BioPAX pathway converted from "Immune System" in the Reactome database. Immune System 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 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 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 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 Interaction of Csk with PAG 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 Reactome DB_ID: 180494 1 plasma membrane GO 0005886 UniProt:Q9NWQ8 PAG1 PAG1 CBP PAG PAG1 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. Reactome http://www.reactome.org Homo sapiens NCBI Taxonomy 9606 UniProt Q9NWQ8 O4'-phospho-L-tyrosine at 317 317 EQUAL O4'-phospho-L-tyrosine [MOD:00048] Chain Coordinates 1 EQUAL 432 EQUAL Reactome DB_ID: 203776 1 cytosol GO 0005829 UniProt:P41240 CSK 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 DB_ID: 202297 1 Csk:p-PAG [plasma membrane] Csk:p-PAG Reactome DB_ID: 180494 1 O4'-phospho-L-tyrosine at 317 317 EQUAL 1 EQUAL 432 EQUAL Reactome DB_ID: 203776 1 1 EQUAL 450 EQUAL 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 2.7.10 Inactivation of Lck by Csk 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 Reactome DB_ID: 113592 1 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 202157 1 Antigen-bearing MHC Class II : TCR complex:CD4:Lck [plasma membrane] Antigen-bearing MHC Class II : TCR complex:CD4:Lck Reactome DB_ID: 198901 1 T-cell receptor complex [plasma membrane] T-cell receptor complex Reactome DB_ID: 198183 1 T-cell receptor [plasma membrane] T-cell receptor Converted from EntitySet in Reactome Reactome DB_ID: 198184 1 TCR chain alpha [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity TCRA [plasma membrane] TRAC [plasma membrane] T-cell receptor alpha chain V region PY14 precursor [plasma membrane] TRAV19 [plasma membrane] UniProt P04437 UniProt P01848 UniProt P01737 UniProt A0A0A6YYK7 Converted from EntitySet in Reactome Reactome DB_ID: 198177 1 TCR chain beta [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity TCRB [plasma membrane] TRBC1 [plasma membrane] TRBV12-3 [plasma membrane] UniProt P04435 UniProt P01850 UniProt P01733 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 Reactome DB_ID: 198902 1 CD3 epsilon gamma [plasma membrane] CD3 epsilon gamma Reactome DB_ID: 197917 1 UniProt:P09693 CD3G CD3G T3G CD3G 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 DB_ID: 197906 1 UniProt:P07766 CD3E CD3E T3E CD3E 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 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 Reactome DB_ID: 198900 1 CD3 epsilon delta [plasma membrane] CD3 epsilon delta Reactome DB_ID: 197906 1 23 EQUAL 207 EQUAL Reactome DB_ID: 198171 1 UniProt:P04234 CD3D CD3D T3D CD3D 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 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 Reactome DB_ID: 198166 2 UniProt:P20963-1 CD247 CD247 TCRZ CD3Z T3Z CD247 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 P20963-1 22 EQUAL 164 EQUAL 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 Reactome DB_ID: 167542 1 UniProt:P01730 CD4 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 DB_ID: 203463 1 MHC Class II bearing antigen peptide [plasma membrane] MHC Class II bearing antigen peptide Reactome DB_ID: 173548 1 Antigen [plasma membrane] Antigen Reactome DB_ID: 2213189 1 MHC class II alpha/beta dimer [plasma membrane] MHC class II alpha/beta dimer Converted from EntitySet in Reactome Reactome DB_ID: 2130476 1 HLA II beta chain [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity HLA class II histocompatibility antigen, DRB1-16 beta chain [plasma membrane] HLA class II histocompatibility antigen, DR beta 5 chain [plasma membrane] HLA class II histocompatibility antigen, DQB1*0602 beta chain precursor [plasma membrane] HLA class II histocompatibility antigen, DRB1-13 beta chain [plasma membrane] HLA class II histocompatibility antigen, DR-1 beta chain precursor [plasma membrane] HLA class II histocompatibility antigen, DRB1-12 beta chain [plasma membrane] HLA class II histocompatibility antigen, DRB1-14 beta chain [plasma membrane] HLA class II histocompatibility antigen, DRB1-8 beta chain [plasma membrane] HLA class II histocompatibility antigen, DRB3-1 beta chain precursor [plasma membrane] HLA class II histocompatibility antigen, DRB1-11 beta chain [plasma membrane] HLA class II histocompatibility antigen, DRB1-15 beta chain [plasma membrane] HLA class II histocompatibility antigen, DRB1-7 beta chain [plasma membrane] HLA class II histocompatibility antigen, DQ [plasma membrane] HLA class II histocompatibility antigen, DRB1-10 beta chain [plasma membrane] HLA class II histocompatibility antigen, DRB1-9 beta chain precursor [plasma membrane] HLA class II histocompatibility antigen, DQ beta 2 chain [plasma membrane] HLA class II histocompatibility antigen, DP [plasma membrane] HLA class II histocompatibility antigen, DR beta 4 chain [plasma membrane] HLA class II histocompatibility antigen, DRB1-1 beta chain [plasma membrane] HLA class II histocompatibility antigen, DRB1-4 beta chain [plasma membrane] UniProt Q29974 UniProt Q30154 UniProt P01920 UniProt Q5Y7A7 UniProt P01912 UniProt Q95IE3 UniProt Q9GIY3 UniProt Q30134 UniProt P79483 UniProt P20039 UniProt P01911 UniProt P13761 UniProt Q30167 UniProt Q9TQE0 UniProt P05538 UniProt P04440 UniProt P13762 UniProt P04229 UniProt P13760 Converted from EntitySet in Reactome Reactome DB_ID: 2130597 1 HLA II alpha chain [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity HLA class II histocompatibility antigen, DR alpha chain precursor [plasma membrane] HLA class II histocompatibility antigen, DQ [plasma membrane] HLA class II histocompatibility antigen, DQ [plasma membrane] HLA class II histocompatibility antigen, DP alpha chain precursor [plasma membrane] UniProt P01903 UniProt P01909 UniProt P01906 UniProt P20036 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 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 Reactome DB_ID: 167609 1 UniProt:P06239 LCK 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 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 Reactome DB_ID: 29370 1 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 Reactome DB_ID: 202154 1 Antigen-bearing MHC Class II : TCR complex:CD4:p-Lck(Y505) [plasma membrane] Antigen-bearing MHC Class II : TCR complex:CD4:p-Lck(Y505) Reactome DB_ID: 202159 1 O4'-phospho-L-tyrosine at 505 505 EQUAL 1 EQUAL 509 EQUAL Reactome DB_ID: 198901 1 Reactome DB_ID: 167542 1 26 EQUAL 458 EQUAL Reactome DB_ID: 203463 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 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 202297 GO 0004713 GO molecular function 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 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 Reactome DB_ID: 6785270 CD45,CD148 [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PTPRC [plasma membrane] PTPRJ [plasma membrane] UniProt P08575 UniProt Q12913 3.1.3.48 Dephosphorylation of Lck-pY505 by CD45 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 Reactome DB_ID: 202154 1 Reactome DB_ID: 29356 1 water [ChEBI:15377] water ChEBI 15377 Reactome DB_ID: 202157 1 Reactome DB_ID: 29372 1 hydrogenphosphate [ChEBI:43474] hydrogenphosphate [PO3(OH)](2-) HYDROGENPHOSPHATE ION hydrogen phosphate [P(OH)O3](2-) HPO4(2-) phosphate INORGANIC PHOSPHATE GROUP ChEBI 43474 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 6785270 GO 0004725 GO molecular function 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 2.7.10 Activation of Lck 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 Reactome DB_ID: 113592 1 Reactome DB_ID: 202157 1 Reactome DB_ID: 29370 1 Reactome DB_ID: 202266 1 Antigen-bearing MHC Class II :TCR complex:CD4: Lck phosphorylated at Tyr394 [plasma membrane] Antigen-bearing MHC Class II :TCR complex:CD4: Lck phosphorylated at Tyr394 Reactome DB_ID: 198901 1 Reactome DB_ID: 202308 1 O4'-phospho-L-tyrosine at 394 394 EQUAL 1 EQUAL 509 EQUAL Reactome DB_ID: 167542 1 26 EQUAL 458 EQUAL Reactome DB_ID: 203463 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 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 202157 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 PTPN22 dissociates from CSK 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 Reactome DB_ID: 8855376 1 PTPN22:CSK [cytosol] PTPN22:CSK Reactome DB_ID: 8852205 1 UniProt:Q9Y2R2 PTPN22 PTPN22 PTPN8 PTPN22 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 DB_ID: 203776 1 1 EQUAL 450 EQUAL 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 DB_ID: 8852205 1 1 EQUAL 807 EQUAL Reactome DB_ID: 203776 1 1 EQUAL 450 EQUAL 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 3.1.3.48 Inactivation of LCK by PTPN22 Inactivation of LCK by PTPN22 Inactivation of LCK by LYP 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 Reactome DB_ID: 29356 1 Reactome DB_ID: 202266 1 Reactome DB_ID: 202157 1 Reactome DB_ID: 29372 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 8852205 1 EQUAL 807 EQUAL 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 2.7.10 Phosphorylation of ITAM motifs in CD3 complexes 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 Reactome DB_ID: 113592 20 Reactome DB_ID: 202266 1 Reactome DB_ID: 29370 20 Reactome DB_ID: 203494 1 Antigen-bearing MHC Class II: TCR with phosphorylated ITAMs:CD4 [plasma membrane] Antigen-bearing MHC Class II: TCR with phosphorylated ITAMs:CD4 Reactome DB_ID: 203493 1 T-cell receptor complex with phosphorylated ITAMs [plasma membrane] T-cell receptor complex with phosphorylated ITAMs Reactome DB_ID: 198183 1 Reactome DB_ID: 202336 1 CD3 epsilon: CD3 delta with phosphorylated ITAMs [plasma membrane] CD3 epsilon: CD3 delta with phosphorylated ITAMs Reactome DB_ID: 202228 1 O4'-phospho-L-tyrosine at 188 188 EQUAL O4'-phospho-L-tyrosine at 199 199 EQUAL 23 EQUAL 207 EQUAL Reactome DB_ID: 202329 1 O4'-phospho-L-tyrosine at 149 149 EQUAL O4'-phospho-L-tyrosine at 160 160 EQUAL 22 EQUAL 171 EQUAL 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 Reactome DB_ID: 202167 1 CD3 epsilon: CD3 gamma with phosphorylated ITAM [plasma membrane] CD3 epsilon: CD3 gamma with phosphorylated ITAM Reactome DB_ID: 202228 1 O4'-phospho-L-tyrosine at 188 188 EQUAL O4'-phospho-L-tyrosine at 199 199 EQUAL 23 EQUAL 207 EQUAL Reactome DB_ID: 202362 1 O4'-phospho-L-tyrosine at 160 160 EQUAL O4'-phospho-L-tyrosine at 171 171 EQUAL 23 EQUAL 182 EQUAL 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 Reactome DB_ID: 202303 1 p-6Y-CD247 dimer [plasma membrane] p-6Y-CD247 dimer CD3 zeta dimer with phosphorylated ITAMs Reactome DB_ID: 202166 2 O4'-phospho-L-tyrosine at 72 72 EQUAL O4'-phospho-L-tyrosine at 83 83 EQUAL O4'-phospho-L-tyrosine at 111 111 EQUAL O4'-phospho-L-tyrosine at 123 123 EQUAL O4'-phospho-L-tyrosine at 142 142 EQUAL O4'-phospho-L-tyrosine at 153 153 EQUAL 22 EQUAL 164 EQUAL 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 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 Reactome DB_ID: 202308 1 O4'-phospho-L-tyrosine at 394 394 EQUAL 1 EQUAL 509 EQUAL Reactome DB_ID: 167542 1 26 EQUAL 458 EQUAL Reactome DB_ID: 203463 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 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 202266 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 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 Recruitment of ZAP-70 to phosphorylated ITAMs 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 Reactome DB_ID: 203494 1 Reactome DB_ID: 202397 1 UniProt:P43403 ZAP70 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 DB_ID: 202330 1 ZAP-70 bound to phosphorylated ITAM motifs [plasma membrane] ZAP-70 bound to phosphorylated ITAM motifs Reactome DB_ID: 203494 1 Reactome DB_ID: 202397 1 1 EQUAL 619 EQUAL 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 2.7.10 Phosphorylation of ZAP-70 by Lck 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 Reactome DB_ID: 202330 1 Reactome DB_ID: 113592 1 Reactome DB_ID: 29370 1 Reactome DB_ID: 202345 1 phospho tyrosine ZAP-70 [plasma membrane] phospho tyrosine ZAP-70 Reactome DB_ID: 203494 1 Reactome DB_ID: 202368 1 O4'-phospho-L-tyrosine at 493 493 EQUAL 1 EQUAL 619 EQUAL 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 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 202266 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 3.1.3.48 PTPN22 dephosphorylates ZAP70 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 Reactome DB_ID: 202345 1 Reactome DB_ID: 29356 1 Reactome DB_ID: 202330 1 Reactome DB_ID: 29372 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 8852205 1 EQUAL 807 EQUAL 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 2.7.10 Activation of ZAP-70 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 