regulatory site required for ZAP70 kinase activity and is phosphorylated by LCK (step 9). This phosphorylation contributes to the active conformation of the catalytic domain. Later ZAP70 undergoes trans-autophosphorylation at Y315 and Y319 (step 10). These sites appear to be positive regulatory sites. ZAP70 achieves its full activation after the trans-autophosphorylation. Activated ZAP70 along with LCK phosphorylates the multiple tyrosine residues in the adaptor protein LAT (step 11). PTPN22 can dephosphorylate and inhibit ZAP70 activity to downregulate TCR signaling (step 12). Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 LEFT-TO-RIGHT Recruitment of ZAP-70 to phosphorylated ITAMs Phosphorylation of the ITAMs by Lck is followed by the recruitment of the ZAP-70 a member of Syk family PTK, to the receptor complex. ZAP-70 is exclusively expressed in T cells and NK cells. The dually phosphorylated ITAMs provide a high-affinity docking site for the tandem SH2-domains of the ZAP-70. Once recruited, ZAP-70 is activated by phosphorylation and will be responsible for the phosphorylation of further downstream molecules. Due to the presence of 10 ITAMs in the TCR complex, up to 10 ZAP-70 molecules may cluster on the fully phosphorylated receptors. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 ZAP70 ZAP-70 Tyrosine-protein kinase ZAP-70 Reactome DB_ID: 202397 UniProt:P43403 ZAP70 ZAP70 SRK FUNCTION Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates motility, adhesion and cytokine expression of mature T-cells, as well as thymocyte development. Contributes also to the development and activation of primary B-lymphocytes. When antigen presenting cells (APC) activate T-cell receptor (TCR), a serie of phosphorylations lead to the recruitment of ZAP70 to the doubly phosphorylated TCR component CD247/CD3Z through ITAM motif at the plasma membrane. This recruitment serves to localization to the stimulated TCR and to relieve its autoinhibited conformation. Release of ZAP70 active conformation is further stabilized by phosphorylation mediated by LCK. Subsequently, ZAP70 phosphorylates at least 2 essential adapter proteins: LAT and LCP2. In turn, a large number of signaling molecules are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation. Furthermore, ZAP70 controls cytoskeleton modifications, adhesion and mobility of T-lymphocytes, thus ensuring correct delivery of effectors to the APC. ZAP70 is also required for TCR-CD247/CD3Z internalization and degradation through interaction with the E3 ubiquitin-protein ligase CBL and adapter proteins SLA and SLA2. Thus, ZAP70 regulates both T-cell activation switch on and switch off by modulating TCR expression at the T-cell surface. During thymocyte development, ZAP70 promotes survival and cell-cycle progression of developing thymocytes before positive selection (when cells are still CD4/CD8 double negative). Additionally, ZAP70-dependent signaling pathway may also contribute to primary B-cells formation and activation through B-cell receptor (BCR).ACTIVITY REGULATION Activated by phosphorylation at Tyr-493 in the activation loop. Inhibited by staurosporine.SUBUNIT Interacts with CD247/CD3Z; this interaction docks ZAP70 at the stimulated TCR (PubMed:1423621, PubMed:7659156, PubMed:26783323). Interacts with NFAM1 (PubMed:15143214). Interacts with adapter protein SLA; this interaction negatively regulates T-cell receptor signaling (PubMed:10449770). Interacts with FCRL3 (PubMed:12051764, PubMed:19843936). Interacts with VAV1 (PubMed:9151714). Interacts with CBL; this interaction promotes ubiquitination, internalization and subsequent degradation of CD247/CD3Z (PubMed:10449770, PubMed:10078535). Identified in a complex with CBL and UBE2L3 (PubMed:10966114). Interacts with SHB (PubMed:12084069). Interacts with adapter protein SLA2; this interaction negatively regulates T-cell receptor signaling. Interacts with CBLB. Interacts (via SH2 domains) with RHOH; this interaction regulates ZAP70 subcellular localization. Interacts with DEF6 (By similarity). Interacts (ubiquitinated form) with OTUD7B and UBASH3B (PubMed:26903241).TISSUE SPECIFICITY Expressed in T- and natural killer cells. Also present in early thymocytes and pro/pre B-cells.DOMAIN Composed of 2 N-terminal SH2 domains and a C-terminal kinase domain. The tandem SH2 domains bind to the doubly phosphorylated tyrosine-based activation motif (ITAM) of CD247/CD3Z and the non-canonical phosphorylated tyrosine-based activation motif (TAM) of RHOH (By similarity). The interdomain B located between the second SH2 and the kinase domain contains 3 tyrosines (Tyr-292, Tyr-315, Tyr-319) that are phosphorylated following TCR activation. These sites have been implicated in binding to other signaling molecules including CBL or VAV1. Thus, ZAP70 can also function as a scaffold by recruiting additional factors to the stimulated TCR complex.PTM Phosphorylated on tyrosine residues upon T-cell antigen receptor (TCR) stimulation. Phosphorylation of Tyr-315 and Tyr-319 are essential for ZAP70 positive function on T-lymphocyte activation whereas Tyr-292 has a negative regulatory role. Within the C-terminal kinase domain, Tyr-492 and Tyr-493 are phosphorylated after TCR induction, Tyr-492 playing a negative regulatory role and Tyr-493 a positive. Tyr-493 is dephosphorylated by PTN22.PTM Ubiquitinated in response to T cell activation. Deubiquitinated by OTUD7B.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. SYK/ZAP-70 subfamily. UniProt P43403 1 EQUAL 619 EQUAL Reactome Database ID Release 78 202397 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202397 Reactome R-HSA-202397 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202397.1 ZAP-70 bound to phosphorylated ITAM motifs Reactome DB_ID: 202330 1 1 Reactome Database ID Release 78 202330 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202330 Reactome R-HSA-202330 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202330.1 Reactome Database ID Release 78 202344 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202344 Reactome R-HSA-202344 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202344.1 9850860 Pubmed 1998 The Syk family of protein tyrosine kinases in T-cell activation and development Chu, DH Morita, CT Weiss, A Immunol Rev 165:167-80 12485116 Pubmed 2003 Positive and negative regulation of T-cell activation through kinases and phosphatases Mustelin, T Tasken, K Biochem J 371:15-27 8520027 Pubmed 1995 The Syk/ZAP-70 protein tyrosine kinase connection to antigen receptor signalling processes van Oers, NS Weiss, A Semin Immunol 7:227-36 LEFT-TO-RIGHT 2.7.10 Phosphorylation of ZAP-70 by Lck In ZAP-70 there are multiple phosphorylation sites (Y292, Y315, Y319, Y492, Y493) which have both positive and negative regulatory effect on its catalytic activity. Tyrosine 493 is a conserved regulatory site found within the activation loop of the kinase domain. This site has shown to be a positive regulatory site required for ZAP-70 kinase activity and is phosphorylated by Lck. This phosphorylation contribute to the active conformation of the catalytic domain. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 phospho tyrosine ZAP-70 Reactome DB_ID: 202345 1 p-Y493-ZAP70 ZAP-70 phosphorylated at Tyr 493 Reactome DB_ID: 202368 493 EQUAL 1 EQUAL 619 EQUAL Reactome Database ID Release 78 202368 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202368 Reactome R-HSA-202368 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202368.1 1 Reactome Database ID Release 78 202345 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202345 Reactome R-HSA-202345 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202345.1 ACTIVATION Reactome Database ID Release 78 202370 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202370 Reactome Database ID Release 78 202168 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202168 Reactome R-HSA-202168 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202168.1 10202147 Pubmed 1999 Phosphorylation of Tyr319 in ZAP-70 is required for T-cell antigen receptor-dependent phospholipase C-gamma1 and Ras activation Williams, BL Irvin, BJ Sutor, SL Chini, CC Yacyshyn, E Bubeck Wardenburg, J Dalton, M Chan, AC Abraham, Robert T EMBO J 18:1832-44 LEFT-TO-RIGHT 3.1.3.48 PTPN22 dephosphorylates ZAP70 Protein tyrosine phosphatase PTPN22 (LYP, PEP) dephosphorylates ZAP70 adaptor protein on tyrosine residue Y493, resulting in reduced activation of ZAP70. Dephosphorylation of ZAP70 contributes to PTPN22-mediated downregulation of TCR signaling (Wu et al. 2006). Authored: Orlic-Milacic, Marija, 2016-02-03 Reviewed: Stanford, Stephanie, 2016-05-10 Reviewed: Bottini, Nunzio, 2016-05-10 Edited: Orlic-Milacic, Marija, 2016-02-03 ACTIVATION Reactome Database ID Release 78 8855381 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8855381 Reactome R-HSA-8855381 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8855381.2 LEFT-TO-RIGHT 2.7.10 Activation of ZAP-70 Later ZAP-70 undergoes trans-autophosphorylation at Y315 and Y319. These sites appear to be positive regulatory sites. ZAP-70 achieve its full activation after the trans-autophosphorylation. Activated ZAP-70 phosphorylates T-cell-specific adaptors, such as LAT and SLP-76 leading to the recruitment and activation of other kinase families and enzymes, resulting in secondary messenger generation and culminating in T cell activation. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Activated ZAP-70 Reactome DB_ID: 202181 1 p-Y315,Y493-ZAP70 ZAP-70 phosphotyrosine at position 315 and 493 Reactome DB_ID: 202252 315 EQUAL 1 EQUAL 619 EQUAL Reactome Database ID Release 78 202252 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202252 Reactome R-HSA-202252 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202252.1 1 Reactome Database ID Release 78 202181 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202181 Reactome R-HSA-202181 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202181.1 ACTIVATION activeUnit: #Protein56 Reactome Database ID Release 78 202191 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202191 Reactome Database ID Release 78 202174 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202174 Reactome R-HSA-202174 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202174.1 Reactome Database ID Release 78 202430 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202430 Reactome R-HSA-202430 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202430.5 Generation of second messenger molecules In addition to serving as a scaffold via auto-phosphorylation, ZAP70 also phosphorylates a restricted set of substrates following TCR stimulation - including LAT (step 13) and LCP2. These substrates have been recognized to play pivotal role in TCR signaling by releasing second messengers. When phosphorylated, LAT and SLP-76 act as adaptor proteins which serve as nucleation points for the construction of a higher order signalosome: PLC-gamma1 (step 14) and GRAP2 (step 15) bind to the LAT on the phosphorylated tyrosine residues. LCP2 is then moved to the signalosome by interacting with the SH3 domains of GRAP2 using their proline rich sequences (step 16). Once LCP2 binds to GRAP2, three LCP2 acidic domain N-term tyrosine residues are phosphorylated by ZAP70 (step 17). These phospho-tyrosine residues act as binding sites to the SH2 domains of ITK (steps 18) and PLC-gamma1 (step 19). PLC-gamma1 is activated by dual phosphorylation on the tyrosine residues at positions 771, 783 and 1254 by ITK (step 20) and ZAP70 (step 21). Phosphorylated PLC-gamma1 subsequently detaches from LAT and LCP2 and translocates to the plasma membrane by binding to phosphatidylinositol-4,5-bisphosphate (PIP2) via its PH domain (step 22). PLC-gamma1 goes on to hydrolyse PIP2 to second messengers DAG and IP3 (step 23). These second messengers are involved in PKC and NF-kB activation and calcium mobilization. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 LEFT-TO-RIGHT 2.7.10 Phosphorylation of TBSMs in LAT The adaptor molecule LAT (Linker for the Activation of T cells) is a membrane protein that links the TCR signal to the cell activation. It has a total 10 (Y36, Y45, Y64, Y110, Y156, Y161, Y200, Y220, and Y255) conserved TBSMs (tyrosine based signaling motifs) in its cytoplasmic region. These tyrosine residues are phosphorylated by the activated ZAP-70 upon TCR/CD3 complex engagement. Phosphorylation of LAT creates binding sites for the Src homology 2 (SH2) domains of other proteins, including PLC-gamma1, Grb2 and Gads, and indirectly binds SOS, Vav, SLP-76, and Itk. The residues Y200, Y220 and Y255 are responsible for Grb2 binding, Y200 and Y220 but not Y255, are necessary for Gads binding and Y161 for the PLC-gamma1 binding (numbering based on Uniprot isoform 1). Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 LAT Linker for activation of T-cells family member 1 Reactome DB_ID: 202322 UniProt:O43561 LAT LAT FUNCTION Required for TCR (T-cell antigen receptor)- and pre-TCR-mediated signaling, both in mature T-cells and during their development. Involved in FCGR3 (low affinity immunoglobulin gamma Fc region receptor III)-mediated signaling in natural killer cells and FCER1 (high affinity immunoglobulin epsilon receptor)-mediated signaling in mast cells. Couples activation of these receptors and their associated kinases with distal intracellular events such as mobilization of intracellular calcium stores, PKC activation, MAPK activation or cytoskeletal reorganization through the recruitment of PLCG1, GRB2, GRAP2, and other signaling molecules.SUBUNIT When phosphorylated, interacts directly with the PIK3R1 subunit of phosphoinositide 3-kinase and the SH2 domains of GRB2, GRAP, GRAP2, PLCG1 and PLCG2. Interacts indirectly with CBL, SOS, VAV, and LCP2. Interacts with SHB, SKAP2 and CLNK (By similarity). Interacts with FCGR1A. Interacts with GRB2, PLCG1 and THEMIS upon TCR activation in thymocytes (By similarity). Interacts with THEMIS2 (By similarity).TISSUE SPECIFICITY Expressed in thymus, T-cells, NK cells, mast cells and, at lower levels, in spleen. Present in T-cells but not B-cells (at protein level).PTM Phosphorylated on tyrosines by ZAP70 upon TCR activation, or by SYK upon other immunoreceptor activation; which leads to the recruitment of multiple signaling molecules. Is one of the most prominently tyrosine-phosphorylated proteins detected following TCR engagement. May be dephosphorylated by PTPRJ. Phosphorylated by ITK leading to the recruitment of VAV1 to LAT-containing complexes.PTM Palmitoylation of Cys-26 and Cys-29 is required for raft targeting and efficient phosphorylation.MISCELLANEOUS Engagement of killer inhibitory receptors (KIR) disrupts the interaction of PLCG1 with LAT and blocks target cell-induced activation of PLC, maybe by inducing the dephosphorylation of LAT. UniProt O43561 1 EQUAL 262 EQUAL Reactome Database ID Release 78 202322 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202322 Reactome R-HSA-202322 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202322.1 5 5 p-5Y-LAT Reactome DB_ID: 202364 161 EQUAL 200 EQUAL 220 EQUAL 255 EQUAL 156 EQUAL 1 EQUAL 262 EQUAL Reactome Database ID Release 78 202364 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202364 Reactome R-HSA-202364 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202364.1 ACTIVATION Reactome Database ID Release 78 202262 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202262 Reactome Database ID Release 78 202245 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202245 Reactome R-HSA-202245 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202245.1 14510693 Pubmed 2003 Hematopoietic adaptors in T-cell signaling: potential applications to transplantation Rudd, CE Wang, H Am J Transplant 3:1204-10 11752630 Pubmed 2000 LAT, the linker for activation of T cells: a bridge between T cell-specific and general signaling pathways Wange, RL Sci STKE 2000:RE1 10811803 Pubmed 2000 Association of Grb2, Gads, and phospholipase C-gamma 1 with phosphorylated LAT tyrosine residues. Effect of LAT tyrosine mutations on T cell angigen receptor-mediated signaling. Zhang, W Trible, RP Zhu, M Liu, SK McGlade, CJ Samelson, LE J Biol Chem 275:23355-61 LEFT-TO-RIGHT Recruitment of Gads to LAT Gads is a member of the Grb2 family containing SH2 and SH3 domains with the arrangement SH3-SH2-SH3. Gads binds to the tyrosine phosphorylated residues Y171 and Y191 of LAT through its SH2 domain. It plays a critical role in signaling from the T cell receptor by promoting the formation of a complex between SLP-76 and LAT. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 GADS GRAP2 GRB2-related adapter protein 2 Reactome DB_ID: 202367 UniProt:O75791 GRAP2 GRAP2 GADS GRB2L GRID FUNCTION Interacts with SLP-76 to regulate NF-AT activation. Binds to tyrosine-phosphorylated shc.SUBUNIT Interacts with phosphorylated LIME1 upon TCR activation (By similarity). Interacts with phosphorylated LAT and LAX1 upon TCR activation. Interacts with SHB. Interacts with PTPN23.SIMILARITY Belongs to the GRB2/sem-5/DRK family. UniProt O75791 1 EQUAL 330 EQUAL Reactome Database ID Release 78 202367 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202367 Reactome R-HSA-202367 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202367.1 GADS:p-5Y-LAT Reactome DB_ID: 202177 1 1 Reactome Database ID Release 78 202177 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202177 Reactome R-HSA-202177 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202177.1 Reactome Database ID Release 78 202325 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202325 Reactome R-HSA-202325 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202325.1 11607830 Pubmed 2001 The role of Gads in hematopoietic cell signalling Liu, SK Berry, DM McGlade, CJ Oncogene 20:6284-90 LEFT-TO-RIGHT Recruitment of SLP-76 to Gads SLP-76 is an adaptor protein that links proximal and distal T cell receptor signaling events through its function as a molecular scaffold in the assembly of multi molecular signaling complexes. SLP-76 consists of three domains that mediate interactions with many different signaling proteins: an N-terminal acidic domain containing three tyrosine phosphorylation sites, a large central proline-rich region, and a C-terminal SH2 domain. The function of SLP-76 is dependent on its association with Gads. SLP-76 constitutively binds through its 'RxxK' motif in the proline rich region to the SH3 domain of Gads upon TCR activation. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 LCP2 SLP-76 Lymphocyte cytosolic protein 2 Reactome DB_ID: 202306 UniProt:Q13094 LCP2 LCP2 FUNCTION Involved in T-cell antigen receptor mediated signaling.SUBUNIT Interacts with SLA. Interacts with CBLB (By similarity). Interacts with GRB2 (PubMed:7706237). Interacts with SHB (PubMed:12084069). Interacts with PRAM1 (PubMed:11301322). Interacts (via SH2 domain) with CD6 (via tyrosine phosphorylated C-terminus) (PubMed:16914752, PubMed:24584089). Interacts with FYB1 and the phosphorylated form of FYB2 (PubMed:27335501).TISSUE SPECIFICITY Highly expressed in spleen, thymus and peripheral blood leukocytes. Highly expressed also in T-cell and monocytic cell lines, expressed at lower level in B-cell lines. Not detected in fibroblast or neuroblastoma cell lines.DOMAIN The SH2 domain mediates interaction with phosphorylated CD6 (PubMed:16914752). The SH2 domain mediates interaction with SHB (PubMed:12084069).PTM Phosphorylated after T-cell receptor activation by ZAP70, ITK and TXK, which leads to the up-regulation of Th1 preferred cytokine IL-2. SYK-dependent phosphorylation is required for recruitment of PI3K signaling components. UniProt Q13094 1 EQUAL 533 EQUAL Reactome Database ID Release 78 202306 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202306 Reactome R-HSA-202306 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202306.1 SLP-76 bound to Gads:LAT Reactome DB_ID: 202151 1 1 Reactome Database ID Release 78 202151 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202151 Reactome R-HSA-202151 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202151.1 Reactome Database ID Release 78 202241 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202241 Reactome R-HSA-202241 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202241.1 LEFT-TO-RIGHT 2.7.10 Phosphorylation of SLP-76 Once SLP-76 is recruited to Gads its rapidly phosphorylated on the tyrosine residues in the N-terminal acidic domain. This domain contains three tyrosine phosphorylation sites, Y113, Y128 and Y145. These tyrosine residues are phosphorylated by tyrosine kinase ZAP-70 and these phosphorylated tyrosine residues provide the binding site for the SH2 domains of the incoming signaling proteins like Vav, Itk and PLC-gamma1. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 3 3 p-Y113,128,145-SLP-76:GADS:LAT Reactome DB_ID: 202162 1 p-SLP-76 p-Y113,128,145-LCP2 p-Y113,Y128,Y145-SLP-76 Lymphocyte cytosolic protein 2 Reactome DB_ID: 202175 113 EQUAL 128 EQUAL 145 EQUAL 1 EQUAL 533 EQUAL Reactome Database ID Release 78 202175 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202175 Reactome R-HSA-202175 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202175.2 1 Reactome Database ID Release 78 202162 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202162 Reactome R-HSA-202162 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202162.2 ACTIVATION activeUnit: #Protein57 Reactome Database ID Release 78 202147 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202147 Reactome Database ID Release 78 202216 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202216 Reactome R-HSA-202216 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202216.1 17652306 Pubmed 2007 Keeping the (kinase) party going: SLP-76 and ITK dance to the beat Qi, Q August, A Sci STKE 2007:pe39 LEFT-TO-RIGHT Recruitment of ITK to SLP-76 ITK is a member of the Tec protein tyrosine kinase family which forms a complex with SLP-76 after TCR activation. ITK has N-terminal pleckstrin homology (PH) domain, a Tec homology (TH) domain, a proline rich domain, a SH3 domain, an SH2 domain and a C-term kinase domain. The SH2 domain of ITK may interact with Y145 within the N-ter acidic domain of SLP-76 and the SH3 domain of the ITK binds the proline rich region of SLP-76. ITK plays an important role in phosphorylating and activating PLC-gamma-1, leading to the development of second-messenger molecules. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 ITK Tyrosine-protein kinase ITK/TSK Reactome DB_ID: 202319 UniProt:Q08881 ITK ITK EMT LYK FUNCTION Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. When antigen presenting cells (APC) activate T-cell receptor (TCR), a series of phosphorylation lead to the recruitment of ITK to the cell membrane, in the vicinity of the stimulated TCR receptor, where it is phosphorylated by LCK. Phosphorylation leads to ITK autophosphorylation and full activation. Once activated, phosphorylates PLCG1, leading to the activation of this lipase and subsequent cleavage of its substrates. In turn, the endoplasmic reticulum releases calcium in the cytoplasm and the nuclear activator of activated T-cells (NFAT) translocates into the nucleus to perform its transcriptional duty. Phosphorylates 2 essential adapter proteins: the linker for activation of T-cells/LAT protein and LCP2. Then, a large number of signaling molecules such as VAV1 are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation (PubMed:12186560, PubMed:12682224, PubMed:21725281). Required for TCR-mediated calcium response in gamma-delta T-cells, may also be involved in the modulation of the transcriptomic signature in the Vgamma2-positive subset of immature gamma-delta T-cells (By similarity). Phosphorylates TBX21 at 'Tyr-530' and mediates its interaction with GATA3 (By similarity).SUBUNIT Homooligomerizes; this association negatively regulates kinase activity (By similarity). Interacts with PPIA/CYPA; this interaction regulates TCR signal strength via a proline-directed conformational switch in ITK. Interacts with THEMIS (By similarity). Interacts with FASLG. Interacts with VAV1; this interaction is important for VAV1 localization and TCR-induced actin polarization. Interacts with TBX21 (By similarity).TISSUE SPECIFICITY T-cell lines and natural killer cell lines.INDUCTION Through a myriad of surface receptors including the TCR/CD3 signaling complex, coreceptors, or chemokine receptors.DOMAIN The N-terminal PH domain allows ITK to be recruited to the plasma membrane by an activated PI3 kinase. This domain contains also a proline-rich region (PRR). The adjoining domain is a SH3 domain, which binds to PRR (from itself or from other proteins). Next, a SH2 domain is required for binding tyrosine-phosphorylated substrates. In the C-terminal region, the kinase domain is required for tyrosine phosphorylation.PTM Phosphorylated at Tyr-512 in the activation loop of the kinase domain by LCK. Subsequent autophosphorylation at Tyr-180 leads to the kinase activation. The autophosphorylated Tyr-180 lies within the substrate binding sequence of the SH3 domain.PTM Ubiquitinated.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. TEC subfamily. UniProt Q08881 1 EQUAL 620 EQUAL Reactome Database ID Release 78 202319 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202319 Reactome R-HSA-202319 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202319.1 ITK:p-Y113,128,145-SLP-76:GADS:LAT Reactome DB_ID: 202359 1 1 Reactome Database ID Release 78 202359 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202359 Reactome R-HSA-202359 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202359.2 Reactome Database ID Release 78 202375 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202375 Reactome R-HSA-202375 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202375.1 LEFT-TO-RIGHT Recruitment of PLC-gamma1 to SLP-76 PLC-gamma1 plays an important role in transducing the external signal in to second messengers by hydrolysing PIP2. PLC-gamma1 contains an N-term PH domain, a catalytic domain 'X' followed by two SH2 domains and an SH3 domain, a C-term catalytic domain 'Y' and a C2 domain (Ca++ binding). PLC-gamma1 interacts with both SLP-76 aswell as LAT. It interacts with its SH3 domain to the proline rich sequence of SLP-76. This interaction aids in localizing PLC-gamma1 to the membrane. This recruitment of PLC-gamma1 to LAT and SLP-76 is essential for its TCR induced tyrosine phosphorylation and activation. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 PLC1 PLCG1 Phospholipase C gamma 1 PLC gamma 1 Reactome DB_ID: 202320 UniProt:P19174 PLCG1 PLCG1 PLC1 FUNCTION Mediates the production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). Plays an important role in the regulation of intracellular signaling cascades. Becomes activated in response to ligand-mediated activation of receptor-type tyrosine kinases, such as PDGFRA, PDGFRB, EGFR, FGFR1, FGFR2, FGFR3 and FGFR4 (By similarity). Plays a role in actin reorganization and cell migration (PubMed:17229814).ACTIVITY REGULATION Activated by phosphorylation on tyrosine residues.SUBUNIT Interacts with AGAP2 via its SH3 domain. Interacts (via SH2 domain) with RET. Interacts with FLT1 (tyrosine-phosphorylated) (By similarity). Interacts (via SH2 domain) with FGFR1, FGFR2, FGFR3 and FGFR4 (phosphorylated). Interacts with LAT (phosphorylated) upon TCR activation. Interacts (via SH3 domain) with the Pro-rich domain of TNK1. Associates with BLNK, VAV1, GRB2 and NCK1 in a B-cell antigen receptor-dependent fashion. Interacts with CBLB in activated T-cells; which inhibits phosphorylation. Interacts with SHB. Interacts (via SH3 domain) with the Arg/Gly-rich-flanked Pro-rich domains of KHDRBS1/SAM68. This interaction is selectively regulated by arginine methylation of KHDRBS1/SAM68. Interacts with INPP5D/SHIP1, THEMIS and CLNK (By similarity). Interacts with AXL, FLT4 and KIT. Interacts with RALGPS1. Interacts (via the SH2 domains) with VIL1 (phosphorylated at C-terminus tyrosine phosphorylation sites). Interacts (via SH2 domain) with PDGFRA and PDGFRB (tyrosine phosphorylated). Interacts with PIP5K1C (By similarity). Interacts with NTRK1 and NTRK2 (phosphorylated upon ligand-binding). Interacts with SYK; activates PLCG1. Interacts with GRB2, LAT and THEMIS upon TCR activation in thymocytes (By similarity). Interacts with TESPA1; the association is increased with prolonged stimulation of the TCR and may facilitate the assembly of the LAT signalosome.SUBUNIT (Microbial infection) Interacts (via SH3 domain) with HEV ORF3 protein.DOMAIN The SH3 domain mediates interaction with CLNK (By similarity). The SH3 domain also mediates interaction with RALGPS1 (PubMed:10747847).PTM Tyrosine phosphorylated in response to signaling via activated FLT3, KIT and PDGFRA (By similarity). Tyrosine phosphorylated by activated FGFR1, FGFR2, FGFR3 and FGFR4. Tyrosine phosphorylated by activated FLT1 and KDR. Tyrosine phosphorylated by activated PDGFRB. The receptor-mediated activation of PLCG1 involves its phosphorylation by tyrosine kinases, in response to ligation of a variety of growth factor receptors and immune system receptors. For instance, SYK phosphorylates and activates PLCG1 in response to ligation of the B-cell receptor. May be dephosphorylated by PTPRJ. Phosphorylated by ITK and TXK on Tyr-783 upon TCR activation in T-cells.PTM Ubiquitinated by CBLB in activated T-cells. UniProt P19174 2 EQUAL 1290 EQUAL Reactome Database ID Release 78 202320 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202320 Reactome R-HSA-202320 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202320.1 PLCG1:p-3Y-SLP-76:Gads:LAT Reactome DB_ID: 202279 1 1 Reactome Database ID Release 78 202279 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202279 Reactome R-HSA-202279 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202279.1 Reactome Database ID Release 78 202331 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202331 Reactome R-HSA-202331 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202331.1 11390650 Pubmed 2001 Identification of a phospholipase C-gamma1 (PLC-gamma1) SH3 domain-binding site in SLP-76 required for T-cell receptor-mediated activation of PLC-gamma1 and NFAT Yablonski, D Kadlecek, T Weiss, A Mol Cell Biol 21:4208-18 11048639 Pubmed 2000 The mechanism of phospholipase C-gamma1 regulation Kim, MJ Kim, E Ryu, SH Suh, PG Exp Mol Med 32:101-9 LEFT-TO-RIGHT Recruitment of PLC-gamma1 to LAT PLC-gamma1 interacts with its SH2 domain to the pY132 residue of LAT. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 PLCG1:p-5Y-LAT Reactome DB_ID: 202240 1 1 Reactome Database ID Release 78 202240 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202240 Reactome R-HSA-202240 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202240.1 Reactome Database ID Release 78 202212 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202212 Reactome R-HSA-202212 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202212.1 LEFT-TO-RIGHT 2.7.10 Phosphorylation of PLC-gamma1 Three tyrosine residues at positions 771, 783 and 1254 in PLC-gamma1 have been identified as the sites of receptor tyrosine kinase phosphorylation. Of these Y783 and Y1254 are required for activation of PLC-gamma1. The phosphorylation of the tyrosine residues and the activation of PLC-gamma1 is mediated by both Syk tyrosine kinase ZAP-70 and Tec kinase ITK. Immunoglobulin superfamily member 2 (IgSF2 or cell surface glycoprotein V7)ligation interferes with T cell activation and IL-2 secretion through a Ca2+ and tyrosine kinase-dependent pathway that inhibits PLC-gamma1 phosphorylation and prevents NF-AT translocation to the nucleus (Soares et al. 1998, 1997). Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 3 Converted from EntitySet in Reactome PLC-gamma1 bound to LAT or SLP-76 Reactome DB_ID: 202318 Reactome Database ID Release 78 202318 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202318 Reactome R-HSA-202318 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202318.1 3 Converted from EntitySet in Reactome Phosphorylated PLC-gamma1 bound to LAT or SLP-76 Reactome DB_ID: 202193 phosphorylated PLC-gamma1 bound to LAT Reactome DB_ID: 202310 1 Phospho-PLC gamma 1 p-Y771,Y783,Y1254-PLCG1 Phospho-Phospholipase C gamma 1 Reactome DB_ID: 202357 771 EQUAL 783 EQUAL 1253 EQUAL 2 EQUAL 1290 EQUAL Reactome Database ID Release 78 202357 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202357 Reactome R-HSA-202357 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202357.1 1 Reactome Database ID Release 78 202310 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202310 Reactome R-HSA-202310 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202310.1 phosphorylated PLC-gamma1 bound to SLP-76 Reactome DB_ID: 202302 1 1 Reactome Database ID Release 78 202302 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202302 Reactome R-HSA-202302 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202302.2 Reactome Database ID Release 78 202193 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202193 Reactome R-HSA-202193 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202193.1 ACTIVATION Converted from EntitySet in Reactome ZAP-70 and ITK tyrosine kinases Reactome DB_ID: 202282 Reactome Database ID Release 78 202282 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202282 Reactome R-HSA-202282 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202282.1 Reactome Database ID Release 78 202180 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202180 Reactome Database ID Release 78 202248 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202248 Reactome R-HSA-202248 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202248.4 9233604 Pubmed 1997 Ligation of the V7 molecule on T cells blocks anergy induction through a CD28-independent mechanism Soares, L R Rivas, A Tsavaler, L Engleman, E G J. Immunol. 159:1115-24 9647226 Pubmed 1998 V7 (CD101) ligation inhibits TCR/CD3-induced IL-2 production by blocking Ca2+ flux and nuclear factor of activated T cell nuclear translocation Soares, L R Tsavaler, L Rivas, A Engleman, E G J. Immunol. 161:209-17 INHIBITION Reactome Database ID Release 78 8866027 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8866027 Reactome R-HSA-8866027 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8866027.2 CD101 Immunoglobulin superfamily member 2 IGSF2_HUMAN Reactome DB_ID: 8866028 UniProt:Q93033 CD101 CD101 EWI101 IGSF2 V7 FUNCTION Plays a role as inhibitor of T-cells proliferation induced by CD3. Inhibits expression of IL2RA on activated T-cells and secretion of IL2. Inhibits tyrosine kinases that are required for IL2 production and cellular proliferation. Inhibits phospholipase C-gamma-1/PLCG1 phosphorylation and subsequent CD3-induced changes in intracellular free calcium. Prevents nuclear translocation of nuclear factor of activated T-cell to the nucleus. Plays a role in the inhibition of T-cell proliferation via IL10 secretion by cutaneous dendritic cells. May be a marker of CD4(+) CD56(+) leukemic tumor cells.TISSUE SPECIFICITY Expressed in lung, thymus and small intestine. Detected in cutaneous dendritic cells, activated T-cells, monocytes and granulocytes as well as with epithelial cells with dendritic morphology. Expressed in some leukemic cells, the CD4(+) CD56(+) blastic tumor cells, as well as in Langerhans cells from LCH (Langerhans cell histiocytosis) patients.PTM N-glycosylated. UniProt Q93033 21 EQUAL 1021 EQUAL Reactome Database ID Release 78 8866028 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8866028 Reactome R-HSA-8866028 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8866028.2 LEFT-TO-RIGHT Disassociation of PLC-gamma1 from LAT The activated PLC-gamma1 detaches from its substrate LAT and translocates to the membrane. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Reactome Database ID Release 78 213406 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=213406 Reactome R-HSA-213406 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-213406.1 LEFT-TO-RIGHT Disassociation of PLC-gamma1 from SLP-76 The activated PLC-gamma1 detaches from its substrate SLP-76 and translocates to the membrane. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Reactome Database ID Release 78 213407 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=213407 Reactome R-HSA-213407 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-213407.1 LEFT-TO-RIGHT Translocation of PLC-gamma1 to PIP2 Activated PLA-gamma1 translocates to the plasmamembrane and interacts with the inositol ring of the membrane bound phosphatidylinositol 4,5-bisphosphate (PIP2) with its PH domain. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 PIP2 PI(4,5)P2 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate Phosphatidylinositol-4,5-bisphosphate 1-phosphatidyl-1D-myo-inositol 4,5- bisphosphate Reactome DB_ID: 179856 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate [ChEBI:18348] 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate PIP2 ChEBI CHEBI:18348 Reactome Database ID Release 78 179856 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=179856 Reactome R-ALL-179856 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-179856.3 COMPOUND C04637 Activated PLC gamma1 bound to PIP2 Reactome DB_ID: 202269 p-PLCG1 p-4Y-PLCG1 p-Y1253,Y472,Y771,Y783-PLCG1 p-Y472,771,783,1253-PLCG1 p4Y-PLCG1 Phospho-Phospholipase C gamma 1 Phospho-PLC gamma 1 Reactome DB_ID: 167679 472 EQUAL 2 EQUAL 1290 EQUAL Reactome Database ID Release 78 167679 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=167679 Reactome R-HSA-167679 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-167679.2 1 1 Reactome Database ID Release 78 202269 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202269 Reactome R-HSA-202269 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202269.1 Reactome Database ID Release 78 202354 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202354 Reactome R-HSA-202354 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202354.1 LEFT-TO-RIGHT 3.1.4.11 PLC-gamma1 hydrolyses PIP2 On recruitment to plasma membrane PLC-gamma1 then hydrolyses PIP2 producing two second messengers, diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). IP3 induces a transient increase in intracellular free Ca++, while DAG is a direct activator of protein kinase C (PKC theta). These process have been implicated in many cellular physiological functions like cell proliferation, cell growth and differentiation. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Edited: Murillo, Julieth, 2020-02-05 IP3 I(1,4,5)P3 1D-myo-inositol 1,4,5-trisphosphate D-myo-Inositol 1,4,5-trisphosphate Inositol 1,4,5-trisphosphate phosphatidylinositol 1,4,5-trisphosphate Reactome DB_ID: 114520 1D-myo-inositol 1,4,5-trisphosphate [ChEBI:16595] 1D-myo-inositol 1,4,5-trisphosphate ChEBI CHEBI:16595 Reactome Database ID Release 78 114520 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=114520 Reactome R-ALL-114520 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-114520.3 COMPOUND C01245 DAG DAGs diacylglycerols diglyceride Reactome DB_ID: 112275 diglyceride [ChEBI:18035] diglyceride ChEBI CHEBI:18035 Reactome Database ID Release 78 112275 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=112275 Reactome R-ALL-112275 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-112275.3 COMPOUND C00165 ACTIVATION activeUnit: #Protein67 Converted from EntitySet in Reactome p-PLCG Phosphorylated Phospholipase C gamma1 and Phosphorylated Phospholipase C gamma2 Reactome DB_ID: 2029095 PLCG2 p-Y753,Y759,Y1217-PLCG2 p-Y1217,Y753,Y759-PLCG2 Phospholipase C gamma 2 phosphorylated at Tyr-753, Tyr-759, and Tyr-1217 1-phosphatidylinositol-4,5-bisphosphate phosphodiesterase gamma-2 PLCG2_HUMAN Reactome DB_ID: 984816 UniProt:P16885 PLCG2 PLCG2 FUNCTION The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes. It is a crucial enzyme in transmembrane signaling.SUBUNIT Interacts (via SH2 domain) with CSF1R (tyrosine phosphorylated). Interacts constitutively with THEMIS2.PTM Phosphorylated on tyrosine residues by CSF1R (By similarity). Phosphorylated on tyrosine residues by BTK and SYK; upon ligand-induced activation of a variety of growth factor receptors and immune system receptors. Phosphorylation leads to increased phospholipase activity. UniProt P16885 753 EQUAL 759 EQUAL 1217 EQUAL 1 EQUAL 1265 EQUAL Reactome Database ID Release 78 984816 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=984816 Reactome R-HSA-984816 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-984816.1 Reactome Database ID Release 78 2029095 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2029095 Reactome R-HSA-2029095 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2029095.1 GENE ONTOLOGY GO:0004435 Reactome Database ID Release 78 202664 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202664 Reactome Database ID Release 78 202407 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202407 Reactome R-HSA-202407 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202407.3 LEFT-TO-RIGHT p-SLP-76 binds ADAP SLP-76 inducibly-associates with ADAP (also known as FYN-binding protein or SLAP-130) a hematopoietic-specific adapter protein. ADAP has been implicated in T cell migration and rearrangement of the actin cytoskeleton. In platelets, adhesion to fibrinogen stimulates the association of SLP-76 with ADAP and VASP (Obergfell et al. 2001). ADAP knockout mice exhibit mild thrombocytopenia (Kasirer-Friede et al. 2007). Authored: Akkerman, JW, 2009-06-03 Reviewed: Poole, AW, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Harper, MT, 2009-11-02 Edited: Jupe, S, 2009-11-03 FYB ADAP FYN-binding protein SLAP-130 Reactome DB_ID: 390925 UniProt:O15117 FYB1 FYB1 FYB SLAP130 FUNCTION Acts as an adapter protein of the FYN and LCP2 signaling cascades in T-cells (By similarity). May play a role in linking T-cell signaling to remodeling of the actin cytoskeleton (PubMed:10747096, PubMed:16980616). Modulates the expression of IL2 (By similarity). Involved in platelet activation (By similarity). Prevents the degradation of SKAP1 and SKAP2 (PubMed:15849195). May be involved in high affinity immunoglobulin epsilon receptor signaling in mast cells (By