Reactome DB_ID: 202345 1 Reactome DB_ID: 113592 1 Reactome DB_ID: 29370 1 Reactome DB_ID: 202181 1 Activated ZAP-70 [plasma membrane] Activated ZAP-70 Reactome DB_ID: 203494 1 Reactome DB_ID: 202252 1 O4'-phospho-L-tyrosine at 493 493 EQUAL O4'-phospho-L-tyrosine at 315 315 EQUAL 1 EQUAL 619 EQUAL 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 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 202345 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 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 2.7.10 Phosphorylation of TBSMs in LAT 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 Reactome DB_ID: 202322 1 UniProt:O43561 LAT 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 DB_ID: 113592 5 Reactome DB_ID: 29370 5 Reactome DB_ID: 202364 1 O4'-phospho-L-tyrosine at 161 161 EQUAL O4'-phospho-L-tyrosine at 200 200 EQUAL O4'-phospho-L-tyrosine at 220 220 EQUAL O4'-phospho-L-tyrosine at 255 255 EQUAL O4'-phospho-L-tyrosine at 156 156 EQUAL 1 EQUAL 262 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 202181 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 Recruitment of Gads to LAT 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 Reactome DB_ID: 202364 1 O4'-phospho-L-tyrosine at 161 161 EQUAL O4'-phospho-L-tyrosine at 200 200 EQUAL O4'-phospho-L-tyrosine at 220 220 EQUAL O4'-phospho-L-tyrosine at 255 255 EQUAL O4'-phospho-L-tyrosine at 156 156 EQUAL 1 EQUAL 262 EQUAL Reactome DB_ID: 202367 1 UniProt:O75791 GRAP2 GRAP2 GRAP2 GRID GADS GRB2L 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 DB_ID: 202177 1 GADS:p-5Y-LAT [plasma membrane] GADS:p-5Y-LAT Reactome DB_ID: 202364 1 O4'-phospho-L-tyrosine at 161 161 EQUAL O4'-phospho-L-tyrosine at 200 200 EQUAL O4'-phospho-L-tyrosine at 220 220 EQUAL O4'-phospho-L-tyrosine at 255 255 EQUAL O4'-phospho-L-tyrosine at 156 156 EQUAL 1 EQUAL 262 EQUAL Reactome DB_ID: 202367 1 1 EQUAL 330 EQUAL 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 Recruitment of SLP-76 to Gads 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 Reactome DB_ID: 202177 1 Reactome DB_ID: 202306 1 UniProt:Q13094 LCP2 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 DB_ID: 202151 1 SLP-76 bound to Gads:LAT [plasma membrane] SLP-76 bound to Gads:LAT Reactome DB_ID: 202177 1 Reactome DB_ID: 202306 1 1 EQUAL 533 EQUAL 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 2.7.10 Phosphorylation of SLP-76 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 Reactome DB_ID: 113592 3 Reactome DB_ID: 202151 1 Reactome DB_ID: 29370 3 Reactome DB_ID: 202162 1 p-Y113,128,145-SLP-76:GADS:LAT [plasma membrane] p-Y113,128,145-SLP-76:GADS:LAT Reactome DB_ID: 202177 1 Reactome DB_ID: 202175 1 O4'-phospho-L-tyrosine at 113 113 EQUAL O4'-phospho-L-tyrosine at 128 128 EQUAL O4'-phospho-L-tyrosine at 145 145 EQUAL 1 EQUAL 533 EQUAL 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 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 202181 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 Recruitment of ITK to SLP-76 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 Reactome DB_ID: 202162 1 Reactome DB_ID: 202319 1 UniProt:Q08881 ITK 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 DB_ID: 202359 1 ITK:p-Y113,128,145-SLP-76:GADS:LAT [plasma membrane] ITK:p-Y113,128,145-SLP-76:GADS:LAT Reactome DB_ID: 202162 1 Reactome DB_ID: 202319 1 1 EQUAL 620 EQUAL 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 Recruitment of PLC-gamma1 to SLP-76 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 Reactome DB_ID: 202162 1 Reactome DB_ID: 202320 1 UniProt:P19174 PLCG1 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 DB_ID: 202279 1 PLCG1:p-3Y-SLP-76:Gads:LAT [plasma membrane] PLCG1:p-3Y-SLP-76:Gads:LAT Reactome DB_ID: 202162 1 Reactome DB_ID: 202320 1 2 EQUAL 1290 EQUAL 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 Recruitment of PLC-gamma1 to LAT 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 Reactome DB_ID: 202320 1 2 EQUAL 1290 EQUAL Reactome DB_ID: 202364 1 O4'-phospho-L-tyrosine at 161 161 EQUAL O4'-phospho-L-tyrosine at 200 200 EQUAL O4'-phospho-L-tyrosine at 220 220 EQUAL O4'-phospho-L-tyrosine at 255 255 EQUAL O4'-phospho-L-tyrosine at 156 156 EQUAL 1 EQUAL 262 EQUAL Reactome DB_ID: 202240 1 PLCG1:p-5Y-LAT [plasma membrane] PLCG1:p-5Y-LAT Reactome DB_ID: 202320 1 2 EQUAL 1290 EQUAL Reactome DB_ID: 202364 1 O4'-phospho-L-tyrosine at 161 161 EQUAL O4'-phospho-L-tyrosine at 200 200 EQUAL O4'-phospho-L-tyrosine at 220 220 EQUAL O4'-phospho-L-tyrosine at 255 255 EQUAL O4'-phospho-L-tyrosine at 156 156 EQUAL 1 EQUAL 262 EQUAL 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 2.7.10 Phosphorylation of PLC-gamma1 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 Reactome DB_ID: 113592 3 Converted from EntitySet in Reactome Reactome DB_ID: 202318 1 PLC-gamma1 bound to LAT or SLP-76 [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 29370 3 Converted from EntitySet in Reactome Reactome DB_ID: 202193 1 Phosphorylated PLC-gamma1 bound to LAT or SLP-76 [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 202282 ZAP-70 and ITK tyrosine kinases [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity 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 Reactome DB_ID: 8866028 UniProt:Q93033 CD101 CD101 EWI101 V7 IGSF2 CD101 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 Disassociation of PLC-gamma1 from LAT 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 DB_ID: 202310 1 phosphorylated PLC-gamma1 bound to LAT [plasma membrane] phosphorylated PLC-gamma1 bound to LAT Reactome DB_ID: 202364 1 O4'-phospho-L-tyrosine at 161 161 EQUAL O4'-phospho-L-tyrosine at 200 200 EQUAL O4'-phospho-L-tyrosine at 220 220 EQUAL O4'-phospho-L-tyrosine at 255 255 EQUAL O4'-phospho-L-tyrosine at 156 156 EQUAL 1 EQUAL 262 EQUAL Reactome DB_ID: 202357 1 O4'-phospho-L-tyrosine at 771 771 EQUAL O4'-phospho-L-tyrosine at 783 783 EQUAL O4'-phospho-L-tyrosine at 1253 1253 EQUAL 2 EQUAL 1290 EQUAL 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 Reactome DB_ID: 202364 1 O4'-phospho-L-tyrosine at 161 161 EQUAL O4'-phospho-L-tyrosine at 200 200 EQUAL O4'-phospho-L-tyrosine at 220 220 EQUAL O4'-phospho-L-tyrosine at 255 255 EQUAL O4'-phospho-L-tyrosine at 156 156 EQUAL 1 EQUAL 262 EQUAL Reactome DB_ID: 202357 1 O4'-phospho-L-tyrosine at 771 771 EQUAL O4'-phospho-L-tyrosine at 783 783 EQUAL O4'-phospho-L-tyrosine at 1253 1253 EQUAL 2 EQUAL 1290 EQUAL 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 Disassociation of PLC-gamma1 from SLP-76 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 DB_ID: 202302 1 phosphorylated PLC-gamma1 bound to SLP-76 [plasma membrane] phosphorylated PLC-gamma1 bound to SLP-76 Reactome DB_ID: 202162 1 Reactome DB_ID: 202357 1 O4'-phospho-L-tyrosine at 771 771 EQUAL O4'-phospho-L-tyrosine at 783 783 EQUAL O4'-phospho-L-tyrosine at 1253 1253 EQUAL 2 EQUAL 1290 EQUAL 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 DB_ID: 202162 1 Reactome DB_ID: 202357 1 O4'-phospho-L-tyrosine at 771 771 EQUAL O4'-phospho-L-tyrosine at 783 783 EQUAL O4'-phospho-L-tyrosine at 1253 1253 EQUAL 2 EQUAL 1290 EQUAL 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 Translocation of PLC-gamma1 to PIP2 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 Reactome DB_ID: 179856 1 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate [ChEBI:18348] 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate PIP2 ChEBI 18348 Reactome DB_ID: 202357 1 O4'-phospho-L-tyrosine at 771 771 EQUAL O4'-phospho-L-tyrosine at 783 783 EQUAL O4'-phospho-L-tyrosine at 1253 1253 EQUAL 2 EQUAL 1290 EQUAL Reactome DB_ID: 202269 1 Activated PLC gamma1 bound to PIP2 [plasma membrane] Activated PLC gamma1 bound to PIP2 Reactome DB_ID: 167679 1 O4'-phospho-L-tyrosine at 472 472 EQUAL O4'-phospho-L-tyrosine at 771 771 EQUAL O4'-phospho-L-tyrosine at 783 783 EQUAL O4'-phospho-L-tyrosine at 1253 1253 EQUAL 2 EQUAL 1290 EQUAL Reactome DB_ID: 179856 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 3.1.4.11 PLC-gamma1 hydrolyses PIP2 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 Reactome DB_ID: 29356 1 Reactome DB_ID: 179856 1 Reactome DB_ID: 114520 1 1D-myo-inositol 1,4,5-trisphosphate [ChEBI:16595] 1D-myo-inositol 1,4,5-trisphosphate ChEBI 16595 Reactome DB_ID: 112275 1 diglyceride [ChEBI:18035] diglyceride ChEBI 18035 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2029095 p-PLCG [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity p-4Y-PLCG1 [plasma membrane] p-Y753,Y759,Y1217-PLCG2 [plasma membrane] UniProt P16885 GO 0004435 GO molecular function 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 p-SLP-76 binds ADAP 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 Reactome DB_ID: 390925 1 UniProt:O15117 FYB1 FYB1 FYB1 SLAP130 FYB 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 DB_ID: 202175 1 O4'-phospho-L-tyrosine at 113 113 EQUAL O4'-phospho-L-tyrosine at 128 128 EQUAL O4'-phospho-L-tyrosine at 145 145 EQUAL 1 EQUAL 533 EQUAL Reactome DB_ID: 430124 1 p-SLP-76:ADAP [cytosol] p-SLP-76:ADAP Reactome DB_ID: 390925 1 2 EQUAL 783 EQUAL Reactome DB_ID: 202175 1 O4'-phospho-L-tyrosine at 113 113 EQUAL O4'-phospho-L-tyrosine at 128 128 EQUAL O4'-phospho-L-tyrosine at 145 145 EQUAL 1 EQUAL 533 EQUAL 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 p-SLP-76:ADAP binds Ena/VASP 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 Reactome DB_ID: 430124 1 Converted from EntitySet in Reactome Reactome DB_ID: 430213 1 Ena/VASP proteins [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity ENAH [cytosol] VASP [cytosol] UniProt Q8N8S7 UniProt P50552 Reactome DB_ID: 430206 1 p-SLP-76:ADAP:Ena/VASP [cytosol] p-SLP-76:ADAP:Ena/VASP Reactome DB_ID: 430124 1 Converted from EntitySet in Reactome Reactome DB_ID: 430213 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 p-SLP-76 binds NCK 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 Reactome DB_ID: 202175 1 O4'-phospho-L-tyrosine at 113 113 EQUAL O4'-phospho-L-tyrosine at 128 128 EQUAL O4'-phospho-L-tyrosine at 145 145 EQUAL 1 EQUAL 533 EQUAL Reactome DB_ID: 197954 1 UniProt:P16333 NCK1 NCK1 NCK NCK1 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 DB_ID: 430188 1 p-SLP-76:NCK1 [cytosol] p-SLP-76:NCK1 Reactome DB_ID: 197954 1 1 EQUAL 377 EQUAL Reactome DB_ID: 202175 1 O4'-phospho-L-tyrosine at 113 113 EQUAL O4'-phospho-L-tyrosine at 128 128 EQUAL O4'-phospho-L-tyrosine at 145 145 EQUAL 1 EQUAL 533 EQUAL 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 NCK binds PAK 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 Reactome DB_ID: 430188 1 Converted from EntitySet in Reactome Reactome DB_ID: 390765 1 PAK1,2,3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PAK3 [cytosol] PAK1 [cytosol] PAK2 [cytosol] UniProt O75914 UniProt Q13153 UniProt Q13177 Reactome DB_ID: 430189 1 p-SLP-76:NCK:PAK [cytosol] p-SLP-76:NCK:PAK Reactome DB_ID: 430188 1 Converted from EntitySet in Reactome Reactome DB_ID: 390765 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 NCK recruits WASP 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 Reactome DB_ID: 430188 1 Reactome DB_ID: 201879 1 UniProt:P42768 WAS WAS IMD2 WAS 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 DB_ID: 430186 1 p-SLP-76:NCK1:WASP [cytosol] p-SLP-76:NCK1:WASP Reactome DB_ID: 430188 1 Reactome DB_ID: 201879 1 2 EQUAL 502 EQUAL 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 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 Recruitment of PI3K to plasma membrane 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 Reactome DB_ID: 202201 1 UniProt:Q6PIZ9 TRAT1 TRAT1 TRAT1 HSPC062 TCRIM 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 O4'-phospho-L-tyrosine at 63 63 EQUAL O4'-phospho-L-tyrosine at 79 79 EQUAL O4'-phospho-L-tyrosine at 110 110 EQUAL 1 EQUAL 186 EQUAL Reactome DB_ID: 74693 1 PI3K [cytosol] PI3K Converted from EntitySet in Reactome Reactome DB_ID: 74689 1 PI3K-catalytic subunit [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PIK3CB [cytosol] PIK3CA [cytosol] UniProt P42338 UniProt P42336 Converted from EntitySet in Reactome Reactome DB_ID: 74688 1 PI3K-regulatory subunit [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PIK3R2 [cytosol] PIK3R1 [cytosol] UniProt O00459 UniProt P27986 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 Reactome DB_ID: 202283 1 PI3K bound to TRAT [plasma membrane] PI3K bound to TRAT Reactome DB_ID: 202201 1 O4'-phospho-L-tyrosine at 63 63 EQUAL O4'-phospho-L-tyrosine at 79 79 EQUAL O4'-phospho-L-tyrosine at 110 110 EQUAL 1 EQUAL 186 EQUAL Reactome DB_ID: 74693 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 2.7.1.153 PI3K bound to TRAT1 phosphorylates PIP2 to PIP3 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 Reactome DB_ID: 113592 1 Reactome DB_ID: 179856 1 Reactome DB_ID: 29370 1 Reactome DB_ID: 179838 1 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate [ChEBI:16618] 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate PIP3 ChEBI 16618 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 202283 GO 0046934 GO molecular function 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 3.1.3.67 Hydrolysis of PIP3 to PI(3,4)P2 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 Reactome DB_ID: 29356 1 Reactome DB_ID: 179838 1 Reactome DB_ID: 29372 1 Reactome DB_ID: 202247 1 1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate [ChEBI:16152] 1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate ChEBI 16152 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 197940 UniProt:Q92835 INPP5D INPP5D INPP5D SHIP1 SHIP 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 GO 0016314 GO molecular function 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 3.1.3.67 PTEN dephosphorylates PIP3 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 Reactome DB_ID: 29356 1 Reactome DB_ID: 179838 1 Reactome DB_ID: 29372 1 Reactome DB_ID: 179856 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 199420 UniProt:P60484 PTEN PTEN TEP1 PTEN MMAC1 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 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 GO 0051898 GO biological process Translocation of PDK1 to Plasma membrane 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 Reactome DB_ID: 202277 1 PIP3, PI(3,4)P2 [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PI(3,4,5)P3 [plasma membrane] PI(3,4)P2 [plasma membrane] Reactome DB_ID: 202210 1 UniProt:O15530 PDPK1 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 DB_ID: 202311 1 PDK1:PIP2,PIP3 [plasma membrane] PDK1:PIP2,PIP3 PDK1 bound to either PIP3 or PI(3,4)P2 Reactome DB_ID: 61459 1 1 EQUAL 556 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 202277 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 Translocation of PKC theta to plasma membrane 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 Reactome DB_ID: 112275 1 Reactome DB_ID: 202185 1 UniProt:Q04759 PRKCQ PRKCQ PRKCT PRKCQ 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 DB_ID: 202187 1 PKC-theta (open): DAG [plasma membrane] PKC-theta (open): DAG Reactome DB_ID: 202346 1 1 EQUAL 706 EQUAL Reactome DB_ID: 112275 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 2.7.10 Change of PKC theta conformation 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 Reactome DB_ID: 113592 1 Reactome DB_ID: 202187 1 Reactome DB_ID: 202300 1 p-Y90-PKC-theta:DAG [plasma membrane] p-Y90-PKC-theta:DAG Reactome DB_ID: 202395 1 O4'-phospho-L-tyrosine at 90 90 EQUAL 1 EQUAL 706 EQUAL Reactome DB_ID: 112275 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 Reactome DB_ID: 29370 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 202266 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 2.7.11 Phosphorylation of PKC theta 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 Reactome DB_ID: 202300 1 Reactome DB_ID: 113592 3 Reactome DB_ID: 29370 3 Reactome DB_ID: 202442 1 Active PKC theta bound to DAG [plasma membrane] Active PKC theta bound to DAG Reactome DB_ID: 112275 1 Reactome DB_ID: 202152 1 O4'-phospho-L-tyrosine at 90 90 EQUAL O-phospho-L-threonine at 538 538 EQUAL O-phospho-L-threonine [MOD:00047] O-phospho-L-serine at 676 676 EQUAL O-phospho-L-serine [MOD:00046] O-phospho-L-serine at 695 695 EQUAL 1 EQUAL 706 EQUAL 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 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 202311 GO 0004674 GO molecular function 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 Translocation of CARMA1 to Plasma membrane 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 Reactome DB_ID: 202161 1 UniProt:Q9BXL7 CARD11 CARD11 CARMA1 CARD11 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 DB_ID: 202311 1 Reactome DB_ID: 202349 1 CARMA1 bound to PDK1 [plasma membrane] CARMA1 bound to PDK1 Reactome DB_ID: 202161 1 1 EQUAL 1154 EQUAL Reactome DB_ID: 202311 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 2.7.11 Phosphorylation of CARMA1 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 Reactome DB_ID: 113592 1 Reactome DB_ID: 202349 1 Reactome DB_ID: 29370 1 Reactome DB_ID: 202440 1 Activated CARMA1 [plasma membrane] Activated CARMA1 Reactome DB_ID: 202438 1 O-phospho-L-serine at 552 552 EQUAL 1 EQUAL 1154 EQUAL Reactome DB_ID: 202311 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 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 202442 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 Oligomerization of CARMA1 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 Reactome DB_ID: 202440 1 Reactome DB_ID: 202438 2 O-phospho-L-serine at 552 552 EQUAL 1 EQUAL 1154 EQUAL Reactome DB_ID: 202445 1 CARMA1 trimer [plasma membrane] CARMA1 trimer Reactome DB_ID: 202438 3 O-phospho-L-serine at 552 552 EQUAL 1 EQUAL 1154 EQUAL Reactome DB_ID: 202311 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 Interaction of Bcl10 to CARMA1 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 Reactome DB_ID: 202447 1 UniProt:O95999 BCL10 BCL10 CIPER CLAP BCL10 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 DB_ID: 202445 1 Reactome DB_ID: 202454 1 Bcl10 bound to CARMA1 [plasma membrane] Bcl10 bound to CARMA1 Reactome DB_ID: 202447 1 1 EQUAL 233 EQUAL Reactome DB_ID: 202445 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 2.7.11 Phosphorylation of Bcl10 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 Reactome DB_ID: 202454 1 Reactome DB_ID: 113592 1 Reactome DB_ID: 29370 1 Reactome DB_ID: 202480 1 Phosphorylated Bcl10 bound to CARMA1 and RIP2 [plasma membrane] Phosphorylated Bcl10 bound to CARMA1 and RIP2 Reactome DB_ID: 202488 1 phosphorylated residue at unknown position phosphorylated residue [MOD:00696] 1 EQUAL 233 EQUAL Reactome DB_ID: 202445 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 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 168402 UniProt:O43353 RIPK2 RIPK2 UNQ277/PRO314/PRO34092 CARDIAK RIPK2 RICK RIP2 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 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 Oligomerization of Bcl10 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 Reactome DB_ID: 202480 1 Reactome DB_ID: 202488 2 phosphorylated residue at unknown position 1 EQUAL 233 EQUAL Reactome DB_ID: 202475 1 Bcl10 trimer bound to CARMA1 trimer [plasma membrane] Bcl10 trimer bound to CARMA1 trimer Reactome DB_ID: 202488 3 phosphorylated residue at unknown position 1 EQUAL 233 EQUAL Reactome DB_ID: 202445 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 Interaction and oligomerization of MALT1 to Bcl10 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 Reactome DB_ID: 202475 1 Reactome DB_ID: 202487 1 MALT1 trimer [cytosol] MALT1 trimer Reactome DB_ID: 202461 3 UniProt:Q9UDY8 MALT1 MALT1 MLT MALT1 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 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 Reactome DB_ID: 202468 1 MALT1 trimer bound to Bcl10 and CARMA1 trimer [plasma membrane] MALT1 trimer bound to Bcl10 and CARMA1 trimer Reactome DB_ID: 202475 1 Reactome DB_ID: 202487 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 Translocation of TRAF6 to CBM complex 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 Reactome DB_ID: 166366 3 UniProt:Q9Y4K3 TRAF6 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 DB_ID: 202468 1 Reactome DB_ID: 202471 1 TRAF6 trimer bound to CBM complex [plasma membrane] TRAF6 trimer bound to CBM complex Reactome DB_ID: 166366 3 1 EQUAL 522 EQUAL Reactome DB_ID: 202468 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 6.3.2.19 Auto-ubiquitination of TRAF6 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 Reactome DB_ID: 450152 3 K63polyUb [cytosol] K63polyUb K63-polyubiquitin Lys-63 polyubiquitin Reactome DB_ID: 202463 3 UBE2N:UBE2V1 [cytosol] UBE2N:UBE2V1 Ubc13:UBE2V1 TRIKA1 TRAF6-regulated IKK activator 1 Reactome DB_ID: 205753 1 UniProt:Q13404 UBE2V1 UBE2V1 UBE2V P/OKcl.19 CROC1 UBE2V1 UEV1 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 DB_ID: 206072 1 UniProt:P61088 UBE2N 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 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 Reactome DB_ID: 202471 1 Reactome DB_ID: 202456 1 Ub-TRAF6 trimer bound to CBM complex [plasma membrane] Ub-TRAF6 trimer bound to CBM complex Reactome DB_ID: 202468 1 Reactome DB_ID: 2685681 3 ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 124 124 EQUAL ubiquitinylated lysine [MOD:01148] 1 EQUAL 522 EQUAL 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 Reactome DB_ID: 202463 3 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 202471 GO 0004842 GO molecular function 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 2.7.11 Activation of TAK1-TAB2 complex 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 Reactome DB_ID: 113592 2 Reactome DB_ID: 202504 1 TAB2/TAK1 complex [cytosol] TAB2/TAK1 complex Reactome DB_ID: 168163 1 UniProt:O43318 MAP3K7 MAP3K7 TAK1 MAP3K7 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 phosphorylated residue at unknown position 1 EQUAL 606 EQUAL Reactome DB_ID: 168116 1 UniProt:Q9NYJ8 TAB2 TAB2 KIAA0733 TAB2 MAP3K7IP2 FUNCTION Adapter required to activate the JNK and NF-kappa-B signaling pathways through the specific recognition of 'Lys-63'-linked polyubiquitin chains by its RanBP2-type zinc finger (NZF) (PubMed:10882101, PubMed:11460167, PubMed:15327770, PubMed:22158122). Acts as an adapter linking MAP3K7/TAK1 and TRAF6 to 'Lys-63'-linked polyubiquitin chains (PubMed:10882101, PubMed:11460167, PubMed:15327770, PubMed:22158122). The RanBP2-type zinc finger (NZF) specifically recognizes Lys-63'-linked polyubiquitin chains unanchored or anchored to the substrate proteins such as RIPK1/RIP1: this acts as a scaffold to organize a large signaling complex to promote autophosphorylation of MAP3K7/TAK1, and subsequent activation of I-kappa-B-kinase (IKK) core complex by MAP3K7/TAK1 (PubMed:15327770, PubMed:22158122). Regulates the IL1-mediated translocation of NCOR1 out of the nucleus (By similarity). Involved in heart development (PubMed:20493459).SUBUNIT Interacts with MAP3K7 and TRAF6 (PubMed:10882101). Identified in the TRIKA2 complex composed of MAP3K7, TAB1 and TAB2 (PubMed:11460167). Binds 'Lys-63'-linked polyubiquitin chains (PubMed:19675569, PubMed:19935683). Interacts with NCOR1 and HDAC3 to form a ternary complex (By similarity). Interacts (via C-terminal) with NUMBL (via PTB domain) (PubMed:18299187). Interacts (via the C-terminus) with DYNC2I2 (via WD domains) (PubMed:19521662). Interacts with RBCK1 (PubMed:17449468). Interacts with TRIM5 (PubMed:21512573).TISSUE SPECIFICITY Widely expressed. In the embryo, expressed in the ventricular trabeculae, endothelial cells of the conotruncal cushions of the outflow tract and in the endothelial cells lining the developing aortic valves.DOMAIN The RanBP2-type zinc finger (NZF) mediates binding to two consecutive 'Lys-63'-linked ubiquitins.PTM Ubiquitinated; following IL1 stimulation or TRAF6 overexpression. Ubiquitination involves RBCK1 leading to proteasomal degradation.PTM Phosphorylated.PTM (Microbial infection) Methylated at Cys-673 by enteropathogenic E.coli protein NleE or S.flexneri protein OspZ: methylation disrupts zinc-binding and ability to bind 'Lys-63'-linked ubiquitin, leading to NF-kappa-B inactivation. UniProt Q9NYJ8 1 EQUAL 693 EQUAL Reactome Database ID Release 78 202504 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=202504 Reactome R-HSA-202504 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-202504.1 Reactome DB_ID: 202456 1 Reactome DB_ID: 29370 2 Reactome DB_ID: 202507 1 TAK1/TAB2 complex bound to TRAF6/CBM complex [plasma membrane] TAK1/TAB2 complex bound to TRAF6/CBM complex Reactome DB_ID: 202516 1 phosphorylated TAK1 bound to TAB2 [cytosol] phosphorylated TAK1 bound to TAB2 Reactome DB_ID: 202527 1 O-phospho-L-threonine at 184 184 EQUAL O-phospho-L-threonine at 187 187 EQUAL 1 EQUAL 606 EQUAL Reactome DB_ID: 168116 1 1 EQUAL 693 EQUAL Reactome Database ID Release 78 202516 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=202516 Reactome R-HSA-202516 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-202516.1 Reactome DB_ID: 202456 1 Reactome Database ID Release 78 202507 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=202507 Reactome R-HSA-202507 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-202507.