similarity).SUBUNIT Part of a complex consisting of SKAP2, FYB1 and PTPNS1 (By similarity). Part of a complex consisting of SKAP2, FYB1 and LILRB3 (By similarity). Part of a complex consisting of SKAP1, FYB1 and CLNK (By similarity). Interacts with CLNK (via its SH2 domain); this interaction allows SKAP1 and FYB1 to recruit FYN to the complex, thus promoting the phosphorylation of CLNK by FYN (By similarity). Interacts with FYN (PubMed:9207119, PubMed:15849195, PubMed:27335501). Interacts with LCP2 (PubMed:9207119, PubMed:27335501). Interacts with SKAP1 (PubMed:9755858, PubMed:9748251, PubMed:9671755, PubMed:10856234, PubMed:15849195, PubMed:16461356, PubMed:27335501). Interacts with SKAP2 (PubMed:9755858, PubMed:9671755, PubMed:10942756). Interacts with FASLG (PubMed:19807924). Interacts with EVL (PubMed:10747096). Interacts with TMEM47 (By similarity). Interacts with LCK (PubMed:27335501).TISSUE SPECIFICITY Expressed in hematopoietic tissues such as myeloid and T-cells, spleen and thymus. Not expressed in B-cells, nor in non-lymphoid tissues.PTM T-cell receptor ligation leads to increased tyrosine phosphorylation. UniProt O15117 2 EQUAL 783 EQUAL Reactome Database ID Release 78 390925 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=390925 Reactome R-HSA-390925 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-390925.1 p-SLP-76:ADAP Reactome DB_ID: 430124 1 1 Reactome Database ID Release 78 430124 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=430124 Reactome R-HSA-430124 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-430124.1 Reactome Database ID Release 78 430135 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=430135 Reactome R-HSA-430135 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-430135.1 11113155 Pubmed 2001 The molecular adapter SLP-76 relays signals from platelet integrin alphaIIbbeta3 to the actin cytoskeleton Obergfell, A Judd, BA del Pozo, MA Schwartz, MA Koretzky, GA Shattil, Sanford J J Biol Chem 276:5916-23 17003372 Pubmed 2007 ADAP is required for normal alphaIIbbeta3 activation by VWF/GP Ib-IX-V and other agonists Kasirer-Friede, A Moran, B Nagrampa-Orje, J Swanson, K Ruggeri, ZM Schraven, B Neel, BG Koretzky, G Shattil, Sanford J Blood 109:1018-25 10747096 Pubmed 2000 Fyn-binding protein (Fyb)/SLP-76-associated protein (SLAP), Ena/vasodilator-stimulated phosphoprotein (VASP) proteins and the Arp2/3 complex link T cell receptor (TCR) signaling to the actin cytoskeleton Krause, M Sechi, AS Konradt, M Monner, D Gertler, FB Wehland, J J Cell Biol 149:181-94 9115214 Pubmed 1997 Molecular cloning of SLAP-130, an SLP-76-associated substrate of the T cell antigen receptor-stimulated protein tyrosine kinases Musci, MA Hendricks-Taylor, LR Motto, DG Paskind, M Kamens, J Turck, CW Koretzky, GA J Biol Chem 272:11674-7 10671560 Pubmed 2000 Functional association between SLAP-130 and SLP-76 in Jurkat T cells Boerth, NJ Judd, BA Koretzky, GA J Biol Chem 275:5143-52 11567141 Pubmed 2001 Coupling of the TCR to integrin activation by Slap-130/Fyb Peterson, EJ Woods, ML Dmowski, SA Derimanov, G Jordan, MS Wu, JN Myung, PS Liu, QH Pribila, JT Freedman, BD Shimizu, Y Koretzky, GA Science 293:2263-5 LEFT-TO-RIGHT p-SLP-76:ADAP binds Ena/VASP ADAP (FYB) is an adaptor protein containing multiple binding motifs including an enabled protein vasodilator-stimulated phosphoprotein homology domain 1 (EVH1)-binding domain. This domain binds Ena-VASP family proteins that regulate actin dynamics. The Ena-VASP family member EVL is found in regions of dynamic actin polymerization, such as F-actin rich patches and the distal tips of microspikes. Authored: Akkerman, JW, 2009-06-03 Reviewed: Poole, AW, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Harper, MT, 2009-11-02 Edited: Jupe, S, 2009-11-03 Converted from EntitySet in Reactome Ena/VASP proteins Reactome DB_ID: 430213 ENAH Protein enabled homolog ENAH_HUMAN Reactome DB_ID: 426406 UniProt:Q8N8S7 ENAH ENAH MENA FUNCTION Ena/VASP proteins are actin-associated proteins involved in a range of processes dependent on cytoskeleton remodeling and cell polarity such as axon guidance and lamellipodial and filopodial dynamics in migrating cells. ENAH induces the formation of F-actin rich outgrowths in fibroblasts. Acts synergistically with BAIAP2-alpha and downstream of NTN1 to promote filipodia formation (By similarity).SUBUNIT Homotetramer (By similarity). Interacts with APBB1IP, APBB1, PFN1 and ROBO4 (PubMed:12941633, PubMed:15469846, PubMed:17686488). Isoforms, containing the polyproline-rich regions with PPLP motifs, bind the WW domain of APBB1IP (PubMed:15469846). Isoforms, containing the PPSY motif, bind, in vitro, to the WW2 and WW3 domains of NEDD4 and to the WW1 domain of YAP1 (By similarity). Binds the SH3 domain of BAIAP2-alpha but only after the autoinhibitory region of BAIAP2-alpha has been blocked by interaction with CDC42 (PubMed:11696321, PubMed:18158903). Interacts, via the EVH1/WH1 domain, with the Pro-rich domains from VCL, ZYX and Listeria monocytogenes actA and with TES (via LIM domains) (PubMed:9312002, PubMed:18158903, PubMed:21278383). The TES LIM domain and the Pro-rich domains from VCL or ZYX compete for the same binding site (PubMed:9312002). Interaction with ZYX is important for targeting ENAH to focal adhesions and enhances production of actin-rich structures at the apical surface of cells (PubMed:10801818). Interacts, through the Pro-rich region, with the C-terminal SH3 domain of DNMPB (By similarity). Binds GPHN (By similarity). Interacts with FAT1 (via EVH1 domains) (By similarity). Heterotrimer with TES and ACTL7A (PubMed:21278383). Interacts with PRPF40A (By similarity).TISSUE SPECIFICITY Expressed in myoepithelia of parotid, breast, bronchial glands and sweat glands. Expressed in colon-rectum muscolaris mucosae epithelium, pancreas acinar ductal epithelium, endometrium epithelium, prostate fibromuscolar stroma and placenta vascular media. Overexpressed in a majority of breast cancer cell lines and primary breast tumor lesions.DOMAIN The EVH2 domain is comprised of 3 regions. Block A is a thymosin-like domain required for G-actin binding. The KLKR motif within this block is essential for the G-actin binding and for actin polymerization. Block B is required for F-actin binding and subcellular location, and Block C for tetramerization.PTM NTN1-induced PKA phosphorylation on Ser-265 directly parallels the formation of filopodial protrusions.MISCELLANEOUS Required to transform actin polymerization into active movement for the propulsive force of Listeria monocytogenes.SIMILARITY Belongs to the Ena/VASP family. UniProt Q8N8S7 1 EQUAL 591 EQUAL Reactome Database ID Release 78 426406 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=426406 Reactome R-HSA-426406 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-426406.1 VASP Vasodilator-stimulated phosphoprotein VASP_HUMAN Reactome DB_ID: 426404 UniProt:P50552 VASP VASP FUNCTION Ena/VASP proteins are actin-associated proteins involved in a range of processes dependent on cytoskeleton remodeling and cell polarity such as axon guidance, lamellipodial and filopodial dynamics, platelet activation and cell migration. VASP promotes actin filament elongation. It protects the barbed end of growing actin filaments against capping and increases the rate of actin polymerization in the presence of capping protein. VASP stimulates actin filament elongation by promoting the transfer of profilin-bound actin monomers onto the barbed end of growing actin filaments. Plays a role in actin-based mobility of Listeria monocytogenes in host cells. Regulates actin dynamics in platelets and plays an important role in regulating platelet aggregation.SUBUNIT Homotetramer. Interacts with PFN1, PFN2, LPP, ACTN1 and ACTG1. Interacts, via the EVH1 domain, with the Pro-rich regions of ZYX. This interaction is important for targeting to focal adhesions and the formation of actin-rich structures at the apical surface of cells. Interacts, via the EVH1 domain, with the Pro-rich domain of Listeria monocytogenes actA. Interacts with APBB1IP. Interacts, via the Pro-rich domain, with the C-terminal SH3 domain of DNMBP (By similarity). Interacts weakly with MEFV.TISSUE SPECIFICITY Highly expressed in platelets.DOMAIN The EVH2 domain is comprised of 3 regions. Block A is a thymosin-like domain required for G-actin binding. The KLKR motif within this block is essential for the G-actin binding and for actin polymerization. Block B is required for F-actin binding and subcellular location, and Block C for tetramerization.DOMAIN The WH1 domain mediates interaction with XIRP1.PTM Major substrate for cAMP-dependent (PKA) and cGMP-dependent protein kinase (PKG) in platelets. The preferred site for PKA is Ser-157, the preferred site for PKG/PRKG1, Ser-239. In ADP-activated platelets, phosphorylation by PKA or PKG on Ser-157 leads to fibrinogen receptor inhibition. Phosphorylation on Thr-278 requires prior phosphorylation on Ser-157 and Ser-239. In response to phorbol ester (PMA) stimulation, phosphorylated by PKC/PRKCA. In response to thrombin, phosphorylated by both PKC and ROCK1. Phosphorylation at Thr-278 by AMPK does not require prior phosphorylation at Ser-157 or Ser-239. Phosphorylation at Ser-157 by PKA is required for localization to the tight junctions in epithelial cells. Phosphorylation modulates F-actin binding, actin filament elongation and platelet activation. Phosphorylation at Ser-322 by AMPK also alters actin filament binding. Carbon monoxide (CO) promotes phosphorylation at Ser-157, while nitric oxide (NO) promotes phosphorylation at Ser-157, but also at Ser-239. Response to NO and CO is blunted in platelets from diabetic patients, and VASP is not phosphorylated efficiently at Ser-157 and Ser-239.MISCELLANEOUS VASP phosphorylation is used to monitor the effect of so-called antiplatelet drugs that reduce platelet reactivity and are used to prevent stent thrombosis, strokes and heart attacks in patients at risk for these problems.SIMILARITY Belongs to the Ena/VASP family. UniProt P50552 2 EQUAL 380 EQUAL Reactome Database ID Release 78 426404 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=426404 Reactome R-HSA-426404 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-426404.1 EVL Ena/VASP-like protein EVL_HUMAN Reactome DB_ID: 426403 UniProt:Q9UI08 EVL EVL RNB6 FUNCTION Ena/VASP proteins are actin-associated proteins involved in a range of processes dependent on cytoskeleton remodeling and cell polarity such as axon guidance and lamellipodial and filopodial dynamics in migrating cells. EVL enhances actin nucleation and polymerization.SUBUNIT Homotetramer (By similarity). Binds to the SH3 domains of ABL1, LYN and SRC. Also binds to profilin, with preference for isoform IIa of PFN2, and the WW domain of APBB1/FE65. Binds to SEMA6A. Interacts, via the Pro-rich region, with the C-terminal SH3 domain of DNMBP. Interacts with RAPH1. Binds, via the EVH1 domain, the Pro-rich domain of Listeria monocytogenes actA (By similarity). Binds, via the EVH1 domain, the Pro-rich domain of ZYX. Interacts with FYB1 (PubMed:10747096). Interacts with ZDHHC17 (PubMed:28882895).DOMAIN The EVH2 domain is comprised of 3 regions. Block A is a thymosin-like domain required for G-actin binding. The KLKR motif within this block is essential for the G-actin binding and for actin polymerization. Block B is required for F-actin binding and subcellular location, and Block C for tetramerization.PTM Phosphorylated by PKA; phosphorylation abolishes binding to SH3 domains of ABL and SRC.MISCELLANEOUS Required to transform actin polymerization into active movement for the propulsive force of Listeria monocytogenes.SIMILARITY Belongs to the Ena/VASP family. UniProt Q9UI08 1 EQUAL 416 EQUAL Reactome Database ID Release 78 426403 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=426403 Reactome R-HSA-426403 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-426403.1 Reactome Database ID Release 78 430213 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=430213 Reactome R-HSA-430213 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-430213.1 p-SLP-76:ADAP:Ena/VASP Reactome DB_ID: 430206 1 1 Reactome Database ID Release 78 430206 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=430206 Reactome R-HSA-430206 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-430206.1 Reactome Database ID Release 78 430201 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=430201 Reactome R-HSA-430201 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-430201.1 11943877 Pubmed 2002 ADAP-ting TCR signaling to integrins Griffiths, EK Penninger, JM Sci STKE 2002:RE3 LEFT-TO-RIGHT p-SLP-76 binds NCK SLP-76 interacts with the adaptor protein NCK1. This interaction involved the SH2 domain of NCK1, leaving 3 three SH3 domains free to interact with other proteins, notably PAK1, N-WASP and Sos. Authored: Akkerman, JW, 2009-06-03 Reviewed: Poole, AW, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Harper, MT, 2009-11-02 Edited: Jupe, S, 2009-11-03 NCK1 Cytoplasmic protein NCK1 NCK1_HUMAN Reactome DB_ID: 197954 UniProt:P16333 NCK1 NCK1 NCK FUNCTION Adapter protein which associates with tyrosine-phosphorylated growth factor receptors, such as KDR and PDGFRB, or their cellular substrates. Maintains low levels of EIF2S1 phosphorylation by promoting its dephosphorylation by PP1. Plays a role in the DNA damage response, not in the detection of the damage by ATM/ATR, but for efficient activation of downstream effectors, such as that of CHEK2. Plays a role in ELK1-dependent transcriptional activation in response to activated Ras signaling. Modulates the activation of EIF2AK2/PKR by dsRNA. May play a role in cell adhesion and migration through interaction with ephrin receptors.SUBUNIT Interacts (via SH2 domain and SH3 domain 2) with EGFR. Interacts with PAK1 and SOS1. Interacts (via SH3 domains) with PKN2. Associates with BLNK, PLCG1, VAV1 and NCK1 in a B-cell antigen receptor-dependent fashion. Interacts with SOCS7. This interaction is required for nuclear import. Part of a complex containing PPP1R15B, PP1 and NCK1. Interacts with RALGPS1. Interacts with CAV2 (tyrosine phosphorylated form). Interacts with ADAM15. Interacts with FASLG. Directly interacts with RASA1. Interacts with isoform 4 of MINK1. Interacts with FLT1 (tyrosine phosphorylated). Interacts with KDR (tyrosine phosphorylated). Interacts (via SH2 domain) with EPHB1; activates the JUN cascade to regulate cell adhesion. Interacts with EPHA2. Interacts (via SH2 domain) with PDGFRB (tyrosine phosphorylated). Interacts with the inactive form of EIF2AK2/PKR.DOMAIN Only the first and third SH3 domains seem to be involved in RASA1-binding; the second SH3 domain and the SH2 domains do not seem to be involved.PTM Phosphorylated on Ser and Tyr residues. Phosphorylated in response to activation of EGFR and FcERI. Phosphorylated by activated PDGFRB. UniProt P16333 1 EQUAL 377 EQUAL Reactome Database ID Release 78 197954 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=197954 Reactome R-HSA-197954 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-197954.1 p-SLP-76:NCK1 Reactome DB_ID: 430188 1 1 Reactome Database ID Release 78 430188 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=430188 Reactome R-HSA-430188 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-430188.1 Reactome Database ID Release 78 430190 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=430190 Reactome R-HSA-430190 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-430190.1 9846482 Pubmed 1998 Regulation of PAK activation and the T cell cytoskeleton by the linker protein SLP-76 Bubeck Wardenburg, J Pappu, R Bu, JY Mayer, B Chernoff, J Straus, D Chan, AC Immunity 9:607-16 LEFT-TO-RIGHT NCK binds PAK NCK binds to PAK through its second SH3 domain. PAK interacts with NCK via the amino terminal SH3 binding domain. This interaction leads to the phosphorylation of NCK at multiple sites. Authored: Akkerman, JW, 2009-06-03 Reviewed: Poole, AW, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Harper, MT, 2009-11-02 Edited: Jupe, S, 2009-11-03 Converted from EntitySet in Reactome PAK1,2,3 Reactome DB_ID: 390765 PAK1 p21-activated kinase Reactome DB_ID: 162629 UniProt:Q13153 PAK1 PAK1 FUNCTION Protein kinase involved in intracellular signaling pathways downstream of integrins and receptor-type kinases that plays an important role in cytoskeleton dynamics, in cell adhesion, migration, proliferation, apoptosis, mitosis, and in vesicle-mediated transport processes (PubMed:11896197, PubMed:30290153). Can directly phosphorylate BAD and protects cells against apoptosis. Activated by interaction with CDC42 and RAC1. Functions as GTPase effector that links the Rho-related GTPases CDC42 and RAC1 to the JNK MAP kinase pathway. Phosphorylates and activates MAP2K1, and thereby mediates activation of downstream MAP kinases. Involved in the reorganization of the actin cytoskeleton, actin stress fibers and of focal adhesion complexes. Phosphorylates the tubulin chaperone TBCB and thereby plays a role in the regulation of microtubule biogenesis and organization of the tubulin cytoskeleton. Plays a role in the regulation of insulin secretion in response to elevated glucose levels. Part of a ternary complex that contains PAK1, DVL1 and MUSK that is important for MUSK-dependent regulation of AChR clustering during the formation of the neuromuscular junction (NMJ). Activity is inhibited in cells undergoing apoptosis, potentially due to binding of CDC2L1 and CDC2L2. Phosphorylates MYL9/MLC2. Phosphorylates RAF1 at 'Ser-338' and 'Ser-339' resulting in: activation of RAF1, stimulation of RAF1 translocation to mitochondria, phosphorylation of BAD by RAF1, and RAF1 binding to BCL2. Phosphorylates SNAI1 at 'Ser-246' promoting its transcriptional repressor activity by increasing its accumulation in the nucleus. In podocytes, promotes NR3C2 nuclear localization. Required for atypical chemokine receptor ACKR2-induced phosphorylation of LIMK1 and cofilin (CFL1) and for the up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. In synapses, seems to mediate the regulation of F-actin cluster formation performed by SHANK3, maybe through CFL1 phosphorylation and inactivation. Plays a role in RUFY3-mediated facilitating gastric cancer cells migration and invasion (PubMed:25766321). In response to DNA damage, phosphorylates MORC2 which activates its ATPase activity and facilitates chromatin remodeling (PubMed:23260667). In neurons, plays a crucial role in regulating GABA(A) receptor synaptic stability and hence GABAergic inhibitory synaptic transmission through its role in F-actin stabilization (By similarity). In hippocampal neurons, necessary for the formation of dendritic spines and excitatory synapses; this function is dependent on kinase activity and may be exerted by the regulation of actomyosin contractility through the phosphorylation of myosin II regulatory light chain (MLC) (By similarity). Along with GIT1, positively regulates microtubule nucleation during interphase (PubMed:27012601).ACTIVITY REGULATION Phosphorylation of Thr-84 by OXSR1 inhibits activation (By similarity). Activated by binding small G proteins. Binding of GTP-bound CDC42 or RAC1 to the autoregulatory region releases monomers from the autoinhibited dimer, and enables activation by phosphorylation of Thr-423.SUBUNIT Homodimer; homodimerization results in autoinhibition (PubMed:30290153). Active as monomer. Interacts with GIT1 (PubMed:27012601). Component of cytoplasmic complexes, which also contains PXN, ARHGEF7 and GIT1. Interacts with NISCH (By similarity). Interacts with DVL1; mediates the formation of a DVL1, MUSK and PAK1 ternary complex involved in AChR clustering (By similarity). Binds to the caspase-cleaved p110 isoform of CDC2L1 and CDC2L2, p110C, but not the full-length proteins (PubMed:12624090). Interacts with ARHGEF7 (PubMed:27012601, PubMed:16101281). Interacts tightly with GTP-bound but not GDP-bound CDC42/P21 and RAC1 (By similarity). Probably found in a ternary complex composed of DSCAM, PAK1 and RAC1. Interacts with DSCAM (via cytoplasmic domain); the interaction is direct and enhanced in presence of RAC1 (PubMed:15169762). Interacts with SCRIB (PubMed:18716323). Interacts with PDPK1 (PubMed:10995762). Interacts (via kinase domain) with RAF1 (PubMed:11733498). Interacts with NCK1 and NCK2 (PubMed:10026169). Interacts with TBCB (PubMed:15831477). Interacts with CRIPAK (PubMed:16278681). Interacts with BRSK2 (By similarity). Interacts with SNAI1 (PubMed:15833848). Interacts with CIB1 isoform 2 (PubMed:23503467). Interacts with CIB1 (via N-terminal region); the interaction is direct, promotes PAK1 activity and occurs in a calcium-dependent manner. Interacts with INPP5K (PubMed:26940976). Interacts with gamma-tubulin (PubMed:27012601).TISSUE SPECIFICITY Overexpressed in gastric cancer cells and tissues (at protein level) (PubMed:25766321).PTM Autophosphorylated in trans, meaning that in a dimer, one kinase molecule phosphorylates the other one. Activated by autophosphorylation at Thr-423 in response to a conformation change, triggered by interaction with GTP-bound CDC42 or RAC1. Activated by phosphorylation at Thr-423 by BRSK2 and by PDPK1. Phosphorylated by JAK2 in response to PRL; this increases PAK1 kinase activity. Phosphorylated at Ser-21 by PKB/AKT; this reduces interaction with NCK1 and association with focal adhesion sites. Upon DNA damage, phosphorylated at Thr-212 and translocates to the nucleoplasm (PubMed:23260667). Phosphorylated at tyrosine residues, which can be enhanced by NTN1 (By similarity).SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. STE20 subfamily. UniProt Q13153 1 EQUAL 545 EQUAL Reactome Database ID Release 78 162629 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=162629 Reactome R-HSA-162629 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-162629.1 PAK2 Reactome DB_ID: 211604 UniProt:Q13177 PAK2 PAK2 FUNCTION Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell motility, cell cycle progression, apoptosis or proliferation. Acts as downstream effector of the small GTPases CDC42 and RAC1. Activation by the binding of active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues. Full-length PAK2 stimulates cell survival and cell growth. Phosphorylates MAPK4 and MAPK6 and activates the downstream target MAPKAPK5, a regulator of F-actin polymerization and cell migration. Phosphorylates JUN and plays an important role in EGF-induced cell proliferation. Phosphorylates many other substrates including histone H4 to promote assembly of H3.3 and H4 into nucleosomes, BAD, ribosomal protein S6, or MBP. Additionally, associates with ARHGEF7 and GIT1 to perform kinase-independent functions such as spindle orientation control during mitosis. On the other hand, apoptotic stimuli such as DNA damage lead to caspase-mediated cleavage of PAK2, generating PAK-2p34, an active p34 fragment that translocates to the nucleus and promotes cellular apoptosis involving the JNK signaling pathway. Caspase-activated PAK2 phosphorylates MKNK1 and reduces cellular translation.ACTIVITY REGULATION Activated by binding small G proteins. Binding of GTP-bound CDC42 or RAC1 to the autoregulatory region releases monomers from the autoinhibited dimer, enables phosphorylation of Thr-402 and allows the kinase domain to adopt an active structure (By similarity). Following caspase cleavage, autophosphorylated PAK-2p34 is constitutively active.SUBUNIT Interacts tightly with GTP-bound but not GDP-bound CDC42/p21 and RAC1. Interacts with SH3MD4. Interacts with SCRIB. Interacts with ARHGEF7 and GIT1. PAK-2p34 interacts with ARHGAP10 (PubMed:15471851, PubMed:16374509, PubMed:18716323, PubMed:19273597). Interacts with RAC1 (PubMed:20696164).SUBUNIT (Microbial infection) Interacts with and activated by HIV-1 Nef.TISSUE SPECIFICITY Ubiquitously expressed. Higher levels seen in skeletal muscle, ovary, thymus and spleen.PTM Full-length PAK2 is autophosphorylated when activated by CDC42/p21. Following cleavage, both peptides, PAK-2p27 and PAK-2p34, become highly autophosphorylated, with PAK-2p27 being phosphorylated on serine and PAK-2p34 on threonine residues, respectively. Autophosphorylation of PAK-2p27 can occur in the absence of any effectors and is dependent on phosphorylation of Thr-402, because PAK-2p27 is acting as an exogenous substrate.PTM During apoptosis proteolytically cleaved by caspase-3 or caspase-3-like proteases to yield active PAK-2p34.PTM Ubiquitinated, leading to its proteasomal degradation.PTM PAK-2p34 is myristoylated.SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. STE20 subfamily. UniProt Q13177 2 EQUAL 524 EQUAL Reactome Database ID Release 78 211604 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=211604 Reactome R-HSA-211604 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-211604.1 PAK3 Serine/threonine-protein kinase PAK 3 PAK3_HUMAN Reactome DB_ID: 428457 UniProt:O75914 PAK3 PAK3 OPHN3 FUNCTION Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell migration, or cell cycle regulation. Plays a role in dendrite spine morphogenesis as well as synapse formation and plasticity. Acts as downstream effector of the small GTPases CDC42 and RAC1. Activation by the binding of active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues. Phosphorylates MAPK4 and MAPK6 and activates the downstream target MAPKAPK5, a regulator of F-actin polymerization and cell migration. Additionally, phosphorylates TNNI3/troponin I to modulate calcium sensitivity and relaxation kinetics of thin myofilaments. May also be involved in early neuronal development. In hippocampal neurons, necessary for the formation of dendritic spines and excitatory synapses; this function is dependent on kinase activity and may be exerted by the regulation of actomyosin contractility through the phosphorylation of myosin II regulatory light chain (MLC) (By similarity).ACTIVITY REGULATION Activated by binding small G proteins. Binding of GTP-bound CDC42 or RAC1 to the autoregulatory region releases monomers from the autoinhibited dimer, enables phosphorylation of Thr-436 and allows the kinase domain to adopt an active structure (By similarity).SUBUNIT Interacts tightly with GTP-bound but not GDP-bound CDC42/p21 and RAC1. Shows highly specific binding to the SH3 domains of phospholipase C-gamma and of adapter protein NCK. Interacts with the C-terminal of APP (By similarity). Interacts with ARHGEF6 and ARHGEF7. Interacts with GIT1 and GIT2 (PubMed:10896954).TISSUE SPECIFICITY Restricted to the nervous system. Highly expressed in postmitotic neurons of the developing and postnatal cerebral cortex and hippocampus.PTM Autophosphorylated when activated by CDC42/p21.PTM Neddylated.SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. STE20 subfamily. UniProt O75914 1 EQUAL 559 EQUAL Reactome Database ID Release 78 428457 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428457 Reactome R-HSA-428457 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428457.1 Reactome Database ID Release 78 390765 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=390765 Reactome R-HSA-390765 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-390765.1 p-SLP-76:NCK:PAK Reactome DB_ID: 430189 1 1 Reactome Database ID Release 78 430189 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=430189 Reactome R-HSA-430189 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-430189.1 Reactome Database ID Release 78 430183 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=430183 Reactome R-HSA-430183 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-430183.1 8824201 Pubmed 1996 Interaction of the Nck adapter protein with p21-activated kinase (PAK1) Bokoch, GM Wang, Y Bohl, BP Sells, MA Quilliam, LA Knaus, UG J Biol Chem 271:25746-9 8798379 Pubmed 1996 The adaptor protein Nck links receptor tyrosine kinases with the serine-threonine kinase Pak1 Galisteo, ML Chernoff, J Su, YC Skolnik, EY Schlessinger, J J Biol Chem 271:20997-1000 LEFT-TO-RIGHT NCK recruits WASP The second SH3 domain of NCK interacts with the carboxy-terminal SH3 domain of WASP. WASP family proteins bind the Arp2/3 complex, stimulating its ability to nucleate actin filaments and induce filament branching. Authored: Akkerman, JW, 2009-06-03 Reviewed: Poole, AW, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Harper, MT, 2009-11-02 Edited: Jupe, S, 2009-11-03 WAS WASP Reactome DB_ID: 201879 UniProt:P42768 WAS WAS IMD2 FUNCTION Effector protein for Rho-type GTPases that regulates actin filament reorganization via its interaction with the Arp2/3 complex (PubMed:12235133, PubMed:12769847, PubMed:16275905). Important for efficient actin polymerization (PubMed:8625410, PubMed:12235133, PubMed:16275905). Possible regulator of lymphocyte and platelet function (PubMed:9405671). Mediates actin filament reorganization and the formation of actin pedestals upon infection by pathogenic bacteria (PubMed:18650809). In addition to its role in the cytoplasmic cytoskeleton, also promotes actin polymerization in the nucleus, thereby regulating gene transcription and repair of damaged DNA (PubMed:20574068). Promotes homologous recombination (HR) repair in response to DNA damage by promoting nuclear actin polymerization, leading to drive motility of double-strand breaks (DSBs) (PubMed:29925947).SUBUNIT Binds the Arp2/3 complex (PubMed:12769847). Interacts with CDC42, RAC, NCK, HCK, FYN, SRC kinase FGR, BTK, ABL1, PSTPIP1, WIP, and to the p85 subunit of PLC-gamma (PubMed:8643625, PubMed:9405671, PubMed:12235133, PubMed:10360578, PubMed:15235593). Interacts (via C-terminus) with ALDOA (PubMed:17329259). Interacts with NCK1 (via SH3 domains) (By similarity). Interacts with FCHSD2 (By similarity).SUBUNIT (Microbial infection) Interacts with E.coli effector protein EspF(U).TISSUE SPECIFICITY Expressed predominantly in the thymus. Also found, to a much lesser extent, in the spleen.DOMAIN The WH1 (Wasp homology 1) domain may bind a Pro-rich ligand.DOMAIN The CRIB (Cdc42/Rac-interactive-binding) region binds to the C-terminal WH2 domain in the autoinhibited state of the protein. Binding of Rho-type GTPases to the CRIB induces a conformation change and leads to activation.PTM Phosphorylated at Tyr-291 by FYN and HCK, inducing WAS effector activity after TCR engagement. Phosphorylation at Tyr-291 enhances WAS activity in promoting actin polymerization and filopodia formation. UniProt P42768 2 EQUAL 502 EQUAL Reactome Database ID Release 78 201879 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=201879 Reactome R-HSA-201879 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-201879.1 p-SLP-76:NCK1:WASP Reactome DB_ID: 430186 1 1 Reactome Database ID Release 78 430186 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=430186 Reactome R-HSA-430186 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-430186.1 Reactome Database ID Release 78 430180 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=430180 Reactome R-HSA-430180 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-430180.1 7565724 Pubmed 1995 Wiskott-Aldrich syndrome protein physically associates with Nck through Src homology 3 domains Rivero-Lezcano, OM Marcilla, A Sameshima, JH Robbins, KC Mol Cell Biol 15:5725-31 10679362 Pubmed 2000 How WASP-family proteins and the Arp2/3 complex convert intracellular signals into cytoskeletal structures Mullins, RD Curr Opin Cell Biol 12:91-6 Reactome Database ID Release 78 202433 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202433 Reactome R-HSA-202433 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202433.3 Downstream TCR signaling Changes in gene expression are required for the T cell to gain full proliferative competence and to produce effector cytokines. Three transcription factors in particular have been found to play a key role in TCR-stimulated changes in gene expression, namely NFkappaB, NFAT and AP-1. A key step in NFkappaB activation is the stimulation and translocation of PRKCQ. The critical element that effects PRKCQ activation is PI3K. PI3K translocates to the plasma membrane by interacting with phospho-tyrosines on CD28 via its two SH2 domains located in p85 subunit (step 24). The p110 subunit of PI3K phosphorylates the inositol ring of PIP2 to generate PIP3 (steps 25). The reverse dephosphorylation process from PIP3 to PIP2 is catalysed by PTEN (step 27). PIP3 may also be dephosphorylated by the phosphatase SHIP to generate PI-3,4-P2 (step 26). PIP3 and PI-3,4-P2 acts as binding sites to the PH domain of PDK1 (step 28) and AKT (step 29). PKB is activated in response to PI3K stimulation by PDK1 (step 30). PDK1 has an essential role in regulating the activation of PRKCQ and recruitment of CBM complex to the immune synapse. PRKCQ is a member of novel class (DAG dependent, Ca++ independent) of PKC and the only member known to translocate to this synapse. Prior to TCR stimulation PRKCQ exists in an inactive closed conformation. TCR signals stimulate PRKCQ (step 31) and release DAG molecules. Subsequently, DAG binds to PRKCQ via the C1 domain and undergoes phosphorylation on tyrosine 90 by LCK to attain an open conformation (step 32). PRKCQ is further phosphorylated by PDK1 on threonine 538 (step 33). This step is critical for PKC activity. CARMA1 translocates to the plasma membrane following the interaction of its SH3 domain with the 'PxxP' motif on PDK1 (step 34). CARMA1 is phosphorylated by PKC-theta on residue S552 (step 35), leading to the oligomerization of CARMA1. This complex acts as a scaffold, recruiting BCL10 to the synapse by interacting with their CARD domains (step 36). BCL10 undergoes phosphorylation mediated by the enzyme RIP2 (step 37). Activated BCL10 then mediates the ubiquitination of IKBKG by recruiting MALT1 and TRAF6. MALT1 binds to BCL10 with its Ig-like domains and undergoes oligomerization (step 38). TRAF6 binds to the oligomerized MALT1 and also undergoes oligomerization (step 39). Oligomerized TRAF6 acts as a ubiquitin-protein ligase, catalyzing auto-K63-linked polyubiquitination (step 40). This K-63 ubiquitinated TRAF6 activates MAP3K7 kinase bound to TAB2 (step 41) and also ubiquitinates IKBKG in the IKK complex (step 44). MAP3K7 undergoes autophosphorylation on residues T184 and T187 and gets activated (step 42). Activated MAP3K7 kinase phosphorylates IKBKB on residues S177 and S181 in the activation loop and activates the IKK kinase activity (step 43). IKBKB phosphorylates the NFKBIA bound to the NFkappaB heterodimer, on residues S19 and S23 (step 45) and directs NFKBIA to 26S proteasome degradation (step 47). The NFkappaB heterodimer with a free NTS sequence finally migrates to the nucleus to regulate gene transcription (step 46). Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 LEFT-TO-RIGHT Recruitment of PI3K to plasma membrane In response to the TCR stimulation, phsophoinositides are phosphorylated on the 3-position of the inositol ring by PI3K to generate lipid second messengers that serve as membrane docking sites for a variety of downstream effector proteins such as PDK1 and PKB. PI3K is a heterodimer comprising a regulatory subunit p85 and a catalytic subunit p110 which associate constitutively and are activated upon interaction with tyrosine-phosphorylated proteins at the plasma membrane. The p85 subunit contains two SH2 domains and an SH3 domain. p85 subunit is involved in interaction with two phsophotyrosine residues of the adaptor protein TRIM with its two SH2 domains. This interaction is important in recruiting the p110 subunit to the plasma membrane and activate the p110 kinase activity, which is normally inhibited in the p85-p110 complex. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Phospho TRAT p-Y63,Y79,Y110-TRAT1 Reactome DB_ID: 202201 UniProt:Q6PIZ9 TRAT1 TRAT1 TCRIM HSPC062 FUNCTION Stabilizes the TCR (T-cell antigen receptor)/CD3 complex at the surface of T-cells.SUBUNIT Homodimer; disulfide-linked. Interacts with CD3Z. When phosphorylated, interacts with PIK3R1.TISSUE SPECIFICITY Strongly expressed in thymus, and to a lesser extent in spleen, lymph node and peripheral blood lymphocytes. Present in T-cells and NK cells, but not B-cells (at protein level).DEVELOPMENTAL STAGE Strongly expressed in fetal thymus at weeks 17-24 of gestation. Undetectable in bone marrow and fetal liver.PTM Phosphorylated on tyrosines by LCK or FYN upon TCR activation. UniProt Q6PIZ9 63 EQUAL 79 EQUAL 110 EQUAL 1 EQUAL 186 EQUAL Reactome Database ID Release 78 202201 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202201 Reactome R-HSA-202201 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202201.1 PI3K Reactome DB_ID: 74693 Converted from EntitySet in Reactome PI3K-catalytic subunit Reactome DB_ID: 74689 PIK3CA PI3K-p110 PI3-kinase p110 subunit alpha Phosphatidylinositol 3-kinase catalytic subunit, alpha isoform (EC 2.7.1.137) (PI3-kinase p110 subunit alpha) (PtdIns-3-kinase p110) (PI3K) Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit, alpha isoform PtdIns- 3-kinase p110 Reactome DB_ID: 74787 UniProt:P42336 PIK3CA PIK3CA FUNCTION Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides (PubMed:15135396, PubMed:23936502, PubMed:28676499). Uses ATP and PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3) (PubMed:15135396, PubMed:28676499). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Participates in cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF. Regulates invadopodia formation through the PDPK1-AKT1 pathway. Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway. Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway. In addition to its lipid kinase activity, it displays a serine-protein kinase activity that results in the autophosphorylation of the p85alpha regulatory subunit as well as phosphorylation of other proteins such as 4EBP1, H-Ras, the IL-3 beta c receptor and possibly others (PubMed:23936502, PubMed:28676499). Plays a role in the positive regulation of phagocytosis and pinocytosis (By similarity).PATHWAY Phospholipid metabolism; phosphatidylinositol phosphate biosynthesis.SUBUNIT Heterodimer of a catalytic subunit PIK3CA and a p85 regulatory subunit (PIK3R1, PIK3R2 or PIK3R3) (PubMed:26593112). Interacts with IRS1 in nuclear extracts (By similarity). Interacts with RUFY3 (By similarity). Interacts with RASD2 (By similarity). Interacts with APPL1. Interacts with HRAS and KRAS (By similarity). Interaction with HRAS/KRAS is required for PI3K pathway signaling and cell proliferation stimulated by EGF and FGF2 (By similarity). Interacts with FAM83B; activates the PI3K/AKT signaling cascade (PubMed:23676467).DOMAIN The PI3K-ABD domain and the PI3K-RBD domain interact with the PI3K/PI4K kinase domain. The C2 PI3K-type domain may facilitate the recruitment to the plasma membrane. The inhibitory interactions with PIK3R1 are mediated by the PI3K-ABD domain and the C2 PI3K-type domain with the iSH2 (inter-SH2) region of PIK3R1, and the C2 PI3K-type domain, the PI3K helical domain, and the PI3K/PI4K kinase domain with the nSH2 (N-terminal SH2) region of PIK3R1.DISEASE PIK3CA mutations are involved in various type of cancer. Most of the cancer-associated mutations are missense mutations and map to one of the three hotspots: Glu-542; Glu-545 and His-1047. Mutated isoforms participate in cellular transformation and tumorigenesis induced by oncogenic receptor tyrosine kinases (RTKs) and HRAS/KRAS. Interaction with HRAS/KRAS is required for Ras-driven tumor formation. Mutations increasing the lipid kinase activity are required for oncogenic signaling. The protein kinase activity may not be required for tumorigenesis.MISCELLANEOUS The avian sarcoma virus 16 genome encodes an oncogene derived from PIK3CA.SIMILARITY Belongs to the PI3/PI4-kinase family. UniProt P42336 1 EQUAL 1068 EQUAL Reactome Database ID Release 78 74787 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74787 Reactome R-HSA-74787 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-74787.1 PIK3CB PI3-kinase p110 catalytic subunit beta Phosphatidylinositol 3-kinase catalytic subunit, beta isoform (EC 2.7.1.137) (PI3-kinase p110 subunit beta) (PtdIns-3-kinase p110) (PI3K) (PI3Kbeta) Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit, beta isoform Reactome DB_ID: 74788 UniProt:P42338 PIK3CB PIK3CB PIK3C1 FUNCTION Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol derivatives at position 3 of the inositol ring to produce 3-phosphoinositides (PubMed:15135396). Uses ATP and PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3) (PubMed:15135396). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Involved in the activation of AKT1 upon stimulation by G-protein coupled receptors (GPCRs) ligands such as CXCL12, sphingosine 1-phosphate, and lysophosphatidic acid. May also act downstream receptor tyrosine kinases. Required in different signaling pathways for stable platelet adhesion and aggregation. Plays a role in platelet activation signaling triggered by GPCRs, alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) and ITAM (immunoreceptor tyrosine-based activation motif)-bearing receptors such as GP6. Regulates the strength of adhesion of ITGA2B/ ITGB3 activated receptors necessary for the cellular transmission of contractile forces. Required for platelet aggregation induced by F2 (thrombin) and thromboxane A2 (TXA2). Has a role in cell survival. May have a role in cell migration. Involved in the early stage of autophagosome formation. Modulates the intracellular level of PtdIns3P (phosphatidylinositol 3-phosphate) and activates PIK3C3 kinase activity. May act as a scaffold, independently of its lipid kinase activity to positively regulate autophagy. May have a role in insulin signaling as scaffolding protein in which the lipid kinase activity is not required. May have a kinase-independent function in regulating cell proliferation and in clathrin-mediated endocytosis. Mediator of oncogenic signal in cell lines lacking PTEN. The lipid kinase activity is necessary for its role in oncogenic transformation. Required for the growth of ERBB2 and RAS driven tumors.PATHWAY Phospholipid metabolism; phosphatidylinositol phosphate biosynthesis.SUBUNIT Heterodimer of a catalytic subunit PIK3CB and a p85 regulatory subunit (PIK3R1, PIK3R2 or PIK3R3). Interaction with PIK3R2 is required for nuclear localization and nuclear export. Part of a complex with PIK3R1 and PTEN. Binding to PTEN may antagonize the lipid kinase activity under normal growth conditions. Part of a complex involved in autophagosome formation composed of PIK3C3 and PIK3R4 (By similarity). Interacts with BECN1, ATG14 and RAB5A (By similarity).TISSUE SPECIFICITY Expressed ubiquitously.DOMAIN The inhibitory interactions with PIK3R1 are mediated by the PI3K-ABD domain and the C2 PI3K-type domain with the iSH2 (inter-SH2) region of PIK3R1; the C2 PI3K-type domain, the PI3K helical domain, and the PI3K/PI4K kinase domain with the nSH2 (N-terminal SH2) region of PIK3R1; and the PI3K/PI4K kinase domain with the cSH2 (C-terminal SH2) region of PIK3R1. The inhibitory interaction between the PI3K-ABD domain and the C2 PI3K-type domain with the iSH2 (inter-SH2) region of PIK3R1 is weak. The nuclear localization signal (NLS) is required for its function in cell survival.PTM Phosphorylation at Ser-1070 down-regulates lipid kinase activity.SIMILARITY Belongs to the PI3/PI4-kinase family. UniProt P42338 1 EQUAL 1070 EQUAL Reactome Database ID Release 78 74788 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74788 Reactome R-HSA-74788 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-74788.1 Reactome Database ID Release 78 74689 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74689 Reactome R-HSA-74689 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-74689.1 1 Converted from EntitySet in Reactome PI3K-regulatory subunit Reactome DB_ID: 74688 PIK3R1 PI3K p85 alpha Phosphatidylinositol 3-kinase regulatory alpha subunit PI3-kinase p85-alpha subunit PtdIns-3-kinase p85-alpha Reactome DB_ID: 74789 UniProt:P27986 PIK3R1 PIK3R1 GRB1 FUNCTION Binds to activated (phosphorylated) protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Necessary for the insulin-stimulated increase in glucose uptake and glycogen synthesis in insulin-sensitive tissues. Plays an important role in signaling in response to FGFR1, FGFR2, FGFR3, FGFR4, KITLG/SCF, KIT, PDGFRA and PDGFRB. Likewise, plays a role in ITGB2 signaling (PubMed:17626883, PubMed:19805105, PubMed:7518429). Modulates the cellular response to ER stress by promoting nuclear translocation of XBP1 isoform 2 in a ER stress- and/or insulin-dependent manner during metabolic overloading in the liver and hence plays a role in glucose tolerance improvement (PubMed:20348923).SUBUNIT Heterodimer of a regulatory subunit PIK3R1 and a p110 catalytic subunit (PIK3CA, PIK3CB or PIK3CD). Interacts (via SH2 domains) with CCDC88A/GIV (tyrosine-phosphorylated form); the interaction enables recruitment of PIK3R1 to the EGFR receptor, enhancing PI3K activity and cell migration (PubMed:21954290). Interacts (via SH2 domain) with CSF1R (tyrosine phosphorylated). Interacts with PIK3R2; the interaction is dissociated in an insulin-dependent manner (By similarity). Interacts with XBP1 isoform 2; the interaction is direct and induces translocation of XBP1 isoform 2 into the nucleus in a ER stress- and/or insulin-dependent but PI3K-independent manner (PubMed:20348923). Interacts with FER. Interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated). Interacts with PTK2/FAK1 (By similarity). Interacts with phosphorylated TOM1L1. Interacts with phosphorylated LIME1 upon TCR and/or BCR activation. Interacts with SOCS7. Interacts with RUFY3. Interacts (via SH2 domain) with CSF1R (tyrosine phosphorylated). Interacts with LYN (via SH3 domain); this enhances enzyme activity (By similarity). Interacts with phosphorylated LAT, LAX1 and TRAT1 upon TCR activation. Interacts with CBLB. The SH2 domains interact with the YTHM motif of phosphorylated INSR in vitro. Also interacts with tyrosine-phosphorylated IGF1R in vitro. Interacts with CD28 and CD3Z upon T-cell activation. Interacts with IRS1 and phosphorylated IRS4, as well as with NISCH and HCST. Interacts with FASLG, KIT and BCR. Interacts with AXL, FGFR1, FGFR2, FGFR3 and FGFR4 (phosphorylated). Interacts with FGR and HCK. Interacts with PDGFRA (tyrosine phosphorylated) and PDGFRB (tyrosine phosphorylated). Interacts with ERBB4 (phosphorylated). Interacts with NTRK1 (phosphorylated upon ligand-binding). Interacts with FAM83B; activates the PI3K/AKT signaling cascade (PubMed:23676467). Interacts with APPL1 and APPL2 (By similarity). Interacts with SRC (PubMed:28903391). Interacts with ALOX5; this interaction bridges ALOX5 with CD40 after CD40 ligation in B cells and leads to the production of reactive oxygen species (ROS) (PubMed:21200133).SUBUNIT (Microbial infection) Interacts with HIV-1 Nef to activate the Nef associated p21-activated kinase (PAK). This interaction depends on the C-terminus of both proteins and leads to increased production of HIV.SUBUNIT (Microbial infection) Interacts with HCV NS5A.SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 UL46; this interaction activates the PI3K/AKT pathway.SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 UL46 and varicella virus ORF12; this interaction activates the PI3K/AKT pathway.TISSUE SPECIFICITY Isoform 2 is expressed in skeletal muscle and brain, and at lower levels in kidney and cardiac muscle. Isoform 2 and isoform 4 are present in skeletal muscle (at protein level).DOMAIN The SH3 domain mediates the binding to CBLB, and to HIV-1 Nef.PTM Polyubiquitinated in T-cells by CBLB; which does not promote proteasomal degradation but impairs association with CD28 and CD3Z upon T-cell activation.PTM Phosphorylated. Tyrosine phosphorylated in response to signaling by FGFR1, FGFR2, FGFR3 and FGFR4. Phosphorylated by CSF1R. Phosphorylated by ERBB4. Phosphorylated on tyrosine residues by TEK/TIE2. Dephosphorylated by PTPRJ. Phosphorylated by PIK3CA at Ser-608; phosphorylation is stimulated by insulin and PDGF. The relevance of phosphorylation by PIK3CA is however unclear (By similarity). Phosphorylated in response to KIT and KITLG/SCF. Phosphorylated by FGR.SIMILARITY Belongs to the PI3K p85 subunit family. UniProt P27986 1 EQUAL 724 EQUAL Reactome Database ID Release 78 74789 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74789 Reactome R-HSA-74789 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-74789.1 PIK3R2 PI3K-p85 beta Phosphatidylinositol 3-kinase regulatory beta subunit PI3-kinase p85-beta subunit PtdIns-3-kinase p85-beta Reactome DB_ID: 74791 UniProt:O00459 PIK3R2 PIK3R2 FUNCTION Regulatory subunit of phosphoinositide-3-kinase (PI3K), a kinase that phosphorylates PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Binds to activated (phosphorylated) protein-tyrosine kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Indirectly regulates autophagy (PubMed:23604317). Promotes nuclear translocation of XBP1 isoform 2 in a ER stress- and/or insulin-dependent manner during metabolic overloading in the liver and hence plays a role in glucose tolerance improvement (By similarity).SUBUNIT Heterodimer of a regulatory subunit PIK3R2 and a p110 catalytic subunit (PIK3CA, PIK3CB or PIK3CD) (PubMed:23604317). Interacts with AXL (PubMed:9178760). Interacts with FLT1 (tyrosine-phosphorylated) and FLT4 (tyrosine-phosphorylated) (PubMed:9600074, PubMed:15102829). Interacts with NYAP1, NYAP2 and MYO16 (By similarity). Interacts with FBXL2; PIK3R2 is a substrate of the SCF(FBXL2) complex (PubMed:23604317). Interacts with PTPN13; dephosphorylates PIK3R2 (PubMed:23604317). Interacts with XBP1 isoform 2; the interaction is direct and induces translocation of XBP1 isoform 2 into the nucleus in a ER stress- and/or insulin-dependent but PI3K-independent manner (By similarity). Interacts with PIK3R1; the interaction is dissociated in an insulin-dependent manner (By similarity). Interacts with SRC (PubMed:28903391).DOMAIN The SH2 2 domain is required for interaction with FBXL2 and PTPN13.PTM Phosphorylated in response to signaling from activated receptor-type protein kinases (PubMed:19690332, PubMed:20068231). Dephosphorylated by PTPRJ (PubMed:18348712). Dephosphorylated at Tyr-655 by PTPN13. Phosphorylation of Tyr-655 impairs while its dephosphorylation promotes interaction with FBXL2 and SCF(FBXL2)-mediated polyubiquitination (PubMed:23604317).PTM Ubiquitinated. Polyubiquitination by the SCF(FBXL2) complex probably promotes proteasomal degradation of PIK3R2.SIMILARITY Belongs to the PI3K p85 subunit family. UniProt O00459 1 EQUAL 728 EQUAL Reactome Database ID Release 78 74791 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74791 Reactome R-HSA-74791 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-74791.1 Reactome Database ID Release 78 74688 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74688 Reactome R-HSA-74688 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-74688.1 1 Reactome Database ID Release 78 74693 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74693 Reactome R-HSA-74693 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-74693.1 ComplexPortal CPX-73 PI3K bound to TRAT Reactome DB_ID: 202283 1 1 Reactome Database ID Release 78 202283 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202283 Reactome R-HSA-202283 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202283.1 Reactome Database ID Release 78 202203 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202203 Reactome R-HSA-202203 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202203.3 16612002 Pubmed 2006 Normal T-cell development and immune functions in TRIM-deficient mice Kolsch, U Arndt, B Reinhold, D Lindquist, JA Juling, N Kliche, S Pfeffer, K Bruyns, E Schraven, B Simeoni, L Mol Cell Biol 26:3639-48 12660731 Pubmed 2003 The role of PI3K in immune cells Koyasu, S Nat Immunol 4:313-9 9687533 Pubmed 1998 T cell receptor (TCR) interacting molecule (TRIM), a novel disulfide-linked dimer associated with the TCR-CD3-zeta complex, recruits intracellular signaling proteins to the plasma membrane Bruyns, E Marie-Cardine, A Kirchgessner, H Sagolla, K Shevchenko, A Mann, M Autschbach, F Bensussan, A Meuer, S Schraven, B J Exp Med 188:561-75 LEFT-TO-RIGHT 2.7.1.153 PI3K bound to TRAT1 phosphorylates PIP2 to PIP3 PI3K enzyme bound to adaptor protein TRIM, uses phosphatidylinositol 4,5-bisphosphate (PIP2) as its substrate and phosphorylates it to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). This PIP3 acts as a membrane anchor for the downstream proteins like PDK1 and PKB. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 PIP3 PI(3,4,5)P3 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate Phosphatidylinositol-3,4,5-trisphosphate Reactome DB_ID: 179838 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate [ChEBI:16618] 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate PIP3 ChEBI CHEBI:16618 Reactome Database ID Release 78 179838 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=179838 Reactome R-ALL-179838 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-179838.3 COMPOUND C05981 ACTIVATION activeUnit: #Protein83 GENE ONTOLOGY GO:0046934 Reactome Database ID Release 78 202288 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202288 Reactome Database ID Release 78 202365 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202365 Reactome R-HSA-202365 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202365.2 LEFT-TO-RIGHT 3.1.3.67 Hydrolysis of PIP3 to PI(3,4)P2 After the generation of PIP3 by PI3K, a part of it is further dephosphorylated to generate other forms of PI which are also involved in signaling. Two major routes for the degradation of PIP3 exists: dephosphorylation by the haematopoietic-specific SH2 domain-containing inositol 5' phosphatase SHIP-1 and dephosphorylation by the 3' phosphoinositide phosphatase PTEN. <br>SHIP-1 appears to set an activation threshold on T cell signaling. SHIP-1 phosphatase activity removes the 5' phosphate of PIP3 and generate phosphatidylinositol 3,4-bisphosphate. PI(3,4)P2 along with PIP3 preferentially binds to the PH domains of PKB and PDK1. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 PI(3,4)P2 1-phosphatidyl-1D-myo-inositol 3,4-bisphosphates 1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate Reactome DB_ID: 202247 1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate [ChEBI:16152] 1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate ChEBI CHEBI:16152 Reactome Database ID Release 78 202247 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202247 Reactome R-ALL-202247 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-202247.3 ACTIVATION SHIP1 INPP5D O00145_HUMAN Reactome DB_ID: 197940 UniProt:Q92835 INPP5D INPP5D SHIP SHIP1 FUNCTION Phosphatidylinositol (PtdIns) phosphatase that specifically hydrolyzes the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) to produce PtdIns(3,4)P2, thereby negatively regulating the PI3K (phosphoinositide 3-kinase) pathways (PubMed:8723348, PubMed:10764818, PubMed:8769125). Able also to hydrolyzes the 5-phosphate of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P3) and inositol 1,3,4,5-tetrakisphosphate (PubMed:9108392, PubMed:10764818, PubMed:8769125). Acts as a negative regulator of B-cell antigen receptor signaling. Mediates signaling from the FC-gamma-RIIB receptor (FCGR2B), playing a central role in terminating signal transduction from activating immune/hematopoietic cell receptor systems. Acts as a negative regulator of myeloid cell proliferation/survival and chemotaxis, mast cell degranulation, immune cells homeostasis, integrin alpha-IIb/beta-3 signaling in platelets and JNK signaling in B-cells. Regulates proliferation of osteoclast precursors, macrophage programming, phagocytosis and activation and is required for endotoxin tolerance. Involved in the control of cell-cell junctions, CD32a signaling in neutrophils and modulation of EGF-induced phospholipase C activity (PubMed:16682172). Key regulator of neutrophil migration, by governing the formation of the leading edge and polarization required for chemotaxis. Modulates FCGR3/CD16-mediated cytotoxicity in NK cells. Mediates the activin/TGF-beta-induced apoptosis through its Smad-dependent expression.ACTIVITY REGULATION Activated upon translocation to the sites of synthesis of PtdIns(3,4,5)P3 in the membrane.SUBUNIT Interacts with tyrosine phosphorylated form of SHC1 (PubMed:8874179). Interacts with tyrosine phosphorylated form of DOK1 (PubMed:10822173). Interacts with tyrosine phosphorylated form of DOK3 (By similarity). Interacts with tyrosine phosphorylated form of SLAMF1/CD150 (PubMed:10229804). Interacts with PTPN11 in response to IL-3 (By similarity). Interacts with receptor EPOR (By similarity). Interacts with receptors MS4A2/FCER1B and FCER1G (By similarity). Interacts with receptors FCGR2B and FCGR3 (By similarity). Interacts with receptor FCGR2A, leading to regulate gene expression during the phagocytic process (By similarity). Interacts with GRB2 (PubMed:8723348, PubMed:9108392). Interacts with PLCG1 (By similarity). Interacts with tyrosine kinases SRC and TEC (By similarity). Interacts with c-Met/MET (By similarity). Interacts with MILR1 (tyrosine-phosphorylated) (By similarity). Can weakly interact (via NPXY motif 2) with DAB2 (via PID domain); the interaction is impaired by tyrosine phosphorylation of the NPXY motif (By similarity). Interacts with FCRL3 and FCRL6 (tyrosine phosphorylated form) (PubMed:20933011, PubMed:19843936). Interacts (via SH2 domain) with tyrosine phosphorylated KLRC1 (via ITIM).TISSUE SPECIFICITY Specifically expressed in immune and hematopoietic cells. Expressed in bone marrow and blood cells. Levels vary considerably within this compartment. Present in at least 74% of immature CD34+ cells, whereas within the more mature population of CD33+ cells, it is present in only 10% of cells. Present in the majority of T-cells, while it is present in a minority of B-cells (at protein level).DOMAIN The SH2 domain interacts with tyrosine phosphorylated forms of proteins such as SHC1 or PTPN11/SHP-2. It competes with that of GRB2 for binding to phosphorylated SHC1 to inhibit the Ras pathway. It is also required for tyrosine phosphorylation (By similarity).DOMAIN The NPXY sequence motif found in many tyrosine-phosphorylated proteins is required for the specific binding of the PID domain.PTM Tyrosine phosphorylated by the members of the SRC family after exposure to a diverse array of extracellular stimuli such as cytokines, growth factors, antibodies, chemokines, integrin ligands and hypertonic and oxidative stress. Phosphorylated upon IgG receptor FCGR2B-binding.SIMILARITY Belongs to the inositol 1,4,5-trisphosphate 5-phosphatase family. UniProt Q92835 1 EQUAL 1189 EQUAL Reactome Database ID Release 78 197940 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=197940 Reactome R-HSA-197940 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-197940.1 GENE ONTOLOGY GO:0016314 Reactome Database ID Release 78 202259 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202259 Reactome Database ID Release 78 202237 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202237 Reactome R-HSA-202237 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202237.2 11884229 Pubmed 2002 Regulation of the immune response by SHIP March, ME Ravichandran, K Semin Immunol 14:37-47 10716940 Pubmed 2000 Structure, function, and biology of SHIP proteins Rohrschneider, LR Fuller, JF Wolf, I Liu, Y Lucas, DM Genes Dev 14:505-20 LEFT-TO-RIGHT 3.1.3.67 PTEN dephosphorylates PIP3 PI(3,4,5)P3 is dephosphorylated to PI (4,5)P2 by PTEN at the plasma membrane At the plasma membrane, phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase aka phosphatase and tensin homolog (PTEN) dephosphorylates phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) (Maehama & Dixon 1998, Myers et al. 1998, Das et al. 2003). The PI3K network is negatively regulated by phospholipid phosphatases that dephosphorylate PIP3, thus hampering AKT activation (Myers et al. 1998). The tumour suppressor PTEN is the primary phospholipid phosphatase.<br>Early studies indicated that magnesium ion, Mg2+, was needed for the catalytic activity of PTEN isolated from bovine thymus (Kabuyama et al. 1996). Subsequent studies have shown that PTEN was catalytically active in buffers free of magnesium and magnesium was not detected as part of the PTEN crystal (Lee et al. 1999). Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reviewed: Wakelam, Michael, 2012-05-14 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Reviewed: Leslie, Nicholas, 2016-09-30 Reviewed: Kriplani, Nisha, 2016-09-30 ACTIVATION PTEN Phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase PTEN PTEN_HUMAN MMAC1 TEP1 Reactome DB_ID: 199420 UniProt:P60484 PTEN PTEN MMAC1 TEP1 FUNCTION Tumor suppressor. Acts as a dual-specificity protein phosphatase, dephosphorylating tyrosine-, serine- and threonine-phosphorylated proteins. Also acts as a lipid phosphatase, removing the phosphate in the D3 position of the inositol ring from phosphatidylinositol 3,4,5-trisphosphate, phosphatidylinositol 3,4-diphosphate, phosphatidylinositol 3-phosphate and inositol 1,3,4,5-tetrakisphosphate with order of substrate preference in vitro PtdIns(3,4,5)P3 &gt; PtdIns(3,4)P2 &gt; PtdIns3P &gt; Ins(1,3,4,5)P4 (PubMed:26504226, PubMed:16824732). The lipid phosphatase activity is critical for its tumor suppressor function. Antagonizes the PI3K-AKT/PKB signaling pathway by dephosphorylating phosphoinositides and thereby modulating cell cycle progression and cell survival. The unphosphorylated form cooperates with MAGI2 to suppress AKT1 activation. Dephosphorylates tyrosine-phosphorylated focal adhesion kinase and inhibits cell migration and integrin-mediated cell spreading and focal adhesion formation. Plays a role as a key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation. May be a negative regulator of insulin signaling and glucose metabolism in adipose tissue. The nuclear monoubiquitinated form possesses greater apoptotic potential, whereas the cytoplasmic nonubiquitinated form induces less tumor suppressive ability. In motile cells, suppresses the formation of lateral pseudopods and thereby promotes cell polarization and directed movement.ACTIVITY REGULATION Enzymatic activity is enhanced in the presence of phosphatidylserine.SUBUNIT Monomer. The unphosphorylated form interacts with the second PDZ domain of MAGI2 and with DLG1 and MAST2 in vitro (PubMed:10646847, PubMed:10760291, PubMed:11707428). Interacts with MAGI2, MAGI3, MAST1 and MAST3, but neither with MAST4 nor with DLG5; interaction with MAGI2 increases protein stability (PubMed:10748157, PubMed:15951562). Interacts with NEDD4 (PubMed:17218260). Interacts with NDFIP1 and NDFIP2; in the presence of NEDD4 or ITCH, this interaction promotes PTEN ubiquitination (PubMed:25801959, PubMed:20534535). Interacts (via C2 domain) with FRK (PubMed:19345329). Interacts with USP7; the interaction is direct (PubMed:18716620). Interacts with ROCK1 (By similarity). Interacts with XIAP/BIRC4 (PubMed:19473982). Interacts with STK11; the interaction phosphorylates PTEN (PubMed:15987703). Interacts with PPP1R16B (PubMed:25007873). Interacts with NOP53; regulates PTEN phosphorylation and increases its stability (PubMed:15355975).TISSUE SPECIFICITY Expressed at a relatively high level in all adult tissues, including heart, brain, placenta, lung, liver, muscle, kidney and pancreas.INDUCTION Down-regulated by TGFB1.DOMAIN The C2 domain binds phospholipid membranes in vitro in a Ca(2+)-independent manner; this binding is important for its tumor suppressor function.PTM Constitutively phosphorylated by CK2 under normal conditions. Phosphorylated in vitro by MAST1, MAST2, MAST3 and STK11. Phosphorylation results in an inhibited activity towards PIP3. Phosphorylation can both inhibit or promote PDZ-binding. Phosphorylation at Tyr-336 by FRK/PTK5 protects this protein from ubiquitin-mediated degradation probably by inhibiting its binding to NEDD4. Phosphorylation by ROCK1 is essential for its stability and activity. Phosphorylation by PLK3 promotes its stability and prevents its degradation by the proteasome.PTM Monoubiquitinated; monoubiquitination is increased in presence of retinoic acid. Deubiquitinated by USP7; leading to its nuclear exclusion. Monoubiquitination of one of either Lys-13 and Lys-289 amino acid is sufficient to modulate PTEN compartmentalization. Ubiquitinated by XIAP/BIRC4.DISEASE PTEN mutations are found in a subset of patients with Proteus syndrome, a genetically heterogeneous condition. The molecular diagnosis of PTEN mutation positive cases classifies Proteus syndrome patients as part of the PTEN hamartoma syndrome spectrum. As such, patients surviving the early years of Proteus syndrome are likely at a greater risk of developing malignancies.DISEASE A microdeletion of chromosome 10q23 involving BMPR1A and PTEN is a cause of chromosome 10q23 deletion syndrome, which shows overlapping features of the following three disorders: Bannayan-Zonana syndrome, Cowden disease and juvenile polyposis syndrome.SIMILARITY Belongs to the PTEN phosphatase protein family. UniProt P60484 2 EQUAL 403 EQUAL Reactome Database ID Release 78 199420 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199420 Reactome R-HSA-199420 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-199420.2 Reactome Database ID Release 78 199445 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199445 Reactome Database ID Release 78 199456 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199456 Reactome R-HSA-199456 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-199456.4 9811831 Pubmed 1998 The lipid phosphatase activity of PTEN is critical for its tumor supressor function Myers, MP Pass, I Batty, IH van der Kaay, J Stolarov, JP Hemmings, BA Downes, CP Tonks, NK Wigler, Michael H Proc Natl Acad Sci U S A 95:13513-8 10555148 Pubmed 1999 Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association Lee, Jie-Oh Yang, Haijuan Georgescu, Maria-Magdalena Di Cristofano, Antonio Maehama, Tomohiko Shi, Y Dixon, Jack Pandolfi, Pier Pavletich, Nikola Cell 99:323-34 12808147 Pubmed 2003 Membrane-binding and activation mechanism of PTEN Das, S Dixon, JE Cho, W Proc Natl Acad Sci U S A 100:7491-6 9593664 Pubmed 1998 The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate Maehama, T Dixon, JE J Biol Chem 273:13375-8 8681945 Pubmed 1996 Purification and characterization of the phosphatidylinositol-3,4,5-trisphosphate phosphatase in bovine thymus Kabuyama, Y Nakatsu, N Homma, Y Fukui, Y Eur. J. Biochem. 238:350-6 GENE ONTOLOGY GO:0051898 gene ontology term for cellular process MI MI:0359 LEFT-TO-RIGHT Translocation of PDK1 to Plasma membrane PI3K activation results in recruitment of the serine/threonine kinase PDK1, (3-phosphoinositide-dependent kinase 1) to the plasma membrane where PDK1 subsequently phosphorylates and activates AKT. PDK1 with its PH domain binds to either PIP3 or PIP2 and is translocated to the plasma membrane. PDK1 seems to exist in an active, phosphorylated configuration under basal conditions (Vanhaesebroeck & Alessi 2000). Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Converted from EntitySet in Reactome PIP3, PI(3,4)P2 Reactome DB_ID: 202277 Reactome Database ID Release 78 202277 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202277 Reactome R-ALL-202277 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-202277.1 PDK1 PDPK1 3-phosphoinositide dependent protein kinase-1 Reactome DB_ID: 202210 UniProt:O15530 PDPK1 PDPK1 PDK1 FUNCTION Serine/threonine kinase which acts as a master kinase, phosphorylating and activating a subgroup of the AGC family of protein kinases. Its targets include: protein kinase B (PKB/AKT1, PKB/AKT2, PKB/AKT3), p70 ribosomal protein S6 kinase (RPS6KB1), p90 ribosomal protein S6 kinase (RPS6KA1, RPS6KA2 and RPS6KA3), cyclic AMP-dependent protein kinase (PRKACA), protein kinase C (PRKCD and PRKCZ), serum and glucocorticoid-inducible kinase (SGK1, SGK2 and SGK3), p21-activated kinase-1 (PAK1), protein kinase PKN (PKN1 and PKN2). Plays a central role in the transduction of signals from insulin by providing the activating phosphorylation to PKB/AKT1, thus propagating the signal to downstream targets controlling cell proliferation and survival, as well as glucose and amino acid uptake and storage. Negatively regulates the TGF-beta-induced signaling by: modulating the association of SMAD3 and SMAD7 with TGF-beta receptor, phosphorylating SMAD2, SMAD3, SMAD4 and SMAD7, preventing the nuclear translocation of SMAD3 and SMAD4 and the translocation of SMAD7 from the nucleus to the cytoplasm in response to TGF-beta. Activates PPARG transcriptional activity and promotes adipocyte differentiation. Activates the NF-kappa-B pathway via phosphorylation of IKKB. The tyrosine phosphorylated form is crucial for the regulation of focal adhesions by angiotensin II. Controls proliferation, survival, and growth of developing pancreatic cells. Participates in the regulation of Ca(2+) entry and Ca(2+)-activated K(+) channels of mast cells. Essential for the motility of vascular endothelial cells (ECs) and is involved in the regulation of their chemotaxis. Plays a critical role in cardiac homeostasis by serving as a dual effector for cell survival and beta-adrenergic response. Plays an important role during thymocyte development by regulating the expression of key nutrient receptors on the surface of pre-T cells and mediating Notch-induced cell growth and proliferative responses. Provides negative feedback inhibition to toll-like receptor-mediated NF-kappa-B activation in macrophages. Isoform 3 is catalytically inactive.ACTIVITY REGULATION Homodimerization regulates its activity by maintaining the kinase in an autoinhibitory conformation. NPRL2 down-regulates its activity by interfering with tyrosine phosphorylation at the Tyr-9, Tyr-373 and Tyr-376 residues. The 14-3-3 protein YWHAQ acts as a negative regulator by association with the residues surrounding the Ser-241 residue. STRAP positively regulates its activity by enhancing its autophosphorylation and by stimulating its dissociation from YWHAQ. SMAD2, SMAD3, SMAD4 and SMAD7 also positively regulate its activity by stimulating its dissociation from YWHAQ. Activated by phosphorylation on Tyr-9, Tyr-373 and Tyr-376 by INSR in response to insulin.SUBUNIT Homodimer in its autoinhibited state. Active as monomer. Interacts with NPRL2, PPARG, PAK1, PTK2B, GRB14, PKN1 (via C-terminus), STRAP and IKKB. The Tyr-9 phosphorylated form interacts with SRC, RASA1 and CRK (via their SH2 domains). Interacts with SGK3 in a phosphorylation-dependent manner. The tyrosine-phosphorylated form interacts with PTPN6. The Ser-241 phosphorylated form interacts with YWHAH and YWHAQ. Binds INSR in response to insulin. Interacts (via PH domain) with SMAD3, SMAD4 and SMAD7. Interacts with PKN2; the interaction stimulates PDPK1 autophosphorylation, its PI(3,4,5)P3-dependent kinase activity toward 'Ser-473' of AKT1 but also activates its kinase activity toward PRKCD and PRKCZ.TISSUE SPECIFICITY Appears to be expressed ubiquitously. The Tyr-9 phosphorylated form is markedly increased in diseased tissue compared with normal tissue from lung, liver, colon and breast.INDUCTION Stimulated by insulin, and the oxidants hydrogen peroxide and peroxovanadate.DOMAIN The PH domain plays a pivotal role in the localization and nuclear import of PDPK1 and is also essential for its homodimerization.DOMAIN The PIF-pocket is a small lobe in the catalytic domain required by the enzyme for the binding to the hydrophobic motif of its substrates. It is an allosteric regulatory site that can accommodate small compounds acting as allosteric inhibitors.PTM Phosphorylation on Ser-241 in the activation loop is required for full activity. PDPK1 itself can autophosphorylate Ser-241, leading to its own activation. Autophosphorylation is inhibited by the apoptotic C-terminus cleavage product of PKN2 (By similarity). Tyr-9 phosphorylation is critical for stabilization of both PDPK1 and the PDPK1/SRC complex via HSP90-mediated protection of PDPK1 degradation. Angiotensin II stimulates the tyrosine phosphorylation of PDPK1 in vascular smooth muscle in a calcium- and SRC-dependent manner. Phosphorylated on Tyr-9, Tyr-373 and Tyr-376 by INSR in response to insulin. Palmitate negatively regulates autophosphorylation at Ser-241 and palmitate-induced phosphorylation at Ser-529 and Ser-501 by PKC/PRKCQ negatively regulates its ability to phosphorylate PKB/AKT1. Phosphorylation at Thr-354 by MELK partially inhibits kinase activity, the inhibition is cooperatively enhanced by phosphorylation at Ser-394 and Ser-398 by MAP3K5.PTM Autophosphorylated; autophosphorylation is inhibited by the apoptotic C-terminus cleavage product of PKN2.PTM Monoubiquitinated in the kinase domain, deubiquitinated by USP4.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. PDPK1 subfamily. UniProt O15530 1 EQUAL 556 EQUAL Reactome Database ID Release 78 202210 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202210 Reactome R-HSA-202210 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202210.1 PDK1:PIP2,PIP3 PDK1 bound to either PIP3 or PI(3,4)P2 Reactome DB_ID: 202311 PDK1 PDPK1 3-phosphoinositide dependent protein kinase-1 Reactome DB_ID: 61459 1 EQUAL 556 EQUAL Reactome Database ID Release 78 61459 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=61459 Reactome R-HSA-61459 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-61459.1 1 1 Reactome Database ID Release 78 202311 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202311 Reactome R-HSA-202311 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202311.1 Reactome Database ID Release 78 202164 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202164 Reactome R-HSA-202164 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202164.1 10698680 Pubmed 2000 The PI3K-PDK1 connection: more than just a road to PKB Vanhaesebroeck, B Alessi, DR Biochem J 346:561-76 LEFT-TO-RIGHT Translocation of PKC theta to plasma membrane DAG along with intracellular calcium signals cooperatively to activate PKCs, which then trigger other pathways such as the NF-kB pathway, ultimately leading to mast cell (MC) degranulation and cytokine production (Wu 2011). PKC theta is a member of the Ca++ independent and DAG dependent, novel PKC subfamily expressed mainly in T cells. It contains, N-term C2 like domain, a pseudosubstrate (PS), DAG binding (C1) domain and a C-term kinase domain. The PS sequence resembles an ideal substrate with the exception that it contains an alanine residue instead of a substrate serine residue, is bound to the kinase domain in the resting state. As a result, PKC theta is maintained in a closed inactive state, which is inaccessible to cellular substrates.<br>MCs express several Protein kinase C (PKC) isozymes and these kinases are involved in both the activation and termination of the degranulation process. PKC-delta is a negative regulator of FCERI mediated mast cell degranulation, whereas PKC-theta facilitates in degranulation (Leitges et al. 2002, Liu et al. 2001). In response to FCERI activation PKC-theta translocates to membrane by binding to DAG with its C1 domain. PKC-theta exists in two conformations closed/inactive and open/active state. In resting state, PKC-theta is autoinhibited where the pseudosubstrate sequence in the N-terminal regulatory region of PKC-theta forms intramolecular interaction with the substrate-binding region in the catalytic domain. This prevents the catalytic domain gaining access to substrates. The allosteric change of PKC-theta from closed to open state involves two important mechanisms: DAG binding to the C1 domains and autophosphorylation of T538 on the activation loop. Interaction with DAG induces conformational change resulting in the exposure of the activation loop of PKC-theta (Wang et al. 2012, Melowic et al. 2007). Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 PKC-theta (closed) PRKQC closed conformation Reactome DB_ID: 202185 UniProt:Q04759 PRKCQ PRKCQ PRKCT FUNCTION Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that mediates non-redundant functions in T-cell receptor (TCR) signaling, including T-cells activation, proliferation, differentiation and survival, by mediating activation of multiple transcription factors such as NF-kappa-B, JUN, NFATC1 and NFATC2. In TCR-CD3/CD28-co-stimulated T-cells, is required for the activation of NF-kappa-B and JUN, which in turn are essential for IL2 production, and participates in the calcium-dependent NFATC1 and NFATC2 transactivation. Mediates the activation of the canonical NF-kappa-B pathway (NFKB1) by direct phosphorylation of CARD11 on several serine residues, inducing CARD11 association with lipid rafts and recruitment of the BCL10-MALT1 complex, which then activates IKK complex, resulting in nuclear translocation and activation of NFKB1. May also play an indirect role in activation of the non-canonical NF-kappa-B (NFKB2) pathway. In the signaling pathway leading to JUN activation, acts by phosphorylating the mediator STK39/SPAK and may not act through MAP kinases signaling. Plays a critical role in TCR/CD28-induced NFATC1 and NFATC2 transactivation by participating in the regulation of reduced inositol 1,4,5-trisphosphate generation and intracellular calcium mobilization. After costimulation of T-cells through CD28 can phosphorylate CBLB and is required for the ubiquitination and subsequent degradation of CBLB, which is a prerequisite for the activation of TCR. During T-cells differentiation, plays an important role in the development of T-helper 2 (Th2) cells following immune and inflammatory responses, and, in the development of inflammatory autoimmune diseases, is necessary for the activation of IL17-producing Th17 cells. May play a minor role in Th1 response. Upon TCR stimulation, mediates T-cell protective survival signal by phosphorylating BAD, thus protecting T-cells from BAD-induced apoptosis, and by up-regulating BCL-X(L)/BCL2L1 levels through NF-kappa-B and JUN pathways. In platelets, regulates signal transduction downstream of the ITGA2B, CD36/GP4, F2R/PAR1 and F2RL3/PAR4 receptors, playing a positive role in 'outside-in' signaling and granule secretion signal transduction. May relay signals from the activated ITGA2B receptor by regulating the uncoupling of WASP and WIPF1, thereby permitting the regulation of actin filament nucleation and branching activity of the Arp2/3 complex. May mediate inhibitory effects of free fatty acids on insulin signaling by phosphorylating IRS1, which in turn blocks IRS1 tyrosine phosphorylation and downstream activation of the PI3K/AKT pathway. Phosphorylates MSN (moesin) in the presence of phosphatidylglycerol or phosphatidylinositol. Phosphorylates PDPK1 at 'Ser-504' and 'Ser-532' and negatively regulates its ability to phosphorylate PKB/AKT1. Phosphorylates CCDC88A/GIV and inhibits its guanine nucleotide exchange factor activity (PubMed:23509302).ACTIVITY REGULATION Novel PKCs (PRKCD, PRKCE, PRKCH and PRKCQ) are calcium-insensitive, but activated by diacylglycerol (DAG) and phosphatidylserine. Three specific sites; Thr-538 (activation loop of the kinase domain), Ser-676 (turn motif) and Ser-695 (hydrophobic region), need to be phosphorylated for its full activation.SUBUNIT Part of a lipid raft complex composed at least of BCL10, CARD11, MALT1 and IKBKB (PubMed:16356855). Interacts with GLRX3 (via N-terminus) (PubMed:10636891). Interacts with ECT2 (PubMed:15254234). Interacts with CCDC88A/GIV; the interaction leads to phosphorylation of CCDC88A and inhibition of its guanine nucleotide exchange factor activity (PubMed:23509302).TISSUE SPECIFICITY Expressed in skeletal muscle, T-cells, megakaryoblastic cells and platelets.DOMAIN The C1 domain, containing the phorbol ester/DAG-type region 1 (C1A) and 2 (C1B), is the diacylglycerol sensor and the C2 domain is a non-calcium binding domain.PTM Autophosphorylation at Thr-219 is required for targeting to the TCR and cellular function of PRKCQ upon antigen receptor ligation. Following TCR stimulation, phosphorylated at Tyr-90 and Ser-685.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. PKC subfamily. UniProt Q04759 1 EQUAL 706 EQUAL Reactome Database ID Release 78 202185 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202185 Reactome R-HSA-202185 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202185.1 PKC-theta (open): DAG Reactome DB_ID: 202187 PRKCQ PKC-theta (open conformation) Reactome DB_ID: 202346 1 EQUAL 706 EQUAL Reactome Database ID Release 78 202346 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202346 Reactome R-HSA-202346 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202346.1 1 1 Reactome Database ID Release 78 202187 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202187 Reactome R-HSA-202187 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202187.1 Reactome Database ID Release 78 202328 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202328 Reactome R-HSA-202328 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202328.2 11358993 Pubmed 2001 Protein kinase C theta is expressed in mast cells and is functionally involved in Fcepsilon receptor I signaling Liu, Y Graham, C Parravicini, V Brown, M J Rivera, J Shaw, S J. Leukoc. Biol. 69:831-40 12473184 Pubmed 2002 Protein kinase C-theta (PKC theta): a key enzyme in T cell life and death Altman, A Villalba, M J Biochem (Tokyo) 132:841-6 17548359 Pubmed 2007 Mechanism of diacylglycerol-induced membrane targeting and activation of protein kinase Ctheta Melowic, Heather R Stahelin, Robert V Blatner, Nichole R Tian, Wen Hayashi, Keitaro Altman, Amnon Cho, Wonhwa J. Biol. Chem. 282:21467-76 16978534 Pubmed 2006 Selective function of PKC-theta in T cells Manicassamy, S Gupta, S Sun, Z Cell Mol Immunol 3:263-70 LEFT-TO-RIGHT 2.7.10 Change of PKC theta conformation PKC theta localizes at the interface between T cells and antigen presenting cells. Upon the T cell activation and release of the second messengers Ca++ and DAG by PLC-gamma1, DAG binds to the C1 domain of the PKC theta thereby enhances the attachment to the plasma membrane. Upon membrane translocation, PKC theta is phosphorylated at tyrosine 90 in the C2 like domain. This phosphorylation is mediated by the tyrosine kinase Lck. These association and, most likely, other regulatory interactions, lead to a change in PKC theta conformation into an open, active state whereby it can now access its substrates and phosphorylate them. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 p-Y90-PKC-theta:DAG Reactome DB_ID: 202300 p-Y90-PRKCQ p-Y90-PKC-theta Reactome DB_ID: 202395 90 EQUAL 1 EQUAL 706 EQUAL Reactome Database ID Release 78 202395 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202395 Reactome R-HSA-202395 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202395.1 1 1 Reactome Database ID Release 78 202300 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202300 Reactome R-HSA-202300 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202300.1 ACTIVATION Reactome Database ID Release 78 202307 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202307 Reactome R-HSA-202307 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202307.1 LEFT-TO-RIGHT 2.7.11 Phosphorylation of PKC theta Raft localized PKC theta is further phosphorylated and activated by PDK1. The threonine residue (T538) in the kinase domain is the potential target of PDK1. Phosphorylation of this site is critical for the PKC theta kinase activity, and its ability to activate NF-kB pathway. PKC theta is later trans-autophopshorylated on putative phosphorylation sites (S676, S695) for the fine-tuning of its kinase activity. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 3 3 Active PKC theta bound to DAG Reactome DB_ID: 202442 1 p-Y90,T538,S676,S695-PRKCQ p-S676,S695,T538,Y90-PRKCQ Active phosphorylated PKC theta Reactome DB_ID: 202152 538 EQUAL O-phospho-L-threonine MOD MOD:00047 676 EQUAL O-phospho-L-serine MOD MOD:00046 695 EQUAL 1 EQUAL 706 EQUAL Reactome Database ID Release 78 202152 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202152 Reactome R-HSA-202152 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202152.1 1 Reactome Database ID Release 78 202442 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202442 Reactome R-HSA-202442 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202442.1 ACTIVATION GENE ONTOLOGY GO:0004674 Reactome Database ID Release 78 202386 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202386 Reactome Database ID Release 78 202222 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202222 Reactome R-HSA-202222 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202222.2 LEFT-TO-RIGHT Translocation of CARMA1 to Plasma membrane CARMA1 and Bcl10 are the possible link between PKC theta and IKK activation. PDK1 is also required for PKC theta mediated activation of IKK. CARMA1 has a N-terminal CARD motif, a coiled coiled region, a linker region, and a MAGUK-typical PDZ, SH3 and a GUK domains. The linker region is proposed to contain a hinge region and a CARD binding domain. CARMA1 exists in an inactive conformation in which the linker region binds to and blocks the accessibility of the CARD motif. CARMA1 is recruited to the plasma membrane by binding to the 'PxxP' motif of membrane bound PDK1 with its SH3 domain. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 CARD11 CARMA1 Reactome DB_ID: 202161 UniProt:Q9BXL7 CARD11 CARD11 CARMA1 FUNCTION Adapter protein that plays a key role in adaptive immune response by transducing the activation of NF-kappa-B downstream of T-cell receptor (TCR) and B-cell receptor (BCR) engagement (PubMed:11278692, PubMed:11356195, PubMed:12356734). Transduces signals downstream TCR or BCR activation via the formation of a multiprotein complex together with BCL10 and MALT1 that induces NF-kappa-B and MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14) pathways (PubMed:11356195). Upon activation in response to TCR or BCR triggering, CARD11 homooligomerizes to form a nucleating helical template that recruits BCL10 via CARD-CARD interaction, thereby promoting polymerization of BCL10 and subsequent recruitment of MALT1: this leads to I-kappa-B kinase (IKK) phosphorylation and degradation, and release of NF-kappa-B proteins for nuclear translocation (PubMed:24074955). Its binding to DPP4 induces T-cell proliferation and NF-kappa-B activation in a T-cell receptor/CD3-dependent manner (PubMed:17287217). Promotes linear ubiquitination of BCL10 by promoting the targeting of BCL10 to RNF31/HOIP (PubMed:27777308). Stimulates the phosphorylation of BCL10 (PubMed:11356195). Also activates the TORC1 signaling pathway (PubMed:28628108).ACTIVITY REGULATION Maintained in an autoinhibited state via homodimerization in which the CARD domain forms an extensive interaction with the adjacent linker and coiled-coil regions (PubMed:31296852). Activation downstream of T-cell receptor (TCR) by phosphorylation by PRKCB and PRKCQ triggers CARD11 homooligomerization and BCL10 recruitment, followed by activation of NF-kappa-B (By similarity).SUBUNIT Homodimer; disulfide-linked (PubMed:24224005). Homomultimer; polymerizes following activation, forming a nucleating helical template that seeds BCL10-filament formation via a CARD-CARD interaction (PubMed:24074955). Interacts (via CARD domain) with BCL10 (via CARD domain); interaction takes place following CARD11 activation and polymerization, leading to the formation of a filamentous CBM complex assembly (PubMed:11278692, PubMed:11356195, PubMed:27777308, PubMed:24074955, PubMed:31296852). Component of a CBM complex (CARD11-BCL10-MALT1) complex involved in NF-kappa-B activation (PubMed:28628108, PubMed:24074955). Found in a membrane raft complex, at least composed of BCL10, CARD11, DPP4 and IKBKB (PubMed:17287217). Interacts (via PDZ domain) with DPP4 (via cytoplasmic tail) (PubMed:17287217).TISSUE SPECIFICITY Detected in adult peripheral blood leukocytes, thymus, spleen and liver. Also found in promyelocytic leukemia HL-60 cells, chronic myelogenous leukemia K-562 cells, Burkitt's lymphoma Raji cells and colorectal adenocarcinoma SW480 cells. Not detected in HeLaS3, MOLT-4, A-549 and G431 cells.DOMAIN The linker region, also named autoinhibitory interface, is less inhibitory on its own than that of CARD9 (PubMed:31296852). The linker region together with the inhibitory domain (ID) are required to prevent constitutive activation and maintain CARD11 in an autoinhibitory state (PubMed:31296852). Disruption of the inhibitory domain (ID) region triggers polymerization and activation, leading to formation of BCL10-nucleating filaments (PubMed:31296852).PTM Phosphorylation at Ser-559, Ser-644 and Ser-652 by PRKCB and PRKCQ leads to a shift from an inactive to an active form that activates the NF-kappa-B signaling. UniProt Q9BXL7 1 EQUAL 1154 EQUAL Reactome Database ID Release 78 202161 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202161 Reactome R-HSA-202161 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202161.1 CARMA1 bound to PDK1 Reactome DB_ID: 202349 1 1 Reactome Database ID Release 78 202349 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202349 Reactome R-HSA-202349 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202349.1 Reactome Database ID Release 78 202394 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202394 Reactome R-HSA-202394 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202394.1 15541657 Pubmed 2004 The roles of CARMA1, Bcl10, and MALT1 in antigen receptor signaling Lin, X Wang, D Semin Immunol 16:429-35 15122200 Pubmed 2004 CARMA1, BCL-10 and MALT1 in lymphocyte development and activation Thome, M Nat Rev Immunol 4:348-59 17468049 Pubmed 2007 Post-translational modifications regulate distinct functions of CARMA1 and BCL10 Thome, M Weil, R Trends Immunol 28:281-8 LEFT-TO-RIGHT 2.7.11 Phosphorylation of CARMA1 Antigen receptor triggered PKC theta dependent linker phosphorylation of S552 residue is required to release this inhibition and expose the CARD motif for downstream Bcl10 recruitment. PDK1 and maybe other unknown adapter proteins bring PKC theta and CARMA1 into close proximity, facilitating PKC theta mediated CARMA1 phosphorylation and consequent activation. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Activated CARMA1 Reactome DB_ID: 202440 p-S552-CARD11 Phosphorylated CARMA1 Reactome DB_ID: 202438 552 EQUAL 1 EQUAL 1154 EQUAL Reactome Database ID Release 78 202438 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202438 Reactome R-HSA-202438 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202438.1 1 1 Reactome Database ID Release 78 202440 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202440 Reactome R-HSA-202440 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202440.1 ACTIVATION Reactome Database ID Release 78 202439 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202439 Reactome Database ID Release 78 202437 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202437 Reactome R-HSA-202437 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202437.1 16356853 Pubmed 2005 Phosphorylation of CARMA1: the link(er) to NF-kappaB activation Rueda, D Thome, M Immunity 23:551-3 LEFT-TO-RIGHT Oligomerization of CARMA1 After the phosphorylation and activation CARMA1 undergoes oligomerization, likely through its CC domain. CARMA1 is thought to oligomerize first as a trimer which triggers downstream oligomerization cascade that is ultimately necessary for the subsequent activation of the IKK complex. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 2 CARMA1 trimer Reactome DB_ID: 202445 3 1 Reactome Database ID Release 78 202445 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202445 Reactome R-HSA-202445 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202445.1 Reactome Database ID Release 78 202443 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202443 Reactome R-HSA-202443 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202443.1 LEFT-TO-RIGHT Interaction of Bcl10 to CARMA1 Bcl10 is recruited to activated, oligomeric CARMA1 through a CARD-CARD interaction. Bcl10 is characterized by an N-terminal CARD motif and a C-terminal extension of ~130 amino acids rich in serine and threonine residues that serve as targets for multiple phosphorylation events. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 BCL10 Bcl10 Reactome DB_ID: 202447 UniProt:O95999 BCL10 BCL10 CIPER CLAP FUNCTION Plays a key role in both adaptive and innate immune signaling by bridging CARD domain-containing proteins to immune activation (PubMed:10187770, PubMed:10364242, PubMed:10400625, PubMed:25365219, PubMed:24074955). Acts by channeling adaptive and innate immune signaling downstream of CARD domain-containing proteins CARD9, CARD11 and CARD14 to activate NF-kappa-B and MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14) pathways which stimulate expression of genes encoding pro-inflammatory cytokines and chemokines (PubMed:24074955). Recruited by activated CARD domain-containing proteins: homooligomerized CARD domain-containing proteins form a nucleating helical template that recruits BCL10 via CARD-CARD interaction, thereby promoting polymerization of BCL10, subsequent recruitment of MALT1 and formation of a CBM complex (PubMed:24074955). This leads to activation of NF-kappa-B and MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14) pathways which stimulate expression of genes encoding pro-inflammatory cytokines and chemokines (PubMed:18287044, PubMed:27777308, PubMed:24074955). Activated by CARD9 downstream of C-type lectin receptors; CARD9-mediated signals are essential for antifungal immunity (PubMed:26488816). Activated by CARD11 downstream of T-cell receptor (TCR) and B-cell receptor (BCR) (PubMed:18264101, PubMed:18287044, PubMed:27777308, PubMed:24074955). Promotes apoptosis, pro-caspase-9 maturation and activation of NF-kappa-B via NIK and IKK (PubMed:10187815).SUBUNIT Homomultimer; homooligomerized following recruitment by CARD domain-containing proteins that form a nucleating helical template that recruits BCL10 via CARD-CARD interaction (PubMed:24074955). Self-associates by CARD-CARD interaction and interacts with other CARD-proteins such as CARD9, CARD10, CARD11 and CARD14 (PubMed:26488816, PubMed:27113748, PubMed:27777308, PubMed:28628108, PubMed:31296852, PubMed:24074955). Forms a complex with CARD14 and MALT1; resulting in the formation of a CBM (CARD14-BCL10-MALT1) complex (PubMed:27113748). Forms a complex with CARD11 and MALT1; resulting in the formation of a CBM (CARD11-BCL10-MALT1) complex (PubMed:28628108, PubMed:24074955). Forms a complex with CARD9 and MALT1; resulting in the formation of a CBM (CARD9-BCL10-MALT1) complex (By similarity). Found in a membrane raft complex, at least composed of BCL10, CARD11, DPP4 and IKBKB (PubMed:17287217). Binds caspase-9 with its C-terminal domain (PubMed:10187815). Interacts with TRAF2 and BIRC2/c-IAP2 (PubMed:11466612). Interacts with PELI2 and SOCS3; these interactions may be mutually exclusive (By similarity).TISSUE SPECIFICITY Ubiquitous.PTM Phosphorylated. Phosphorylation results in dissociation from TRAF2 and binding to BIRC2/c-IAP2 (PubMed:11466612). Phosphorylated by IKBKB/IKKB (PubMed:17213322).PTM Ubiquitinated via both 'Lys-63'-linked and linear ('Met-1'-linked) polyubiquitin chains in response to T-cell receptor (TCR) activation (PubMed:18287044, PubMed:27777308). Ubiquitination is recognized by IKBKG/NEMO, the regulatory subunit of I-kappa-B kinase (IKK), and is required for TCR-induced NF-kappa-B activation (PubMed:18287044, PubMed:27777308). Linear ubiquitination at Lys-17, Lys-31 and Lys-63 is mediated by RNF31/HOIP; linear ubiquitination is recognized with much higher affinity than 'Lys-63'-linked ubiquitin by IKBKG/NEMO (PubMed:27777308). CARD11 is required for linear ubiquitination by HOIP by promoting the targeting of BCL10 to RNF31/HOIP (PubMed:27777308).PTM Proteolytically cleaved by MALT1; required for T-cell activation.DISEASE A chromosomal aberration involving BCL10 is recurrent in low-grade mucosa-associated lymphoid tissue (MALT lymphoma). Translocation t(1;14)(p22;q32). Although the BCL10/IgH translocation leaves the coding region of BCL10 intact, frequent BCL10 mutations could be attributed to the Ig somatic hypermutation mechanism resulting in nucleotide transitions. UniProt O95999 1 EQUAL 233 EQUAL Reactome Database ID Release 78 202447 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202447 Reactome R-HSA-202447 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202447.1 Bcl10 bound to CARMA1 Reactome DB_ID: 202454 1 1 Reactome Database ID Release 78 202454 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202454 Reactome R-HSA-202454 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202454.1 Reactome Database ID Release 78 202466 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202466 Reactome R-HSA-202466 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202466.1 LEFT-TO-RIGHT 2.7.11 Phosphorylation of Bcl10 Upon interaction with CARMA1, Bcl10 undergoes phosphorylation and oligomerization. The oligomerized Bcl10 acts as a adaptor for the incoming MALT1 and TRAF6. Phosphorylation events of Bcl10 can both positively and negatively regulate the NF-kB pathway. Phosphorylation of Bcl10 that depends on the Ser/Thr kinase RIP2 and correlated with the physical association of Bcl10 with RIP2 has a activation effect on the NF-kB pathway. The target sites of RIP2-mediated phosphorylation has not yet been identified. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Phosphorylated Bcl10 bound to CARMA1 and RIP2 Reactome DB_ID: 202480 p-BCL10 phosphorylated Bcl10 Reactome DB_ID: 202488 phosphorylated residue MOD MOD:00696 1 EQUAL 233 EQUAL Reactome Database ID Release 78 202488 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202488 Reactome R-HSA-202488 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202488.1 1 1 Reactome Database ID Release 78 202480 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202480 Reactome R-HSA-202480 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202480.1 ACTIVATION RIP2 RIPK2 RICK receptor-interacting serine-threonine kinase 2 Reactome DB_ID: 168402 UniProt:O43353 RIPK2 RIPK2 CARDIAK RICK RIP2 UNQ277/PRO314/PRO34092 FUNCTION Serine/threonine/tyrosine kinase that plays an essential role in modulation of innate and adaptive immune responses. Upon stimulation by bacterial peptidoglycans, NOD1 and NOD2 are activated, oligomerize and recruit RIPK2 through CARD-CARD domains. Contributes to the tyrosine phosphorylation of the guanine exchange factor ARHGEF2 through Src tyrosine kinase leading to NF-kappaB activation by NOD2. Once recruited, RIPK2 autophosphorylates and undergoes 'Lys-63'-linked polyubiquitination by E3 ubiquitin ligases XIAP, BIRC2 and BIRC3. The polyubiquitinated protein mediates the recruitment of MAP3K7/TAK1 to IKBKG/NEMO and induces 'Lys-63'-linked polyubiquitination of IKBKG/NEMO and subsequent activation of IKBKB/IKKB. In turn, NF-kappa-B is released from NF-kappa-B inhibitors and translocates into the nucleus where it activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. Plays also a role during engagement of the T-cell receptor (TCR) in promoting BCL10 phosphorylation and subsequent NF-kappa-B activation. Plays a role in the inactivation of RHOA in response to NGFR signaling (PubMed:26646181).SUBUNIT Found in a signaling complex consisting of at least ARHGEF2, NOD2 and RIPK2. Interacts with ARHGEF2; the interaction mediates tyrosine phosphorylation of RIPK2 by Src kinase CSK. Binds to CFLAR/CLARP and CASP1 via their CARD domains. Binds to BIRC3/c-IAP1 and BIRC2/c-IAP2, TRAF1, TRAF2, TRAF5 and TRAF6. May be a component of both the TNFRSF1A and TNRFSF5/CD40 receptor complex. Interacts with NOD1. Interacts (via CARD domain) with NOD2 (via CARD domain) (PubMed:19592251, PubMed:21887730, PubMed:27812135). Interacts with MAP3K4; this interaction sequesters RIPK2 from the NOD2 signaling pathway. Interacts with IKBKG/NEMO. The polyubiquitinated protein interacts with MAP3K7/TAK1. Interacts with XIAP/BIRC4. Interacts with NLRP10. Interacts with CARD9. Interacts with INAVA; the interaction takes place upon PRR stimulation (PubMed:28436939). Interacts (via CARD domain) with NGFR (via death domain) (PubMed:26646181).TISSUE SPECIFICITY Detected in heart, brain, placenta, lung, peripheral blood leukocytes, spleen, kidney, testis, prostate, pancreas and lymph node.DOMAIN Contains an N-terminal kinase domain and a C-terminal caspase activation and recruitment domain (CARD) that mediates the recruitment of CARD-containing proteins.PTM Autophosphorylated. Autophosphorylation at Tyr-474 is necessary for effective NOD2 signaling. Phosphorylated. Phosphorylation at Tyr-381 by Src kinase CSK occurs in a ARHGEF2-dependent manner and is required for NOD2-dependent innate immune activation.PTM Ubiquitinated on Lys-209; undergoes 'Lys-63'-linked polyubiquitination catalyzed by ITCH. Polyubiquitinated with 'Lys-48' and 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2, leading to activation of NF-kappa-B. Also undergoes 'Met-1'-linked polyubiquitination; the head-to-tail linear polyubiquitination is mediated by the LUBAC complex in response to NOD2 stimulation. Linear polyubiquitination is restricted by FAM105B/otulin, probably to limit NOD2-dependent proinflammatory signaling activation of NF-kappa-B. Undergoes 'Lys-63'-linked deubiquitination by MYSM1 to attenuate NOD2-mediated inflammation and tissue damage (By similarity).PTM (Microbial infection) Acetylation of Ser-174, Ser-176 and Ser-178 by Yersinia YopJ prevents phosphorylation and activation, thereby promoting cell death.SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. UniProt O43353 1 EQUAL 540 EQUAL Reactome Database ID Release 78 168402 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168402 Reactome R-HSA-168402 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-168402.1 Reactome Database ID Release 78 168546 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168546 Reactome Database ID Release 78 202459 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202459 Reactome R-HSA-202459 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202459.1 LEFT-TO-RIGHT Oligomerization of Bcl10 Association with RIP2 and its phosphorylation allows subsequent trimerization of Bcl10. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 2 Bcl10 trimer bound to CARMA1 trimer Reactome DB_ID: 202475 3 1 Reactome Database ID Release 78 202475 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202475 Reactome R-HSA-202475 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202475.1 Reactome Database ID Release 78 202489 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202489 Reactome R-HSA-202489 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202489.1 LEFT-TO-RIGHT Interaction and oligomerization of MALT1 to Bcl10 Oligomerized Bcl10 facilitates the association with MALT1 to form the CBM signalosome. MALT1 possesses one death domain (DD) and 2 immunoglobulin-like domains (Ig-like) in its N-terminal region and a caspase like domain (CLD) in its C-terminal region. The region between amino acids 107 and 119 of Bcl10 bind to the two Ig-like domains of MALT1. After binding to CARMA1 and Bcl10 complex, MALT1 also undergoes oligomerization. Only the oligomerized forms of Bcl10 and MALT1 are capable of activating IKK. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 MALT1 trimer Reactome DB_ID: 202487 MALT1 Mucosa-associated lymphoid tissue lymphoma translocation protein 1 Reactome DB_ID: 202461 UniProt:Q9UDY8 MALT1 MALT1 MLT FUNCTION Protease that enhances BCL10-induced activation: acts via formation of CBM complexes that channel adaptive and innate immune signaling downstream of CARD domain-containing proteins (CARD9, CARD11 and CARD14) to activate NF-kappa-B and MAP kinase p38 pathways which stimulate expression of genes encoding pro-inflammatory cytokines and chemokines (PubMed:11262391, PubMed:18264101, PubMed:24074955). Mediates BCL10 cleavage: MALT1-dependent BCL10 cleavage plays an important role in T-cell antigen receptor-induced integrin adhesion (PubMed:11262391, PubMed:18264101). Involved in the induction of T helper 17 cells (Th17) differentiation (PubMed:11262391, PubMed:18264101). Cleaves RC3H1 and ZC3H12A in response to T-cell receptor (TCR) stimulation which releases their cooperatively repressed targets to promote Th17 cell differentiation (By similarity). Also mediates cleavage of N4BP1 in T-cells following TCR-mediated activation, leading to N4BP1 inactivation (PubMed:31133753). May also have ubiquitin ligase activity: binds to TRAF6, inducing TRAF6 oligomerization and activation of its ligase activity (PubMed:14695475).SUBUNIT Homooligomer; forms oligomers which bind to TRAF6 (PubMed:15125833). Forms a complex with CARD14 and MALT1; resulting in the formation of a CBM (CARD14-BCL10-MALT1) complex (PubMed:27113748). Forms a complex with CARD11 and MALT1; resulting in the formation of a CBM (CARD11-BCL10-MALT1) complex (PubMed:28628108, PubMed:24074955). Forms a complex with CARD9 and MALT1; resulting in the formation of a CBM (CARD9-BCL10-MALT1) complex (By similarity).TISSUE SPECIFICITY Highly expressed in peripheral blood mononuclear cells. Detected at lower levels in bone marrow, thymus and lymph node, and at very low levels in colon and lung.DISEASE A chromosomal aberration involving MALT1 is recurrent in low-grade mucosa-associated lymphoid tissue (MALT lymphoma). Translocation t(11;18)(q21;q21) with BIRC2. This translocation is found in approximately 50% of cytogenetically abnormal low-grade MALT lymphoma.SIMILARITY Belongs to the peptidase C14B family. UniProt Q9UDY8 1 EQUAL 824 EQUAL Reactome Database ID Release 78 202461 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202461 Reactome R-HSA-202461 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202461.1 3 Reactome Database ID Release 78 202487 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202487 Reactome R-HSA-202487 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202487.1 MALT1 trimer bound to Bcl10 and CARMA1 trimer Reactome DB_ID: 202468 1 1 Reactome Database ID Release 78 202468 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202468 Reactome R-HSA-202468 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202468.1 Reactome Database ID Release 78 202478 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202478 Reactome R-HSA-202478 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202478.1 15125833 Pubmed 2004 The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes Sun, L Deng, L Ea, CK Xia, ZP Chen, ZJ Mol Cell 14:289-301 LEFT-TO-RIGHT Translocation of TRAF6 to CBM complex TRAF6, which plays central role in innate immune responses, is implicated as proximal downstream effector of MALT1. TRAF6 is a member of the TRAF proteins. It contains an N-term RING domain, followed by several Zn finger domains and C-term MATH domain. The MALT1 oligomers bind to TRAF6, induce TRAF6 oligomerization and thereby activate the ubiquitin ligase activity of TRAF6 to polyubiquitinate itself and NEMO. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 TRAF6 Reactome DB_ID: 166366 UniProt:Q9Y4K3 TRAF6 TRAF6 RNF85 FUNCTION E3 ubiquitin ligase that, together with UBE2N and UBE2V1, mediates the synthesis of 'Lys-63'-linked-polyubiquitin chains conjugated to proteins, such as IKBKG, IRAK1, AKT1 and AKT2. Also mediates ubiquitination of free/unanchored polyubiquitin chain that leads to MAP3K7 activation. Leads to the activation of NF-kappa-B and JUN. May be essential for the formation of functional osteoclasts. Seems to also play a role in dendritic cells (DCs) maturation and/or activation. Represses c-Myb-mediated transactivation, in B-lymphocytes. Adapter protein that seems to play a role in signal transduction initiated via TNF receptor, IL-1 receptor and IL-17 receptor. Regulates osteoclast differentiation by mediating the activation of adapter protein complex 1 (AP-1) and NF-kappa-B, in response to RANK-L stimulation. Together with MAP3K8, mediates CD40 signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Homotrimer. Homooligomer. N-terminal region is dimeric while C-terminal region is trimeric; maybe providing a mode of oligomerization. Upon IL1B treatment, forms a complex with PELI1, IRAK1, IRAK4 and MYD88; this complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation. Direct binding of SMAD6 to PELI1 prevents the complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression. Binds to TNFRSF5/CD40 and TNFRSF11A/RANK. Associates with NGFR, TNFRSF17, IRAK2, IRAK3, RIPK2, MAP3K1, MAP3K5, MAP3K14, CSK, TRAF, TRAF-interacting protein TRIP and TNF receptor associated protein TDP2. Interacts with IL17R. Interacts with SQSTM1 bridging NTRK1 and NGFR. Forms a ternary complex with SQSTM1 and PRKCZ (By similarity). Interacts with PELI2 and PELI3. Binds UBE2V1. Interacts with TAX1BP1. Interacts with ZNF675. Interacts with ARRB1 and ARRB2. Interacts with MAP3K7 and TAB1/MAP3K7IP1; during IL-1 signaling. Interacts with UBE2N. Interacts with TGFBR1, HDAC1 and RANGAP1. Interacts with AKT1, AKT2 and AKT3. Interacts (via TRAF domains) with NUMBL (via C-terminal). Interacts with RBCK1. Interacts with LIMD1 (via LIM domains) (By similarity). Interacts with RSAD2/viperin (By similarity). Interacts (via C-terminus) with EIF2AK2/PKR (via the kinase catalytic domain) (By similarity). Interacts with ZFAND5. Interacts with IL1RL1. Interacts with TRAFD1. Interacts with AJUBA. Interacts with MAVS/IPS1. Interacts (via TRAF domains) with DYNC2I2 (via WD domains). Interacts with IFIT3 (via N-terminus). Interacts with TICAM2. Interacts with CARD14. Interacts with CD40 and MAP3K8; the interaction is required for ERK activation (By similarity). Interacts with TICAM1 and this interaction is enhanced in the presence of WDFY1 (PubMed:25736436). Interacts with TANK; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with USP10; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with ZC3H12A; this interaction increases in response to DNA damage and is stimulated by TANK (PubMed:25861989). Interacts with WDFY3 (By similarity). Interacts with TRIM13 (PubMed:28087809). Interacts with GPS2 (By similarity). Interacts (via C-terminus) with SASH1 (PubMed:23776175). Interacts with LRRC19 (PubMed:25026888). Interacts with IL17RA AND TRAF3IP2. Interacts with TOMM70 (PubMed:20628368).TISSUE SPECIFICITY Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.DOMAIN The coiled coil domain mediates homo- and hetero-oligomerization.DOMAIN The MATH/TRAF domain binds to receptor cytoplasmic domains.PTM Sumoylated on Lys-124, Lys-142 and Lys-453 with SUMO1.PTM Polyubiquitinated on Lys-124 by TRAF3IP2; after cell stimulation with IL17A (PubMed:19825828). Polyubiquitinated on Lys-124; after cell stimulation with IL1B or TGFB. This ligand-induced cell stimulation leads to dimerization/oligomerization of TRAF6 molecules, followed by auto-ubiquitination which involves UBE2N and UBE2V1 and leads to TRAF6 activation. This 'Lys-63' site-specific poly-ubiquitination appears to be associated with the activation of signaling molecules. Endogenous autoubiquitination occurs only for the cytoplasmic form. Deubiquitinated by USP10 in a TANK-dependent manner, leading to the negative regulation of NF-kappaB signaling upon DNA damage (PubMed:25861989). LRRC19 induces 'Lys-63' ubiquitination (PubMed:25026888).SIMILARITY Belongs to the TNF receptor-associated factor family. A subfamily. UniProt Q9Y4K3 1 EQUAL 522 EQUAL Reactome Database ID Release 78 166366 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=166366 Reactome R-HSA-166366 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-166366.1 3 TRAF6 trimer bound to CBM complex Reactome DB_ID: 202471 3 1 Reactome Database ID Release 78 202471 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202471 Reactome R-HSA-202471 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202471.1 Reactome Database ID Release 78 202472 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202472 Reactome R-HSA-202472 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202472.1 LEFT-TO-RIGHT 6.3.2.19 Auto-ubiquitination of TRAF6 TRAF6 possesses ubiquitin ligase activity and undergoes K-63-linked auto-ubiquitination after its oligomerization. In the first step, ubiquitin is activated by an E1 ubiquitin activating enzyme. The activated ubiquitin is transferred to a E2 conjugating enzyme (a heterodimer of proteins Ubc13 and Uev1A) forming the E2-Ub thioester. Finally, in the presence of ubiquitin-protein ligase E3 (TRAF6, a RING-domain E3), ubiquitin is attached to the target protein (TRAF6 on residue Lysine 124) through an isopeptide bond between the C-terminus of ubiquitin and the epsilon-amino group of a lysine residue in the target protein. In contrast to K-48-linked ubiquitination that leads to the proteosomal degradation of the target protein, K-63-linked polyubiquitin chains act as a scaffold to assemble protein kinase complexes and mediate their activation through proteosome-independent mechanisms. This K63 polyubiquitinated TRAF6 activates the TAK1 kinase complex. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Edited: Garapati, P V, 2010-11-08 K63polyUb K63-polyubiquitin Lys-63 polyubiquitin Reactome DB_ID: 450152 Reactome Database ID Release 78 450152 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450152 Reactome R-HSA-450152 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450152.2 ChEBI 36080 3 TRIKA1 UBE2N:UBE2V1 Ubc13:UBE2V1 TRAF6-regulated IKK activator 1 Reactome DB_ID: 202463 UBE2V1 Reactome DB_ID: 205753 UniProt:Q13404 UBE2V1 UBE2V1 CROC1 UBE2V UEV1 P/OKcl.19 FUNCTION Has no ubiquitin ligase activity on its own. The UBE2V1-UBE2N heterodimer catalyzes the synthesis of non-canonical poly-ubiquitin chains that are linked through Lys-63. This type of poly-ubiquitination activates IKK and does not seem to involve protein degradation by the proteasome. Plays a role in the activation of NF-kappa-B mediated by IL1B, TNF, TRAF6 and TRAF2. Mediates transcriptional activation of target genes. Plays a role in the control of progress through the cell cycle and differentiation. Plays a role in the error-free DNA repair pathway and contributes to the survival of cells after DNA damage. Promotes TRIM5 capsid-specific restriction activity and the UBE2V1-UBE2N heterodimer acts in concert with TRIM5 to generate 'Lys-63'-linked polyubiquitin chains which activate the MAP3K7/TAK1 complex which in turn results in the induction and expression of NF-kappa-B and MAPK-responsive inflammatory genes. Together with RNF135 and UBE2N, catalyzes the viral RNA-dependent 'Lys-63'-linked polyubiquitination of RIG-I/DDX58 to activate the downstream signaling pathway that leads to interferon beta production (PubMed:31006531). UBE2V1-UBE2N together with TRAF3IP2 E3 ubiquitin ligase mediate 'Lys-63'-linked polyubiquitination of TRAF6, a component of IL17A-mediated signaling pathway.SUBUNIT Heterodimer with UBE2N (PubMed:11057907, PubMed:16307917, PubMed:16893187). Interacts (UBE2V2-UBE2N heterodimer) with the E3 ligase STUB1 (via the U-box domain); the complex has a specific 'Lys-63'-linked polyubiquitination activity (PubMed:16307917). Interacts with TRAF6 (PubMed:11057907, PubMed:16307917).TISSUE SPECIFICITY Highly expressed in thyroid, pancreas, spinal cord, lymph node, trachea, adrenal gland, bone marrow and pancreas. Detected at low levels in heart, breast, placenta, brain, liver, kidney, stomach and lung.INDUCTION Down-regulated during differentiation of cultured colon adenocarcinoma cells.MISCELLANEOUS In human, PESD1/KUA and UBE2V1/UEV1 are adjacent genes which can produce independent proteins and can also be fused to form a PESD1-UBE2V1 hybrid protein.SIMILARITY Belongs to the ubiquitin-conjugating enzyme family. UniProt Q13404 2 EQUAL 147 EQUAL Reactome Database ID Release 78 205753 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=205753 Reactome R-HSA-205753 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-205753.1 1 UBE2N UBE2N(1-152) Ubc13 Reactome DB_ID: 206072 UniProt:P61088 UBE2N UBE2N BLU FUNCTION The UBE2V1-UBE2N and UBE2V2-UBE2N heterodimers catalyze the synthesis of non-canonical 'Lys-63'-linked polyubiquitin chains. This type of polyubiquitination does not lead to protein degradation by the proteasome. Mediates transcriptional activation of target genes. Plays a role in the control of progress through the cell cycle and differentiation. Plays a role in the error-free DNA repair pathway and contributes to the survival of cells after DNA damage. Acts together with the E3 ligases, HLTF and SHPRH, in the 'Lys-63'-linked poly-ubiquitination of PCNA upon genotoxic stress, which is required for DNA repair. Appears to act together with E3 ligase RNF5 in the 'Lys-63'-linked polyubiquitination of JKAMP thereby regulating JKAMP function by decreasing its association with components of the proteasome and ERAD. Promotes TRIM5 capsid-specific restriction activity and the UBE2V1-UBE2N heterodimer acts in concert with TRIM5 to generate 'Lys-63'-linked polyubiquitin chains which activate the MAP3K7/TAK1 complex which in turn results in the induction and expression of NF-kappa-B and MAPK-responsive inflammatory genes. Together with RNF135 and UB2V1, catalyzes the viral RNA-dependent 'Lys-63'-linked polyubiquitination of RIG-I/DDX58 to activate the downstream signaling pathway that leads to interferon beta production (PubMed:28469175, PubMed:31006531). UBE2V1-UBE2N together with TRAF3IP2 E3 ubiquitin ligase mediate 'Lys-63'-linked polyubiquitination of TRAF6, a component of IL17A-mediated signaling pathway.ACTIVITY REGULATION Activity is inhibited by binding to OTUB1, which prevents 'Lys-63'-linked polyubiquitination (PubMed:20725033, PubMed:22325355, PubMed:22367539). Activity is inhibited by GPS2, leading to prevent 'Lys-63'-linked polyubiquitination (By similarity).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Heterodimer with UBE2V2 (PubMed:10089880, PubMed:11473255, PubMed:14562038, PubMed:16307917, PubMed:16307917). Interacts (UBE2V2-UBE2N heterodimer) with the E3 ligase STUB1 (via the U-box domain); the complex has a specific 'Lys-63'-linked polyubiquitination activity (PubMed:16307917). Interacts with RNF8 and RNF168 (PubMed:16215985, PubMed:19203578). Interacts with RNF11 (PubMed:18615712). Interacts with the E3 ligases, HLTF and SHPRH; the interactions promote the 'Lys-63'-linked polyubiquitination of PCNA upon genotoxic stress and lead to DNA repair (PubMed:17108083, PubMed:17130289, PubMed:18316726, PubMed:18719106). Interacts with ARIH2 (via RING-type 2) (PubMed:19340006). Interacts with OTUB1; leading to inhibit E2-conjugating activity (PubMed:20725033, PubMed:22325355, PubMed:22367539). Interacts with GPS2; leading to inhibit E2-conjugating activity (By similarity). Interacts with DDX58 and RNF135; involved in DDX58 ubiquitination and activation (PubMed:28469175).PTM Conjugation to ISG15 impairs formation of the thioester bond with ubiquitin but not interaction with UBE2V2.SIMILARITY Belongs to the ubiquitin-conjugating enzyme family. UniProt P61088 1 EQUAL 152 EQUAL Reactome Database ID Release 78 206072 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=206072 Reactome R-HSA-206072 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-206072.1 1 Reactome Database ID Release 78 202463 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202463 Reactome R-HSA-202463 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202463.2 ComplexPortal CPX-485 3 Ub-TRAF6 trimer bound to CBM complex Reactome DB_ID: 202456 1 K63polyUb-TRAF6 K63-polyubiquitinated TRAF6 Oligo-K63-poly Ub-TRAF6 Poly-ubiquitinated TRAF6 Reactome DB_ID: 2685681 124 EQUAL ubiquitinylated lysine MOD MOD:01148 1 EQUAL 522 EQUAL Reactome Database ID Release 78 2685681 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2685681 Reactome R-HSA-2685681 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2685681.3 3 Reactome Database ID Release 78 202456 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202456 Reactome R-HSA-202456 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202456.1 3 ACTIVATION activeUnit: #Protein102 GENE ONTOLOGY GO:0004842 Reactome Database ID Release 78 203801 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=203801 Reactome Database ID Release 78 202453 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202453 Reactome R-HSA-202453 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202453.1 17135271 Pubmed 2007 Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation Lamothe, B Besse, A Campos, AD Webster, WK Wu, H Darnay, BG J Biol Chem 282:4102-12 LEFT-TO-RIGHT 2.7.11 Activation of TAK1-TAB2 complex Ubiquitinated TRAF6 recruits TAB2 and activates the TAB2-associated TAK1 kianse by promoting the autophosphorylation of TAK1. TAB2 contains an N-term pseudophosphatase domain, which is indispensable for TAK1 activation, and a C-term domain that binds to and activates TAK1. The activation of TAK1/TAB2 complex requires a ubiquitination reaction catalysed by E1, Ubc13/Uev1A (E2) and TRAF6 (E3). TAK1 undergoes autophosphorylation on residues T184 and T187 and gets activated. Activated TAK1 then phosphorylates and activates IKK beta. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 2 TAB2/TAK1 complex Reactome DB_ID: 202504 p-TAK1 p-MAP3K7 TAK1-P Reactome DB_ID: 168163 UniProt:O43318 MAP3K7 MAP3K7 TAK1 FUNCTION Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signal transduction of TRAF6, various cytokines including interleukin-1 (IL-1), transforming growth factor-beta (TGFB), TGFB-related factors like BMP2 and BMP4, toll-like receptors (TLR), tumor necrosis factor receptor CD40 and B-cell receptor (BCR). Ceramides are also able to activate MAP3K7/TAK1. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K1/MEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs, c-jun N-terminal kinases (JNKs) and I-kappa-B kinase complex (IKK). Both p38 MAPK and JNK pathways control the transcription factors activator protein-1 (AP-1), while nuclear factor-kappa B is activated by IKK. MAP3K7 activates also IKBKB and MAPK8/JNK1 in response to TRAF6 signaling and mediates BMP2-induced apoptosis. In osmotic stress signaling, plays a major role in the activation of MAPK8/JNK1, but not that of NF-kappa-B. Promotes TRIM5 capsid-specific restriction activity. Phosphorylates RIPK1 at 'Ser-321' which positively regulates RIPK1 interaction with RIPK3 to promote necroptosis but negatively regulates RIPK1 kinase activity and its interaction with FADD to mediate apoptosis (By similarity).ACTIVITY REGULATION Activated by proinflammatory cytokines and in response to physical and chemical stresses, including osmotic stress, oxidative stress, arsenic and ultraviolet light irradiation. Activated by 'Lys-63'-linked polyubiquitination and by autophosphorylation. Association with TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2 promotes activation through autophosphorylation, whereas PPM1B/PP2CB, PP2A and PPP6C dephosphorylation leads to inactivation.SUBUNIT Can form homodimer (PubMed:27426733). Binds both upstream activators and downstream substrates in multimolecular complexes. Interacts with TAB1/MAP3K7IP1, TAB2/MAP3K7IP2 and TAB3/MAP3K7IP3 (PubMed:10838074, PubMed:11460167, PubMed:12242293, PubMed:14670075, PubMed:16289117, PubMed:19675569, PubMed:8638164). Identified in the TRIKA2 complex composed of MAP3K7/TAK1, TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2 (PubMed:11460167). Interacts with PPM1L and PPM1B/PP2CB (PubMed:11104763). Interaction with PP2A and PPP6C leads to its repressed activity (PubMed:17079228). Interacts with TRAF6 and TAB1/MAP3K7IP1; during IL-1 signaling (PubMed:10094049, PubMed:12242293). Interacts with TAOK1 and TAOK2; interaction with TAOK2 interferes with MAP3K7 interaction with IKKA, thus preventing NF-kappa-B activation (PubMed:16893890). Interacts with DYNC2I2 (via WD domains) (PubMed:19521662). Interacts with CYLD and RBCK1 (PubMed:17449468, PubMed:17548520). Interacts with TGFBR1; induces MAP3K7/TAK1 activation by TRAF6 (PubMed:18758450). Interacts with MAPK8IP1 and SMAD6 (By similarity). Interacts with isoform 1 of VRK2 (PubMed:18286207). Interacts with DAB2; the interaction is induced by TGF-beta stimulation and may mediate TGF-beta stimulated JNK activation (PubMed:15894542). Interacts with TRIM5 (PubMed:21512573). Part of a complex containing ITCH, NDFIP1 and MAP3K7 (By similarity). Interacts with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation (PubMed:26334375). Interacts with PLEKHM1 (via N- and C-terminus) (By similarity). Interacts with TRIM8 (PubMed:22084099). Found in a complex with SH3RF1, RAC2, MAP2K7/MKK7, MAPK8IP1/JIP1, MAPK8/JNK1 and MAPK9/JNK2 (By similarity). Interacts with SASH1 (PubMed:23776175). Interacts with RIPK1 (By similarity).SUBUNIT (Microbial infection) Interacts with herpes simplex virus 2 protein US2; this interaction induces MAP3K7 phosphorylation and subsequent activation.TISSUE SPECIFICITY Isoform 1A is the most abundant in ovary, skeletal muscle, spleen and blood mononuclear cells. Isoform 1B is highly expressed in brain, kidney and small intestine. Isoform 1C is the major form in prostate. Isoform 1D is the less abundant form.PTM Association with TAB1/MAP3K7IP1 promotes autophosphorylation at Ser-192 and subsequent activation. Association with TAB2/MAP3K7IP2, itself associated with free unanchored Lys-63 polyubiquitin chain, promotes autophosphorylation and subsequent activation of MAP3K7. Dephosphorylation at Ser-192 by PPM1B/PP2CB and at Thr-187 by PP2A and PPP6C leads to inactivation.PTM 'Lys-48'-linked polyubiquitination at Lys-72 is induced by TNFalpha, and leads to proteasomal degradation. Undergoes 'Lys-48'-linked polyubiquitination catalyzed by ITCH (By similarity). Requires 'Lys-63'-linked polyubiquitination for autophosphorylation and subsequent activation. 'Lys-63'-linked ubiquitination does not lead to proteasomal degradation. Deubiquitinated by CYLD, a protease that selectively cleaves 'Lys-63'-linked ubiquitin chains. Deubiquitinated by Y.enterocolitica YopP.PTM (Microbial infection) Cleaved and inactivated by the proteases 3C of coxsackievirus A16 and human enterovirus D68, allowing the virus to disrupt TRAF6-triggered NF-kappa-B induction.PTM (Microbial infection) Acetylation of Thr-184 and Thr-187 by Yersinia YopJ prevents phosphorylation and activation, thus blocking the MAPK signaling pathway.SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily. UniProt O43318