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 202504 Reactome Database ID Release 78 202514 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=202514 Reactome Database ID Release 78 202510 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=202510 Reactome R-HSA-202510 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-202510.1 16056267 Pubmed 2005 Ubiquitin signalling in the NF-kappaB pathway Chen, ZJ Nat Cell Biol 7:758-65 17496917 Pubmed 2007 Ubiquitin-mediated activation of TAK1 and IKK Adhikari, A Xu, M Chen, ZJ Oncogene 26:3214-26 2.7.11 Activation of IKK complex Activation of IKK complex The IkB kinase (IKK) complex serves as the master regulator for the activation of NF-kB by various stimuli. It contains two catalytic subunits, IKK alpha and IKK beta, and a regulatory subunit, IKKgamma/NEMO. The activation of IKK complex is dependent on the phosphorylation of IKK alpha/beta at its activation loop and the K63-linked ubiquitination of NEMO. This basic trimolecular complex is referred to as the IKK complex. <br>IKK subunits have a N-term kinase domain a leucine zipper (LZ) motifs, a helix-loop-helix (HLH) and a C-ter NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs. IKK beta is the major IKK catalytic subunit for NF-kB activation. Activated TAK1 phosphorylate IKK beta on serine residues (S177 and S181) in the activation loop and thus activate the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB 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 Reactome DB_ID: 168113 1 CHUK:IKBKB:IKBKG [cytosol] CHUK:IKBKB:IKBKG IKKA:IKBKB:IKBKG IKK complex Inhibitor of KappaB kinase (IKK) Complex Reactome DB_ID: 168104 1 UniProt:O15111 CHUK CHUK TCF16 CHUK IKKA FUNCTION Serine kinase that plays an essential role in the NF-kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses. Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-B on serine residues. These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome. In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. Negatively regulates the pathway by phosphorylating the scaffold protein TAXBP1 and thus promoting the assembly of the A20/TNFAIP3 ubiquitin-editing complex (composed of A20/TNFAIP3, TAX1BP1, and the E3 ligases ITCH and RNF11). Therefore, CHUK plays a key role in the negative feedback of NF-kappa-B canonical signaling to limit inflammatory gene activation. As part of the non-canonical pathway of NF-kappa-B activation, the MAP3K14-activated CHUK/IKKA homodimer phosphorylates NFKB2/p100 associated with RelB, inducing its proteolytic processing to NFKB2/p52 and the formation of NF-kappa-B RelB-p52 complexes. In turn, these complexes regulate genes encoding molecules involved in B-cell survival and lymphoid organogenesis. Participates also in the negative feedback of the non-canonical NF-kappa-B signaling pathway by phosphorylating and destabilizing MAP3K14/NIK. Within the nucleus, phosphorylates CREBBP and consequently increases both its transcriptional and histone acetyltransferase activities. Modulates chromatin accessibility at NF-kappa-B-responsive promoters by phosphorylating histones H3 at 'Ser-10' that are subsequently acetylated at 'Lys-14' by CREBBP. Additionally, phosphorylates the CREBBP-interacting protein NCOA3. Also phosphorylates FOXO3 and may regulate this pro-apoptotic transcription factor (PubMed:12789342, PubMed:15084260, PubMed:17434128, PubMed:20434986, PubMed:20501937, PubMed:21765415). Phosphorylates RIPK1 at 'Ser-25' which represses its kinase activity and consequently prevents TNF-mediated RIPK1-dependent cell death (By similarity).ACTIVITY REGULATION Activated when phosphorylated and inactivated when dephosphorylated.SUBUNIT Component of the I-kappa-B-kinase (IKK) core complex consisting of CHUK, IKBKB and IKBKG; probably four alpha/CHUK-beta/IKBKB dimers are associated with four gamma/IKBKG subunits. The IKK core complex seems to associate with regulatory or adapter proteins to form a IKK-signalosome holo-complex (PubMed:10195894, PubMed:12612076). The IKK complex associates with TERF2IP/RAP1, leading to promote IKK-mediated phosphorylation of RELA/p65 (By similarity). Part of a complex composed of NCOA2, NCOA3, CHUK/IKKA, IKBKB, IKBKG and CREBBP (PubMed:11971985). Part of a 70-90 kDa complex at least consisting of CHUK/IKKA, IKBKB, NFKBIA, RELA, ELP1 and MAP3K14 (PubMed:9751059). Directly interacts with TRPC4AP (By similarity). May interact with TRAF2 (PubMed:19150425). Interacts with NALP2 (PubMed:15456791). May interact with MAVS/IPS1 (PubMed:16177806). Interacts with ARRB1 and ARRB2 (PubMed:15173580). Interacts with NLRC5; prevents CHUK phosphorylation and kinase activity (PubMed:20434986). Interacts with PIAS1; this interaction induces PIAS1 phosphorylation (PubMed:17540171). Interacts with ZNF268 isoform 2; the interaction is further increased in a TNF-alpha-dependent manner (PubMed:23091055). Interacts with FOXO3 (PubMed:15084260). Interacts with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation (PubMed:26334375). Interacts with LRRC14 (PubMed:27426725). Interacts with SASH1 (PubMed:23776175). Directly interacts with DDX3X after the physiological activation of the TLR7 and TLR8 pathways; this interaction enhances CHUK autophosphorylation (PubMed:30341167).SUBUNIT (Microbial infection) Interacts with InlC of Listeria monocytogenes.TISSUE SPECIFICITY Widely expressed.DOMAIN The kinase domain is located in the N-terminal region. The leucine zipper is important to allow homo- and hetero-dimerization. At the C-terminal region is located the region responsible for the interaction with NEMO/IKBKG.PTM Phosphorylated by MAP3K14/NIK, AKT and to a lesser extent by MEKK1, and dephosphorylated by PP2A. Autophosphorylated.PTM (Microbial infection) Acetylation of Thr-179 by Yersinia YopJ prevents phosphorylation and activation, thus blocking the I-kappa-B signaling pathway.SIMILARITY Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily. UniProt O15111 1 EQUAL 745 EQUAL Reactome DB_ID: 168108 1 UniProt:Q9Y6K9 IKBKG IKBKG FIP3 IKBKG NEMO FUNCTION Regulatory subunit of the IKK core complex which phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF-kappa-B complex and ultimately the degradation of the inhibitor (PubMed:9751060, PubMed:14695475, PubMed:20724660). Its binding to scaffolding polyubiquitin plays a key role in IKK activation by multiple signaling receptor pathways (PubMed:16547522, PubMed:18287044, PubMed:19033441, PubMed:21606507, PubMed:27777308, PubMed:19185524). Can recognize and bind both 'Lys-63'-linked and linear polyubiquitin upon cell stimulation, with a much highr affinity for linear polyubiquitin (PubMed:16547522, PubMed:18287044, PubMed:27777308, PubMed:19033441, PubMed:21606507, PubMed:19185524). Could be implicated in NF-kappa-B-mediated protection from cytokine toxicity. Essential for viral activation of IRF3 (PubMed:19854139). Involved in TLR3- and IFIH1-mediated antiviral innate response; this function requires 'Lys-27'-linked polyubiquitination (PubMed:20724660).FUNCTION (Microbial infection) Also considered to be a mediator for HTLV-1 Tax oncoprotein activation of NF-kappa-B.SUBUNIT Homodimer; disulfide-linked (PubMed:18164680). Component of the I-kappa-B-kinase (IKK) core complex consisting of CHUK, IKBKB and IKBKG; probably four alpha/CHUK-beta/IKBKB dimers are associated with four gamma/IKBKG subunits (PubMed:9751060, PubMed:9891086, PubMed:11080499, PubMed:18462684, PubMed:17977820). The IKK core complex seems to associate with regulatory or adapter proteins to form a IKK-signalosome holo-complex (PubMed:9751060, PubMed:9891086, PubMed:11080499). The IKK complex associates with TERF2IP/RAP1, leading to promote IKK-mediated phosphorylation of RELA/p65 (By similarity). Part of a complex composed of NCOA2, NCOA3, CHUK/IKKA, IKBKB, IKBKG and CREBBP (PubMed:11971985). Interacts with COPS3, CYLD, NALP2, TRPC4AP and PIDD1 (PubMed:15456791, PubMed:16360037, PubMed:12917691, PubMed:11418127). Interacts with ATM; the complex is exported from the nucleus (PubMed:16497931). Interacts with TRAF6 (PubMed:17728323). Interacts with IKBKE (PubMed:23453969). Interacts with TANK; the interaction is enhanced by IKBKE and TBK1 (PubMed:12133833). Part of a ternary complex consisting of TANK, IKBKB and IKBKG (PubMed:12133833). Interacts with ZFAND5 (PubMed:14754897). Interacts with RIPK2 (PubMed:18079694). Interacts with TNIP1 and TNFAIP3; TNIP1 facilitates the TNFAIP3-mediated de-ubiquitination of IKBKG (PubMed:11389905, PubMed:22099304). Interacts with TNFAIP3; the interaction is induced by TNF stimulation and by polyubiquitin (PubMed:11389905, PubMed:22099304). Binds (via UBAN region) polyubiquitin; binds both 'Lys-63'-linked and linear polyubiquitin, with higher affinity for linear ubiquitin (PubMed:16547522, PubMed:19033441, PubMed:21606507, PubMed:19185524). Interacts with NLRP10 (PubMed:22672233). 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 (PubMed:25861989). Interacts with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation (PubMed:26334375). Interacts with TRIM29; this interaction induces IKBKG/NEMO ubiquitination and proteolytic degradation (PubMed:27695001). Interacts with TRIM13; this interaction leads to IKBKG/NEMO ubiquitination (PubMed:25152375). Interacts with ARFIP2 (PubMed:26296658). Interacts with RIPK1 (By similarity). Interacts with (ubiquitinated) BCL10; interaction with polyubiquitinated BCL10 via both 'Lys-63'-linked and linear ubiquitin is required for TCR-induced NF-kappa-B activation (PubMed:18287044, PubMed:27777308).SUBUNIT (Microbial infection) Interacts with Molluscum contagiosum virus protein MC005; this interaction inhibits NF-kappa-B activation.SUBUNIT (Microbial infection) Interacts with HTLV-1 Tax oncoprotein; the interaction activates IKBKG.SUBUNIT (Microbial infection) Interacts with Shigella flexneri ipah9.8; the interaction promotes TNIP1-dependent 'Lys-27'-linked polyubiquitination of IKBKG which perturbs NF-kappa-B activation during bacterial infection.TISSUE SPECIFICITY Heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.DOMAIN The leucine-zipper domain and the CCHC NOA-type zinc-fingers constitute the UBAN region and are essential for polyubiquitin binding and for the activation of IRF3.PTM Phosphorylation at Ser-68 attenuates aminoterminal homodimerization.PTM Polyubiquitinated on Lys-285 through 'Lys-63'; the ubiquitination is mediated by NOD2 and RIPK2 and probably plays a role in signaling by facilitating interactions with ubiquitin domain-containing proteins and activates the NF-kappa-B pathway. Polyubiquitinated on Lys-399 through 'Lys-63'; the ubiquitination is mediated by BCL10, MALT1 and TRAF6 and probably plays a role in signaling by facilitating interactions with ubiquitin domain-containing proteins and activates the NF-kappa-B pathway. Monoubiquitinated on Lys-277 and Lys-309; promotes nuclear export. Polyubiquitinated through 'Lys-27' by TRIM23; involved in antiviral innate and inflammatory responses. Linear polyubiquitinated on Lys-111, Lys-143, Lys-226, Lys-246, Lys-264, Lys-277, Lys-285, Lys-292, Lys-302, Lys-309 and Lys-326; the head-to-tail polyubiquitination is mediated by the LUBAC complex and plays a key role in NF-kappa-B activation. Deubiquitinated by USP10 in a TANK-dependent and -independent manner, leading to the negative regulation of NF-kappa-B signaling upon DNA damage (PubMed:25861989).PTM Sumoylated on Lys-277 and Lys-309 with SUMO1; the modification results in phosphorylation of Ser-85 by ATM leading to a replacement of the sumoylation by mono-ubiquitination on these residues.PTM Neddylated by TRIM40, resulting in stabilization of NFKBIA and down-regulation of NF-kappa-B activity.PTM (Microbial infection) Cleaved by hepatitis A virus (HAV) protease 3C allowing the virus to disrupt the host innate immune signaling.PTM (Microbial infection) Polyubiquitinated on Lys-309 and Lys-321 via 'Lys-27'-linked ubiquitin by Shigella flexneri E3 ubiquitin-protein ligase ipah9.8, leading to its degradation by the proteasome. UniProt Q9Y6K9 1 EQUAL 419 EQUAL Reactome DB_ID: 168114 1 UniProt:O14920 IKBKB IKBKB IKBKB IKKB FUNCTION Serine kinase that plays an essential role in the NF-kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses (PubMed:30337470). Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation. Phosphorylates inhibitors of NF-kappa-B on 2 critical serine residues. These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome. In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. In addition to the NF-kappa-B inhibitors, phosphorylates several other components of the signaling pathway including NEMO/IKBKG, NF-kappa-B subunits RELA and NFKB1, as well as IKK-related kinases TBK1 and IKBKE (PubMed:11297557, PubMed:20410276). IKK-related kinase phosphorylations may prevent the overproduction of inflammatory mediators since they exert a negative regulation on canonical IKKs. Phosphorylates FOXO3, mediating the TNF-dependent inactivation of this pro-apoptotic transcription factor (PubMed:15084260). Also phosphorylates other substrates including NCOA3, BCL10 and IRS1 (PubMed:17213322). Within the nucleus, acts as an adapter protein for NFKBIA degradation in UV-induced NF-kappa-B activation (PubMed:11297557). Phosphorylates RIPK1 at 'Ser-25' which represses its kinase activity and consequently prevents TNF-mediated RIPK1-dependent cell death (By similarity). Phosphorylates the C-terminus of IRF5, stimulating IRF5 homodimerization and translocation into the nucleus (PubMed:25326418).SUBUNIT Component of the I-kappa-B-kinase (IKK) core complex consisting of CHUK, IKBKB and IKBKG; probably four alpha/CHUK-beta/IKBKB dimers are associated with four gamma/IKBKG subunits. The IKK core complex seems to associate with regulatory or adapter proteins to form a IKK-signalosome holo-complex (PubMed:12612076). The IKK complex associates with TERF2IP/RAP1, leading to promote IKK-mediated phosphorylation of RELA/p65 (By similarity). Part of a complex composed of NCOA2, NCOA3, CHUK/IKKA, IKBKB, IKBKG and CREBBP (PubMed:11971985). Part of a 70-90 kDa complex at least consisting of CHUK/IKKA, IKBKB, NFKBIA, RELA, ELP1 and MAP3K14 (PubMed:9751059). Found in a membrane raft complex, at least composed of BCL10, CARD11, DPP4 and IKBKB (PubMed:17287217). Interacts with SQSTM1 through PRKCZ or PRKCI (PubMed:10356400). Forms an NGF-induced complex with IKBKB, PRKCI and TRAF6 (By similarity). May interact with MAVS/IPS1 (PubMed:16177806). Interacts with NALP2 (PubMed:15456791). Interacts with TICAM1 (PubMed:14739303). Interacts with FAF1; the interaction disrupts the IKK complex formation (PubMed:17684021). Interacts with ATM (PubMed:16497931). Part of a ternary complex consisting of TANK, IKBKB and IKBKG (PubMed:12133833). Interacts with NIBP; the interaction is direct (PubMed:15951441). Interacts with ARRB1 and ARRB2 (PubMed:15173580). Interacts with TRIM21 (PubMed:19675099). Interacts with NLRC5; prevents IKBKB phosphorylation and kinase activity (PubMed:20434986). Interacts with PDPK1 (PubMed:16207722). Interacts with EIF2AK2/PKR (PubMed:10848580). The phosphorylated form interacts with PPM1A and PPM1B (PubMed:18930133). Interacts with ZNF268 isoform 2; the interaction is further increased in a TNF-alpha-dependent manner (PubMed:23091055). Interacts with IKBKE (PubMed:23453969). Interacts with NAA10, leading to NAA10 degradation (PubMed:19716809). Interacts with FOXO3 (PubMed:15084260). Interacts with AKAP13 (PubMed:23090968). Interacts with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation (PubMed:26334375). Interacts with LRRC14; disrupts IKBKB-IKBKG interaction preventing I-kappa-B-kinase (IKK) core complex formation and leading to a decrease of IKBKB phosphorylation and NF-kappaB activation (PubMed:27426725). Interacts with SASH1 (PubMed:23776175). Interacts with ARFIP2 (PubMed:26296658).SUBUNIT (Microbial infection) Interacts with Yersinia YopJ.SUBUNIT (Microbial infection) Interacts with vaccinia virus protein B14.TISSUE SPECIFICITY Highly expressed in heart, placenta, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis and peripheral blood.DOMAIN The kinase domain is located in the N-terminal region. The leucine zipper is important to allow homo- and hetero-dimerization. At the C-terminal region is located the region responsible for the interaction with NEMO/IKBKG.PTM Upon cytokine stimulation, phosphorylated on Ser-177 and Ser-181 by MEKK1 and/or MAP3K14/NIK as well as TBK1 and PRKCZ; which enhances activity. Once activated, autophosphorylates on the C-terminal serine cluster; which decreases activity and prevents prolonged activation of the inflammatory response. Phosphorylated by the IKK-related kinases TBK1 and IKBKE, which is associated with reduced CHUK/IKKA and IKBKB activity and NF-kappa-B-dependent gene transcription. Dephosphorylated at Ser-177 and Ser-181 by PPM1A and PPM1B.PTM (Microbial infection) Acetylation of Thr-180 by Yersinia YopJ prevents phosphorylation and activation, thus blocking the I-kappa-B pathway.PTM Ubiquitinated. Monoubiquitination involves TRIM21 that leads to inhibition of Tax-induced NF-kappa-B signaling. According to PubMed:19675099, 'Ser-163' does not serve as a monoubiquitination site. According to PubMed:16267042, ubiquitination on 'Ser-163' modulates phosphorylation on C-terminal serine residues.PTM (Microbial infection) Monoubiquitination by TRIM21 is disrupted by Yersinia YopJ.PTM Hydroxylated by PHD1/EGLN2, loss of hydroxylation under hypoxic conditions results in activation of NF-kappa-B.SIMILARITY Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily. UniProt O14920 1 EQUAL 756 EQUAL Reactome Database ID Release 78 168113 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=168113 Reactome R-HSA-168113 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-168113.3 Reactome DB_ID: 113592 2 Reactome DB_ID: 29370 2 Reactome DB_ID: 202513 1 p-S177,S181-IKKB:IKKA:NEMO [cytosol] p-S177,S181-IKKB:IKKA:NEMO IKK complex with phosphorylated IKK beta Reactome DB_ID: 168104 1 1 EQUAL 745 EQUAL Reactome DB_ID: 168108 1 1 EQUAL 419 EQUAL Reactome DB_ID: 202506 1 O-phospho-L-serine at 177 177 EQUAL O-phospho-L-serine at 181 181 EQUAL 1 EQUAL 756 EQUAL Reactome Database ID Release 78 202513 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=202513 Reactome R-HSA-202513 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-202513.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 202507 Reactome Database ID Release 78 202517 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=202517 Reactome Database ID Release 78 202500 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=202500 Reactome R-HSA-202500 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-202500.1 17047224 Pubmed 2006 Regulation and function of IKK and IKK-related kinases Hacker, H Karin, M Sci STKE 2006:re13 6.3.2.19 Ubiquitination of NEMO by TRAF6 Ubiquitination of NEMO by TRAF6 During the phosphorylation of the IKK beta, the regulatory subunit NEMO undergoes K-63-linked polyubiquitination. Ubiquitinated TRAF6 trimer, acts as a E3 ligase and induces this ubiquitination. The ubiquitin target sites in NEMO are not yet clearly identified. Studies of different NF-kB signaling pathways revealed several potential ubiquitination sites on NEMO (e.g., K285, K277, K309 and K399) (Fuminori 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 Reactome DB_ID: 450152 1 Reactome DB_ID: 202463 1 Reactome DB_ID: 202513 1 Reactome DB_ID: 202562 1 p-S177,S181-IKKB:IKKA:pUb-NEMO [cytosol] p-S177,S181-IKKB:IKKA:pUb-NEMO Reactome DB_ID: 168104 1 1 EQUAL 745 EQUAL Reactome DB_ID: 202530 1 ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 321 321 EQUAL ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 325 325 EQUAL ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 326 326 EQUAL ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at unknown position 1 EQUAL 419 EQUAL Reactome DB_ID: 202506 1 O-phospho-L-serine at 177 177 EQUAL O-phospho-L-serine at 181 181 EQUAL 1 EQUAL 756 EQUAL Reactome Database ID Release 78 202562 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=202562 Reactome R-HSA-202562 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-202562.1 Reactome DB_ID: 202463 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 202456 Reactome Database ID Release 78 202486 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=202486 Reactome Database ID Release 78 202534 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=202534 Reactome R-HSA-202534 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-202534.1 17728323 Pubmed 2007 Identification of TRAF6-dependent NEMO polyubiquitination sites through analysis of a new NEMO mutation causing incontinentia pigmenti Sebban-Benin, H Pescatore, A Fusco, F Pascuale, V Gautheron, J Yamaoka, S Moncla, A Ursini, MV Courtois, G Hum Mol Genet 127: 19136968 Pubmed 2009 Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation Tokunaga, Fuminori Sakata, Shin-ichi Saeki, Yasushi Satomi, Yoshinori Kirisako, Takayoshi Kamei, Kiyoko Nakagawa, Tomoko Kato, Michiko Murata, Shigeo Yamaoka, Shoji Yamamoto, M Akira, Shizuo Takao, Toshifumi Tanaka, Keiji Iwai, Kazuhiro Nat. Cell Biol. 11:123-32 2.7.11 p-S177,S181-IKKB:IKKA:pUb-NEMO phosphorylates IkB-alpha:NF-kB p-S177,S181-IKKB:IKKA:pUb-NEMO phosphorylates IkB-alpha:NF-kB NF-kB is sequestered in the cytosol of unstimulated cells through the interactions with a class of inhibitor proteins, called IkBs, which mask the nuclear localization signal (NLS) of NF-kB and prevent its nuclear translocation. A key event in NF-kB activation involves phosphorylation of IkB (at sites equivalent to Ser32 and Ser36 of IkB-alpha or Ser19 and Ser22 of IkB-beta) by IKK. The phosphorylated IkB-alpha is recognized by the E3 ligase complex and targeted for ubiquitin-mediated proteasomal degradation, releasing the NF-kB dimer p50/p65 into the nucleus to turn on target genes. (Karin & Ben-Neriah 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 Reactome DB_ID: 113592 2 Reactome DB_ID: 193938 1 IkB(alpha):NF-kB complex [cytosol] IkB(alpha):NF-kB complex Reactome DB_ID: 194043 1 NFKB1(1-433):RELA [cytosol] NFKB1(1-433):RELA p50/p65 complex NF-kB complex Reactome DB_ID: 168172 1 UniProt:Q04206 RELA RELA NFKB3 RELA FUNCTION NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52. The heterodimeric RELA-NFKB1 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. The NF-kappa-B heterodimeric RELA-NFKB1 and RELA-REL complexes, for instance, function as transcriptional activators. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. The inhibitory effect of I-kappa-B on NF-kappa-B through retention in the cytoplasm is exerted primarily through the interaction with RELA. RELA shows a weak DNA-binding site which could contribute directly to DNA binding in the NF-kappa-B complex. Beside its activity as a direct transcriptional activator, it is also able to modulate promoters accessibility to transcription factors and thereby indirectly regulate gene expression. Associates with chromatin at the NF-kappa-B promoter region via association with DDX1. Essential for cytokine gene expression in T-cells (PubMed:15790681). The NF-kappa-B homodimeric RELA-RELA complex appears to be involved in invasin-mediated activation of IL-8 expression. Key transcription factor regulating the IFN response during SARS-CoV-2 infection (PubMed:33440148).SUBUNIT Component of the NF-kappa-B p65-p50 complex. Component of the NF-kappa-B p65-c-Rel complex. Homodimer; component of the NF-kappa-B p65-p65 complex. Component of the NF-kappa-B p65-p52 complex. May interact with ETHE1. Binds TLE5 and TLE1. Interacts with TP53BP2. Binds to and is phosphorylated by the activated form of either RPS6KA4 or RPS6KA5. Interacts with ING4 and this interaction may be indirect. Interacts with CARM1, USP48 and UNC5CL. Interacts with IRAK1BP1 (By similarity). Interacts with NFKBID (By similarity). Interacts with NFKBIA (PubMed:1493333). Interacts with GSK3B. Interacts with NFKBIB (By similarity). Interacts with NFKBIE. Interacts with NFKBIZ. Interacts with EHMT1 (via ANK repeats) (By similarity). Part of a 70-90 kDa complex at least consisting of CHUK, IKBKB, NFKBIA, RELA, ELP1 and MAP3K14. Interacts with HDAC3; HDAC3 mediates the deacetylation of RELA. Interacts with HDAC1; the interaction requires non-phosphorylated RELA. Interacts with CBP; the interaction requires phosphorylated RELA. Interacts (phosphorylated at 'Thr-254') with PIN1; the interaction inhibits p65 binding to NFKBIA. Interacts with SOCS1. Interacts with UXT. Interacts with MTDH and PHF11. Interacts with ARRB2. Interacts with NFKBIA (when phosphorylated), the interaction is direct; phosphorylated NFKBIA is part of a SCF(BTRC)-like complex lacking CUL1. Interacts with RNF25. Interacts (via C-terminus) with DDX1. Interacts with UFL1 and COMMD1. Interacts with BRMS1; this promotes deacetylation of 'Lys-310'. Interacts with NOTCH2 (By similarity). Directly interacts with MEN1; this interaction represses NFKB-mediated transactivation. Interacts with AKIP1, which promotes the phosphorylation and nuclear retention of RELA. Interacts (via the RHD) with GFI1; the interaction, after bacterial lipopolysaccharide (LPS) stimulation, inhibits the transcriptional activity by interfering with the DNA-binding activity to target gene promoter DNA. Interacts (when acetylated at Lys-310) with BRD4; leading to activation of the NF-kappa-B pathway. Interacts with MEFV. Interacts with CLOCK (By similarity). Interacts (via N-terminus) with CPEN1; this interaction induces proteolytic cleavage of p65/RELA subunit and inhibition of NF-kappa-B transcriptional activity (PubMed:18212740). Interacts with FOXP3. Interacts with CDK5RAP3; stimulates the interaction of RELA with HDAC1, HDAC2 and HDAC3 thereby inhibiting NF-kappa-B transcriptional activity (PubMed:17785205). Interacts with DHX9; this interaction is direct and activates NF-kappa-B-mediated transcription (PubMed:15355351). Interacts with LRRC25 (PubMed:29044191). Interacts with TBX21 (By similarity). Interacts with KAT2A (By similarity). Interacts with ZBTB7A; involved in the control by RELA of the accessibility of target gene promoters (PubMed:29813070). Directly interacts with DDX3X; this interaction may trap RELA in the cytoplasm, impairing nuclear relocalization upon TNF activating signals (PubMed:27736973).SUBUNIT (Microbial infection) Interacts with human respiratory syncytial virus (HRSV) protein M2-1.SUBUNIT (Microbial infection) Interacts with molluscum contagiosum virus MC132.SUBUNIT (Microbial infection) Interacts with herpes virus 8 virus protein LANA1.DOMAIN The transcriptional activation domain 3/TA3 does not participate in the direct transcriptional activity of RELA but is involved in the control by RELA of the accessibility of target gene promoters. Mediates interaction with ZBTB7A.DOMAIN The transcriptional activation domain 1/TA1 and the transcriptional activation domain 2/TA2 have direct transcriptional activation properties (By similarity). The 9aaTAD motif found within the transcriptional activation domain 2 is a conserved motif present in a large number of transcription factors that is required for their transcriptional transactivation activity (PubMed:17467953).PTM Ubiquitinated by RNF182, leading to its proteasomal degradation. Degradation is required for termination of NF-kappa-B response.PTM Monomethylated at Lys-310 by SETD6. Monomethylation at Lys-310 is recognized by the ANK repeats of EHMT1 and promotes the formation of repressed chromatin at target genes, leading to down-regulation of NF-kappa-B transcription factor activity. Phosphorylation at Ser-311 disrupts the interaction with EHMT1 without preventing monomethylation at Lys-310 and relieves the repression of target genes (By similarity).PTM Phosphorylation at Ser-311 disrupts the interaction with EHMT1 and promotes transcription factor activity (By similarity). Phosphorylation on Ser-536 stimulates acetylation on Lys-310 and interaction with CBP; the phosphorylated and acetylated forms show enhanced transcriptional activity. Phosphorylation at Ser-276 by RPS6KA4 and RPS6KA5 promotes its transactivation and transcriptional activities.PTM Reversibly acetylated; the acetylation seems to be mediated by CBP, the deacetylation by HDAC3 and SIRT2. Acetylation at Lys-122 enhances DNA binding and impairs association with NFKBIA. Acetylation at Lys-310 is required for full transcriptional activity in the absence of effects on DNA binding and NFKBIA association. Acetylation at Lys-310 promotes interaction with BRD4. Acetylation can also lower DNA-binding and results in nuclear export. Interaction with BRMS1 promotes deacetylation of Lys-310. Lys-310 is deacetylated by SIRT2.PTM S-nitrosylation of Cys-38 inactivates the enzyme activity.PTM Sulfhydration at Cys-38 mediates the anti-apoptotic activity by promoting the interaction with RPS3 and activating the transcription factor activity.PTM Sumoylation by PIAS3 negatively regulates DNA-bound activated NF-kappa-B.PTM Proteolytically cleaved within a conserved N-terminus region required for base-specific contact with DNA in a CPEN1-mediated manner, and hence inhibits NF-kappa-B transcriptional activity (PubMed:18212740).DISEASE A chromosomal aberration involving ZFTA is found in more than two-thirds of supratentorial ependymomas. Translocation with ZFTA produces a ZFTA-RELA fusion protein. ZFTA-RELA translocations are potent oncogenes that probably transform neural stem cells by driving an aberrant NF-kappa-B transcription program (PubMed:24553141). UniProt Q04206 1 EQUAL 551 EQUAL Reactome DB_ID: 168168 1 UniProt:P19838 NFKB1 NFKB1 NFKB1 FUNCTION NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52 and the heterodimeric p65-p50 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. NF-kappa-B heterodimeric p65-p50 and RelB-p50 complexes are transcriptional activators. The NF-kappa-B p50-p50 homodimer is a transcriptional repressor, but can act as a transcriptional activator when associated with BCL3. NFKB1 appears to have dual functions such as cytoplasmic retention of attached NF-kappa-B proteins by p105 and generation of p50 by a cotranslational processing. The proteasome-mediated process ensures the production of both p50 and p105 and preserves their independent function, although processing of NFKB1/p105 also appears to occur post-translationally. p50 binds to the kappa-B consensus sequence 5'-GGRNNYYCC-3', located in the enhancer region of genes involved in immune response and acute phase reactions. In a complex with MAP3K8, NFKB1/p105 represses MAP3K8-induced MAPK signaling; active MAP3K8 is released by proteasome-dependent degradation of NFKB1/p105.SUBUNIT Component of the NF-kappa-B p65-p50 complex. Component of the NF-kappa-B p65-p50 complex. Homodimer; component of the NF-kappa-B p50-p50 complex. Component of the NF-kappa-B p105-p50 complex. Component of the NF-kappa-B p50-c-Rel complex. Component of a complex consisting of the NF-kappa-B p50-p50 homodimer and BCL3. Also interacts with MAP3K8. NF-kappa-B p50 subunit interacts with NCOA3 coactivator, which may coactivate NF-kappa-B dependent expression via its histone acetyltransferase activity. Interacts with DSIPI; this interaction prevents nuclear translocation and DNA-binding. Interacts with SPAG9 and UNC5CL. NFKB1/p105 interacts with CFLAR; the interaction inhibits p105 processing into p50. NFKB1/p105 forms a ternary complex with MAP3K8 and TNIP2. Interacts with GSK3B; the interaction prevents processing of p105 to p50. NFKB1/p50 interacts with NFKBIE. NFKB1/p50 interacts with NFKBIZ. Nuclear factor NF-kappa-B p50 subunit interacts with NFKBID (By similarity). Directly interacts with MEN1. Interacts with HIF1AN.INDUCTION By phorbol ester and TNF.DOMAIN The C-terminus of p105 might be involved in cytoplasmic retention, inhibition of DNA-binding, and transcription activation.DOMAIN Glycine-rich region (GRR) appears to be a critical element in the generation of p50.PTM While translation occurs, the particular unfolded structure after the GRR repeat promotes the generation of p50 making it an acceptable substrate for the proteasome. This process is known as cotranslational processing. The processed form is active and the unprocessed form acts as an inhibitor (I kappa B-like), being able to form cytosolic complexes with NF-kappa B, trapping it in the cytoplasm. Complete folding of the region downstream of the GRR repeat precludes processing.PTM Phosphorylation at 'Ser-903' and 'Ser-907' primes p105 for proteolytic processing in response to TNF-alpha stimulation. Phosphorylation at 'Ser-927' and 'Ser-932' are required for BTRC/BTRCP-mediated proteolysis.PTM Polyubiquitination seems to allow p105 processing.PTM S-nitrosylation of Cys-61 affects DNA binding.PTM The covalent modification of cysteine by 15-deoxy-Delta12,14-prostaglandin-J2 is autocatalytic and reversible. It may occur as an alternative to other cysteine modifications, such as S-nitrosylation and S-palmitoylation. UniProt P19838 1 EQUAL 433 EQUAL Reactome Database ID Release 78 194043 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=194043 Reactome R-HSA-194043 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-194043.2 Reactome DB_ID: 168151 1 UniProt:P25963 NFKBIA NFKBIA NFKBIA MAD3 IKBA NFKBI FUNCTION Inhibits the activity of dimeric NF-kappa-B/REL complexes by trapping REL dimers in the cytoplasm through masking of their nuclear localization signals. On cellular stimulation by immune and proinflammatory responses, becomes phosphorylated promoting ubiquitination and degradation, enabling the dimeric RELA to translocate to the nucleus and activate transcription.SUBUNIT Interacts with RELA; the interaction requires the nuclear import signal. Interacts with NKIRAS1 and NKIRAS2. Part of a 70-90 kDa complex at least consisting of CHUK, IKBKB, NFKBIA, RELA, ELP1 and MAP3K14. Interacts with isoform 1 and isoform 2 of RWDD3; the interaction enhances sumoylation. Interacts (when phosphorylated at the 2 serine residues in the destruction motif D-S-G-X(2,3,4)-S) with BTRC. Associates with the SCF(BTRC) complex, composed of SKP1, CUL1 and BTRC; the association is mediated via interaction with BTRC. Part of a SCF(BTRC)-like complex lacking CUL1, which is associated with RELA; RELA interacts directly with NFKBIA. Interacts with PRMT2. Interacts with PRKACA in platelets; this interaction is disrupted by thrombin and collagen. Interacts with HIF1AN. Interacts with MEFV. Interacts with DDRGK1; positively regulates NFKBIA phosphorylation and degradation.SUBUNIT (Microbial infection) Interacts with HBV protein X.INDUCTION Induced in adherent monocytes.PTM Phosphorylated; disables inhibition of NF-kappa-B DNA-binding activity. Phosphorylation at positions 32 and 36 is prerequisite to recognition by UBE2D3 leading to polyubiquitination and subsequent degradation.PTM Sumoylated; sumoylation requires the presence of the nuclear import signal. Sumoylation blocks ubiquitination and proteasome-mediated degradation of the protein thereby increasing the protein stability.PTM Monoubiquitinated at Lys-21 and/or Lys-22 by UBE2D3. Ubiquitin chain elongation is then performed by CDC34 in cooperation with the SCF(FBXW11) E3 ligase complex, building ubiquitin chains from the UBE2D3-primed NFKBIA-linked ubiquitin. The resulting polyubiquitination leads to protein degradation. Also ubiquitinated by SCF(BTRC) following stimulus-dependent phosphorylation at Ser-32 and Ser-36.PTM Deubiquitinated by porcine reproductive and respiratory syndrome virus Nsp2 protein, which thereby interferes with NFKBIA degradation and impairs subsequent NF-kappa-B activation.SIMILARITY Belongs to the NF-kappa-B inhibitor family. UniProt P25963 1 EQUAL 317 EQUAL Reactome Database ID Release 78 193938 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=193938 Reactome R-HSA-193938 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-193938.1 Reactome DB_ID: 29370 2 Reactome DB_ID: 5607671 1 p-S32,36-IkB-alpha:NF-kB complex [cytosol] p-S32,36-IkB-alpha:NF-kB complex Reactome DB_ID: 194043 1 Reactome DB_ID: 177677 1 O-phospho-L-serine at 32 32 EQUAL O-phospho-L-serine at 36 36 EQUAL 1 EQUAL 317 EQUAL Reactome Database ID Release 78 5607671 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=5607671 Reactome R-HSA-5607671 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-5607671.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 202562 Reactome Database ID Release 78 202546 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=202546 Reactome Database ID Release 78 202541 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=202541 Reactome R-HSA-202541 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-202541.2 8601309 Pubmed 1996 Site-specific phosphorylation of IkappaBalpha by a novel ubiquitination-dependent protein kinase activity Chen, Z J Parent, L Maniatis, T Cell 84:853-62 17363905 Pubmed 2007 Phosphorylation and ubiquitination of the IkappaB kinase complex by two distinct signaling pathways Shambharkar, PB Blonska, M Pappu, BP Li, H You, Y Sakurai, H Darnay, BG Hara, H Penninger, J Lin, X EMBO J 26:1794-805 9252186 Pubmed 1997 A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB DiDonato, JA Hayakawa, M Rothwarf, DM Zandi, E Karin, M Nature 388:548-54 15371334 Pubmed 2004 Signaling to NF-kappaB Hayden, MS Ghosh, S Genes Dev 18:2195-224 10837071 Pubmed 2000 Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity Karin, M Ben-Neriah, Y Annu. Rev. Immunol. 18:621-63 15145317 Pubmed 2004 The two NF-kappaB activation pathways and their role in innate and adaptive immunity Bonizzi, G Karin, M Trends Immunol 25:280-8 6.3.2.19 beta-TRCP ubiquitinates IkB-alpha in p-S32,33-IkB-alpha:NF-kB complex beta-TRCP ubiquitinates IkB-alpha in p-S32,33-IkB-alpha:NF-kB complex Two major signaling steps are required for the removal of IkappaB (IkB) alpha an inhibitor of NF-kB: activation of the IkB kinase (IKK) and degradation of the phosphorylated IkB alpha. IKK activation and IkB degradation involve different ubiquitination modes; the former is mediated by K63-ubiquitination and the later by K48-ubiquitination. Mutational analysis of IkB alpha has indicated that K21 and K22 are the primary sites for addition of multiubiquitination chains while K38 and K47 are the secondary sites. In a transesterification reaction the ubiquitin is transferred from the ubiquitin-activating enzyme (E1) to an E2 ubiquitin-conjugating enzyme, which may, in turn, transfer the ubiquitin to an E3 ubiquitin protein ligase. UBE2D2 (UBC4) or UBE2D1 (UBCH5) or CDC34 (UBC3) acts as the E2 and SCF (SKP1-CUL1-F-box)-beta-TRCP complex acts as the E3 ubiquitin ligase (Strack et al. 2000, Wu et al. 2010). beta-TRCP (beta-transducin repeats-containing protein) is the substrate recognition subunit for the SCF-beta-TRCP E3 ubiquitin ligase. beta-TRCP binds specifically to phosphorylated IkB alpha and recruits it to the SCF complex, allowing the associated E2, such as UBC4 and or UBCH5 to ubiquitinate Ikappa B alpha (Baldi et al. 1996, Rodriguez et al. 1996, Scherer et al. 1995, Alkalay et al. 1995). Authored: Garapati, P V, 2014-07-14 Reviewed: Geijtenbeek, Teunis B H, 2014-09-02 Edited: Garapati, P V, 2014-07-14 Converted from EntitySet in Reactome Reactome DB_ID: 912722 4 K48-Ub [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Ub-580-UBC(533-608) [cytosol] Ub-48-UBB(1-76) [cytosol] Ub-200-UBC(153-228) [cytosol] Ub-124-UBB(77-152) [cytosol] Ub-428-UBC(381-456) [cytosol] Ub-48-UBC(1-76) [cytosol] Ub-504-UBC(457-532) [cytosol] Ub-48-UBA52(1-76) [cytosol] Ub-124-UBC(77-152) [cytosol] Ub-352-UBC(305-380) [cytosol] Ub-48-RPS27A(1-76) [cytosol] Ub-656-UBC(609-684) [cytosol] Ub-200-UBB(153-228) [cytosol] Ub-276-UBC(229-304) [cytosol] UniProt P0CG48 UniProt P0CG47 UniProt P62987 UniProt P62979 Reactome DB_ID: 5607671 1 Reactome DB_ID: 5607687 1 SCF-beta-TRCP [cytosol] SCF-beta-TRCP Converted from EntitySet in Reactome Reactome DB_ID: 5607666 1 beta-TrCP [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity FBXW11 [cytosol] BTRC [cytosol] UniProt Q9UKB1 UniProt Q9Y297 Reactome DB_ID: 174150 1 UniProt:P63208 SKP1 SKP1 TCEB1L OCP2 EMC19 SKP1A SKP1 FUNCTION Essential component of the SCF (SKP1-CUL1-F-box protein) ubiquitin ligase complex, which mediates the ubiquitination of proteins involved in cell cycle progression, signal transduction and transcription. In the SCF complex, serves as an adapter that links the F-box protein to CUL1. The functional specificity of the SCF complex depends on the F-box protein as substrate recognition component. SCF(BTRC) and SCF(FBXW11) direct ubiquitination of CTNNB1 and participate in Wnt signaling. SCF(FBXW11) directs ubiquitination of phosphorylated NFKBIA. SCF(BTRC) directs ubiquitination of NFKBIB, NFKBIE, ATF4, SMAD3, SMAD4, CDC25A, FBXO5, CEP68 and probably NFKB2 (PubMed:25704143). SCF(SKP2) directs ubiquitination of phosphorylated CDKN1B/p27kip and is involved in regulation of G1/S transition. SCF(SKP2) directs ubiquitination of ORC1, CDT1, RBL2, ELF4, CDKN1A, RAG2, FOXO1A, and probably MYC and TAL1. SCF(FBXW7) directs ubiquitination of cyclin E, NOTCH1 released notch intracellular domain (NICD), and probably PSEN1. SCF(FBXW2) directs ubiquitination of GCM1. SCF(FBXO32) directs ubiquitination of MYOD1. SCF(FBXO7) directs ubiquitination of BIRC2 and DLGAP5. SCF(FBXO33) directs ubiquitination of YBX1. SCF(FBXO11) directs ubiquitination of BCL6 and DTL but does not seem to direct ubiquitination of TP53. SCF(BTRC) mediates the ubiquitination of NFKBIA at 'Lys-21' and 'Lys-22'; the degradation frees the associated NFKB1-RELA dimer to translocate into the nucleus and to activate transcription. SCF(CCNF) directs ubiquitination of CCP110. SCF(FBXL3) and SCF(FBXL21) direct ubiquitination of CRY1 and CRY2. SCF(FBXO9) directs ubiquitination of TTI1 and TELO2. SCF(FBXO10) directs ubiquitination of BCL2.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Interacts with KDM2B, forming heterodimers (PubMed:27568929). The KDM2B-SKP1 heterodimeric complex interacts with the PCGF1-BCORL heterodimeric complex to form a homotetrameric polycomb repression complex 1 (PRC1.1) (PubMed:27568929). Component of multiple SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complexes formed of CUL1, SKP1, RBX1 and a variable F-box domain-containing protein as substrate-specific subunit. Component of the SCF(FBXW11) complex containing FBXW11. Component of the SCF(SKP2) complex containing SKP2, in which it interacts directly with SKP1, SKP2 and RBX1. Component of the SCF(FBXW2) complex containing FBXw2. Component of the SCF(FBXO32) complex containing FBXO32. Component of the probable SCF(FBXO7) complex containing FBXO7. Component of the SCF(FBXO10) complex containing FBXO10. Component of the SCF(FBXO11) complex containing FBXO11. Component of the SCF(FBXO25) complex containing FBXO25. Component of the SCF(FBXO33) complex containing FBXO33. Component of the probable SCF(FBXO4) complex containing FBXO4. Component of the SCF(FBXO44) complex, composed of SKP1, CUL1 and FBXO44. Component of the SCF(BTRC) complex, composed of SKP1, CUL1 and BTRC. This complex binds phosphorylated NFKBIA. Part of a SCF complex consisting of CUL1, RBX1, SKP1 and FBXO2. Component of a SCF(SKP2)-like complex containing CUL1, SKP1, TRIM21 and SKP2. Component of the SCF(FBXO17) complex, composed of SKP1, CUL1 and FBXO17. Component of the SCF(FBXO27) complex, composed of SKP1, CUL1 and FBXO27. Component of the SCF(CCNF) complex consisting of CUL1, RBX1, SKP1 and CCNF. Component of the SCF(FBXL3) complex composed of CUL1, SKP1, RBX1 and FBXL3. Component of the SCF(FBXL21) complex composed of CUL1, SKP1, RBX1 and FBXL21. Component of the SCF(FBXO9) composed of CUL1, SKP1, RBX1 and FBXO9. Component of the SCF(FBXW7) composed of CUL1, SKP1, RBX1 and FBXW7 (PubMed:28727686). Interacts with CEP68 (PubMed:25503564). Interacts with NOTCH2 (PubMed:29149593). Interacts with FBXW15 (By similarity). The SKP1-KDM2A and SKP1-KDM2B complexes interact with UBB (PubMed:30033217).SUBUNIT (Microbial infection) Interacts with vaccinia virus protein C9L.PTM Undergoes autophagy-mediated degradation in the liver in a time-dependent manner.SIMILARITY Belongs to the SKP1 family. UniProt P63208 2 EQUAL 163 EQUAL Reactome DB_ID: 174230 1 UniProt:Q13616 CUL1 CUL1 CUL1 FUNCTION Core component of multiple cullin-RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes, which mediate the ubiquitination of proteins involved in cell cycle progression, signal transduction and transcription. SCF complexes and ARIH1 collaborate in tandem to mediate ubiquitination of target proteins (PubMed:27565346). In the SCF complex, serves as a rigid scaffold that organizes the SKP1-F-box protein and RBX1 subunits. May contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. The E3 ubiquitin-protein ligase activity of the complex is dependent on the neddylation of the cullin subunit and exchange of the substrate recognition component is mediated by TIP120A/CAND1. The functional specificity of the SCF complex depends on the F-box protein as substrate recognition component. SCF(BTRC) and SCF(FBXW11) direct ubiquitination of CTNNB1 and participate in Wnt signaling. SCF(FBXW11) directs ubiquitination of phosphorylated NFKBIA. SCF(BTRC) directs ubiquitination of NFKBIB, NFKBIE, ATF4, SMAD3, SMAD4, CDC25A, FBXO5 and probably NFKB2. SCF(BTRC) and/or SCF(FBXW11) direct ubiquitination of CEP68 (PubMed:25704143, PubMed:25503564). SCF(SKP2) directs ubiquitination of phosphorylated CDKN1B/p27kip and is involved in regulation of G1/S transition. SCF(SKP2) directs ubiquitination of ORC1, CDT1, RBL2, ELF4, CDKN1A, RAG2, FOXO1A, and probably MYC and TAL1. SCF(FBXW7) directs ubiquitination of CCNE1, NOTCH1 released notch intracellular domain (NICD), and probably PSEN1. SCF(FBXW2) directs ubiquitination of GCM1. SCF(FBXO32) directs ubiquitination of MYOD1. SCF(FBXO7) directs ubiquitination of BIRC2 and DLGAP5. SCF(FBXO33) directs ubiquitination of YBX1. SCF(FBXO1) directs ubiquitination of BCL6 and DTL but does not seem to direct ubiquitination of TP53. SCF(BTRC) mediates the ubiquitination of NFKBIA at 'Lys-21' and 'Lys-22'; the degradation frees the associated NFKB1-RELA dimer to translocate into the nucleus and to activate transcription. SCF(CCNF) directs ubiquitination of CCP110. SCF(FBXL3) and SCF(FBXL21) direct ubiquitination of CRY1 and CRY2. SCF(FBXO9) directs ubiquitination of TTI1 and TELO2. SCF(FBXO10) directs ubiquitination of BCL2.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Component of multiple SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complexes formed of CUL1, SKP1, RBX1 and a variable F-box domain-containing protein as substrate-specific subunit (PubMed:10230406, PubMed:15145941, PubMed:15531760, PubMed:16714087, PubMed:16797541, PubMed:17098746, PubMed:18203720, PubMed:20596027, PubMed:22405651, PubMed:22113614, PubMed:23263282, PubMed:23431138, PubMed:25503564, PubMed:11961546, PubMed:22748924). Component of the SCF(FBXW11) complex containing FBXW11. Component of the SCF(SKP2) complex containing SKP2, in which it interacts directly with SKP1, SKP2 and RBX1. Component of the SCF(FBXW2) complex containing FBXW2. Component of the SCF(FBXO32) complex containing FBXO32. Component of the probable SCF(FBXO7) complex containing FBXO7. Component of the SCF(FBXO10) complex containing FBXO10. Component of the SCF(FBXO11) complex containing FBXO11. Component of the SCF(FBXO25) complex containing FBXO25. Component of the SCF(FBXO33) complex containing FBXO33. Component of the probable SCF(FBXO4) complex containing FBXO4. Component of the SCF(FBXO44) complex, composed of SKP1, CUL1 and FBXO44. Component of the SCF(BTRC) complex, composed of SKP1, CUL1 and BTRC. This complex binds phosphorylated NFKBIA. Part of a SCF complex consisting of CUL1, RBX1, SKP1 and FBXO2. Component of a SCF(SKP2)-like complex containing CUL1, SKP1, TRIM21 and SKP2. Component of the SCF(FBXO17) complex, composed of SKP1, CUL1 and FBXO17. Component of the SCF(FBXO27) complex, composed of SKP1, CUL1 and FBXO27. Component of the SCF(CCNF) complex consisting of CUL1, RBX1, SKP1 and CCNF. Component of the SCF(FBXL3) complex composed of CUL1, SKP1, RBX1 and FBXL3. Component of the SCF(FBXL21) complex composed of CUL1, SKP1, RBX1 and FBXL21. Component of the SCF(FBXO9) composed of CUL1, SKP1, RBX1 and FBXO9. Component of the SCF(FBXW7) composed of CUL1, SKP1, RBX1 and FBXW7 (PubMed:22405651). Interacts with CHEK2; mediates CHEK2 ubiquitination and regulates its function. Part of a complex with TIP120A/CAND1 and RBX1. The unneddylated form interacts with TIP120A/CAND1 and the interaction mediates the exchange of the F-box substrate-specific subunit. Can self-associate. Interacts with FBXW8. Interacts with RNF7. Interacts with CUL7; the interaction seems to be mediated by FBXW8. Interacts with TRIM21. Interacts with COPS2. Interacts with UBE2M (PubMed:21940857). Identified in a complex with RBX1 and GLMN (PubMed:22405651, PubMed:22748924). Interacts with CEP68 as part of the SCF(FBXW11) complex; the interaction is probably mediated by FBXW11 and the complex also contains CDK5RAP2 and PCNT (PubMed:25503564). Interacts (when neddylated) with ARIH1; leading to activate the E3 ligase activity of ARIH1 (PubMed:24076655, PubMed:27565346). Interacts with COPS9 isoform 2 (PubMed:23776465). Interacts with UBXN1 (PubMed:28152074). Interacts with KAT7, probably as part of an SCF complex; the interaction mediates KAT7 ubiquitination (By similarity). Interacts with NOTCH2 (PubMed:29149593). Part of a complex that contains DCUN1D5, CUL1 and RBX1; this complex is bridged by CUL1 (PubMed:24192928). Interacts (unneddylated form) with DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5; these interactions promote the cullin neddylation (PubMed:24192928, PubMed:26906416, PubMed:23201271, PubMed:21940857, PubMed:25349211, PubMed:28581483).SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus BPLF1.SUBUNIT (Microbial infection) Interacts with Human adenovirus early E1A protein; this interaction inhibits RBX1-CUL1-dependent elongation reaction of ubiquitin chains by the SCF(FBXW7) complex.SUBUNIT (Microbial infection) Interacts with vaccinia virus protein C9L.TISSUE SPECIFICITY Expressed in lung fibroblasts.PTM Neddylated; which enhances the ubiquitination activity of SCF and prevents binding of the inhibitor CAND1. Deneddylated via its interaction with the COP9 signalosome (CSN) complex (PubMed:10597293, PubMed:10713156, PubMed:15537541, PubMed:18805092).PTM (Microbial infection) Deneddylated by Epstein-Barr virus BPLF1 leading to a S-phase-like environment that is required for efficient replication of the viral genome (PubMed:20190741).SIMILARITY Belongs to the cullin family. UniProt Q13616 1 EQUAL 776 EQUAL Reactome Database ID Release 78 5607687 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=5607687 Reactome R-HSA-5607687 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-5607687.1 Converted from EntitySet in Reactome Reactome DB_ID: 5607669 1 UBE2D2,UBE2D1,(CDC34) [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity UBE2D1 [cytosol] UBE2D2 [cytosol] UniProt P51668 UniProt P62837 Reactome DB_ID: 5607697 1 K48PolyUb-K21,22-p-S32,36-IkBA:NF-kB complex [cytosol] K48PolyUb-K21,22-p-S32,36-IkBA:NF-kB complex Reactome DB_ID: 194043 1 Reactome DB_ID: 5607659 1 O-phospho-L-serine at 32 32 EQUAL O-phospho-L-serine at 36 36 EQUAL ubiquitinylated lysine (K48polyUb [cytosol]) at 21 21 EQUAL ubiquitinylated lysine (K48polyUb [cytosol]) at 22 22 EQUAL 1 EQUAL 317 EQUAL Reactome Database ID Release 78 5607697 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=5607697 Reactome R-HSA-5607697 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-5607697.1 Reactome DB_ID: 5607687 1 Converted from EntitySet in Reactome Reactome DB_ID: 5607669 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 5607687 Reactome Database ID Release 78 5607710 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=5607710 Reactome Database ID Release 78 5607728 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=5607728 Reactome R-HSA-5607728 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-5607728.3 14514672 Pubmed 2003 Signal-induced ubiquitination of I kappaB Kinase-beta Carter, Robert S Pennington, Kevin N Ungurait, Bradley J Arrate, Pia Ballard, Dean W J. Biol. Chem. 278:48903-6 7479848 Pubmed 1995 Stimulation-dependent I kappa B alpha phosphorylation marks the NF-kappa B inhibitor for degradation via the ubiquitin-proteasome pathway Alkalay, I Yaron, A Hatzubai, A Orian, A Ciechanover, A Ben-Neriah, Y Proc Natl Acad Sci U S A 92:10599-603 20347421 Pubmed 2010 Priming and extending: a UbcH5/Cdc34 E2 handoff mechanism for polyubiquitination on a SCF substrate Wu, K Kovacev, J Pan, ZQ Mol Cell 37:784-96 9990853 Pubmed 1999 Signal-induced ubiquitination of IkappaBalpha by the F-box protein Slimb/beta-TrCP Spencer, E Jiang, J Chen, ZJ Genes Dev 13:284-94 7479976 Pubmed 1995 Signal-induced degradation of I kappa B alpha requires site-specific ubiquitination Scherer, DC Brockman, JA Chen, Z Maniatis, T Ballard, DW Proc Natl Acad Sci U S A 92:11259-63 8550590 Pubmed 1996 Critical role for lysines 21 and 22 in signal-induced, ubiquitin-mediated proteolysis of I kappa B-alpha Baldi, L Brown, K Franzoso, G Siebenlist, U J. Biol. Chem. 271:376-9 10918611 Pubmed 2000 SCF(beta-TRCP) and phosphorylation dependent ubiquitinationof I kappa B alpha catalyzed by Ubc3 and Ubc4 Strack, P Caligiuri, M Pelletier, M Boisclair, M Theodoras, A Beer-Romero, P Glass, S Parsons, T Copeland, R A Auger, K R Benfield, P Brizuela, L Rolfe, M Oncogene 19:3529-36 8649784 Pubmed 1996 Identification of lysine residues required for signal-induced ubiquitination and degradation of I kappa B-alpha in vivo Rodriguez, M S Wright, J Thompson, J Thomas, D Baleux, F Virelizier, J L Hay, R T Arenzana-Seisdedos, F Oncogene 12:2425-35 26S proteasome processes K48PolyUb-K21,22-p-S32,36-IkBA:NF-kB complex to form NF-kB complex 26S proteasome processes K48PolyUb-K21,22-p-S32,36-IkBA:NF-kB complex to form NF-kB complex Following ubiquitination NF-kappa-B inhibitor alpha (NFKBIA or IκBα) is rapidly degraded by 26S-proteasome, allowing NF-kB to translocate into the nucleus where it activates gene transcription (Spencer et al. 1999).<p>Severe acute respiratory syndrome coronavirus (SARS-CoV) 1a-encoded papain-like protease (PLPro or nsp3) was found to cleave Lys48-linked polyUb chains of NFKBIA (IκBα) (Békés M et al. 2016;Ratia K et al. 2014) suggesting an inhibitory effect of SARS-CoV-1 nsp3 on 26S proteasome-dependent degradation of NFKBIA. Authored: Garapati, P V, 2014-07-14 Reviewed: Geijtenbeek, Teunis B H, 2014-09-02 Edited: Garapati, P V, 2014-07-14 Reactome DB_ID: 5607697 1 Reactome DB_ID: 194043 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 68819 26S proteasome [cytosol] 26S proteasome Reactome DB_ID: 68792 1 UniProt:O00232 PSMD12 PSMD12 PSMD12 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex (PubMed:27428775,PubMed:27342858). The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP) (PubMed:27428775,PubMed:27342858). The regulatory particle is made of a lid composed of 9 subunits including PSMD12, a base containing 6 ATPases and few additional components (PubMed:27428775,PubMed:27342858). Interacts with ERCC6 (PubMed:26030138).SIMILARITY Belongs to the proteasome subunit p55 family. UniProt O00232 2 EQUAL 456 EQUAL Reactome DB_ID: 68814 1 UniProt:Q9UL46 PSME2 PSME2 PSME2 FUNCTION Implicated in immunoproteasome assembly and required for efficient antigen processing. The PA28 activator complex enhances the generation of class I binding peptides by altering the cleavage pattern of the proteasome.SUBUNIT Heterodimer of PSME1 and PSME2, which forms a hexameric ring.INDUCTION By IFNG/IFN-gamma.SIMILARITY Belongs to the PA28 family. UniProt Q9UL46 2 EQUAL 239 EQUAL Reactome DB_ID: 68816 1 UniProt:P61289 PSME3 PSME3 PSME3 FUNCTION Subunit of the 11S REG-gamma (also called PA28-gamma) proteasome regulator, a doughnut-shaped homoheptamer which associates with the proteasome. 11S REG-gamma activates the trypsin-like catalytic subunit of the proteasome but inhibits the chymotrypsin-like and postglutamyl-preferring (PGPH) subunits. Facilitates the MDM2-p53/TP53 interaction which promotes ubiquitination- and MDM2-dependent proteasomal degradation of p53/TP53, limiting its accumulation and resulting in inhibited apoptosis after DNA damage. May also be involved in cell cycle regulation. Mediates CCAR2 and CHEK2-dependent SIRT1 inhibition (PubMed:25361978).SUBUNIT Homoheptamer; the stability of the heptamer is essential for the specific activation of the trypsine-like subunit and inhibition of the chymotrypsin-like and postglutamyl-preferring (PGPH) subunits of the proteasome. Interacts with p53/TP53 and MDM2. Interacts with MAP3K3 (By similarity). Associates with the proteasome. Interacts with CCAR2. Interacts with PSME3IP1 (via C-terminus); the interaction is direct and promotes the association of PSME3 with the 20S proteasome (PubMed:29934401). Interacts with COIL; the interaction is inhibited by PSME3IP1 (PubMed:29934401).SUBUNIT (Microbial infection) Interacts with human cytomegalovirus UL27.INDUCTION Up-regulated in thyroid carcinoma cells.DOMAIN The C-terminal sequences affect heptamer stability and proteasome affinity.PTM Phosphorylated by MAP3K3 (By similarity). Phosphorylation at Ser-247 promotes its association with CCAR2.PTM Acetylation at the major site Lys-195 is important for oligomerization and ability to degrade its target substrates. Deacetylated by SIRT1.SIMILARITY Belongs to the PA28 family. UniProt P61289 2 EQUAL 254 EQUAL Reactome DB_ID: 68777 1 UniProt:P43686 PSMC4 PSMC4 TBP7 PSMC4 MIP224 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC4 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC4 and few additional components (PubMed:27428775,PubMed:27342858). Interacts with NR1I3. Interacts with PAAF1 (PubMed:15831487). Interacts with TRIM5 (PubMed:22078707). Interacts with ZFAND1 (PubMed:29804830).SIMILARITY Belongs to the AAA ATPase family. UniProt P43686 1 EQUAL 418 EQUAL Reactome DB_ID: 68798 1 UniProt:O43242 PSMD3 PSMD3 PSMD3 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD3, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Interacts with UBQLN1 (via ubiquitin-like domain) (PubMed:15147878). Interacts with ERCC6 (PubMed:26030138).SIMILARITY Belongs to the proteasome subunit S3 family. UniProt O43242 1 EQUAL 534 EQUAL Reactome DB_ID: 68756 1 UniProt:P28072 PSMB6 PSMB6 PSMB6 LMPY Y FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Within the 20S core complex, PSMB6 displays a peptidylglutamyl-hydrolizing activity also termed postacidic or caspase-like activity, meaning that the peptides bond hydrolysis occurs directly after acidic residues.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interacts with HIV-1 protein Tat.INDUCTION Down-regulated by IFNG/IFN-gamma (at protein level). Up-regulated in anaplastic thyroid cancer cell lines.SIMILARITY Belongs to the peptidase T1B family. UniProt P28072 35 EQUAL 239 EQUAL Reactome DB_ID: 68774 1 UniProt:P17980 PSMC3 PSMC3 PSMC3 TBP1 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC3 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC3 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with PAAF1 (PubMed:15831487).SUBUNIT (Microbial infection) Interacts with HIV-1 Tat.PTM Sumoylated by UBE2I in response to MEKK1-mediated stimuli.SIMILARITY Belongs to the AAA ATPase family. UniProt P17980 1 EQUAL 439 EQUAL Reactome DB_ID: 68786 1 UniProt:Q99460 PSMD1 PSMD1 PSMD1 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases and few additional components including PSMD1 (PubMed:27428775, PubMed:27342858). Interacts with ADRM1 (PubMed:16990800, PubMed:16906146). Interacts with ZFAND1 (PubMed:29804830).SIMILARITY Belongs to the proteasome subunit S1 family. UniProt Q99460 1 EQUAL 953 EQUAL Reactome DB_ID: 68808 1 UniProt:P48556 PSMD8 PSMD8 PSMD8 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD8, a base containing 6 ATPases and few additional components. Interacts with DDI2 (PubMed:29290612). Interacts with TASOR (By similarity).SIMILARITY Belongs to the proteasome subunit S14 family.CAUTION It is uncertain whether Met-1 or Met-64 is the initiator. UniProt P48556 1 EQUAL 350 EQUAL Reactome DB_ID: 68753 1 UniProt:P28074 PSMB5 PSMB5 PSMB5 X LMPX MB1 FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Within the 20S core complex, PSMB5 displays a chymotrypsin-like activity.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Directly interacts with POMP (PubMed:15944226). Interacts with ABCB1 and TAP1 (PubMed:15488952).SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.INDUCTION Down-regulated by IFNG/IFN-gamma (at protein level). Induced in breast cancer tissue. Up-regulated by sulforaphane in breast cancer cells.SIMILARITY Belongs to the peptidase T1B family. UniProt P28074 60 EQUAL 263 EQUAL Reactome DB_ID: 68780 1 UniProt:P62195 PSMC5 PSMC5 PSMC5 SUG1 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC5 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC5 and few additional components (PubMed:27428775, PubMed:27342858). Component of a complex with USP49 and RUVBL1 (PubMed:23824326). Interacts with PRPF19. Interacts with TRIM5 (PubMed:22078707). Interacts with NDC80 (PubMed:9295362, PubMed:10409732). Interacts with PAAF1 (PubMed:15831487). Interacts, in vitro, with the thyroid hormone receptor (in a thyroid hormone T3-dependent manner) and with retinoid X receptor (RXR) (By similarity). Interacts with ERCC6 (PubMed:26030138).SIMILARITY Belongs to the AAA ATPase family. UniProt P62195 2 EQUAL 406 EQUAL Reactome DB_ID: 68768 1 UniProt:P62191 PSMC1 PSMC1 PSMC1 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC1 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC1 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with SCA7 (PubMed:11734547). Interacts with NGLY1 (PubMed:15358861). Interacts with PAAF1 (PubMed:15831487).SIMILARITY Belongs to the AAA ATPase family. UniProt P62191 2 EQUAL 440 EQUAL Reactome DB_ID: 68771 1 UniProt:P35998 PSMC2 PSMC2 MSS1 PSMC2 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC2 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC2 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with NDC80/HEC; this interaction is detected only during M phase. Interacts and SQSTM1 (PubMed:15340068). Interacts with PAAF1 (PubMed:15831487). Directly interacts with TRIM5 (PubMed:22078707).INDUCTION Expression is not cell cycle-dependent and occurs throughout the cell cycle.SIMILARITY Belongs to the AAA ATPase family. UniProt P35998 2 EQUAL 433 EQUAL Reactome DB_ID: 68722 1 UniProt:O00487 PSMD14 PSMD14 PSMD14 POH1 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. The PSMD14 subunit is a metalloprotease that specifically cleaves 'Lys-63'-linked polyubiquitin chains within the complex. Plays a role in response to double-strand breaks (DSBs): acts as a regulator of non-homologous end joining (NHEJ) by cleaving 'Lys-63'-linked polyubiquitin, thereby promoting retention of JMJD2A/KDM4A on chromatin and restricting TP53BP1 accumulation. Also involved in homologous recombination repair by promoting RAD51 loading.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD4, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Within the complex, PSMD4 interacts with subunit PSMD7 through their respective MPN domain. Interacts with TXNL1 (PubMed:19349277).TISSUE SPECIFICITY Widely expressed. Highest levels in heart and skeletal muscle.SIMILARITY Belongs to the peptidase M67A family. PSMD14 subfamily. UniProt O00487 1 EQUAL 310 EQUAL Reactome DB_ID: 68724 1 UniProt:P25786 PSMA1 PSMA1 PSMA1 HC2 NU PSC2 PROS30 FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular pro