BioPAX pathway converted from "C-type lectin receptors (CLRs)" in the Reactome database. C-type lectin receptors (CLRs) C-type lectin receptors (CLRs) This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> CLEC7A (Dectin-1) signaling CLEC7A (Dectin-1) signaling This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2.7.10 SRC kinase phosphorylates CLEC7A:1,3-beta-D-glucan SRC kinase phosphorylates CLEC7A:1,3-beta-D-glucan SRC kinase phosphorylates Dectin-1:1,3-beta-D-glucan This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 1 cytosol GO 0005829 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP Reactome http://www.reactome.org ChEBI 30616 Reactome DB_ID: 9824045 1 plasma membrane GO 0005886 CLEC7A:1,3-beta-D-glucan [plasma membrane] CLEC7A:1,3-beta-D-glucan Reactome DB_ID: 9824043 1 UniProt:Q6QLQ4 Clec7a Clec7a Dectin1 Clec7a Clecsf12 Bgr FUNCTION Lectin that functions as pattern recognizing receptor (PRR) specific for beta-1,3-linked and beta-1,6-linked glucans, which constitute cell wall constituents from pathogenic bacteria and fungi (PubMed:11544516, PubMed:17159984, PubMed:15213161). Necessary for the TLR2-mediated inflammatory response and activation of NF-kappa-B: upon beta-glucan binding, recruits SYK via its ITAM motif and promotes a signaling cascade that activates some CARD domain-BCL10-MALT1 (CBM) signalosomes, leading to the 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:12719479, PubMed:15731053, PubMed:16825490, PubMed:32358020). Enhances cytokine production in macrophages and dendritic cells (PubMed:15845454). Mediates production of reactive oxygen species in the cell (PubMed:12719479, PubMed:15731053, PubMed:16825490). Mediates phagocytosis of C.albicans conidia (PubMed:15729357, PubMed:16825490). Binds T-cells in a way that does not involve their surface glycans and plays a role in T-cell activation (PubMed:10779524). Stimulates T-cell proliferation (PubMed:10779524). Induces phosphorylation of SCIMP after binding beta-glucans (PubMed:27288407).SUBUNIT Homodimer (PubMed:17473009). Interacts with SYK; participates in leukocyte activation in presence of fungal pathogens (PubMed:15845454).TISSUE SPECIFICITY Detected in spleen (at protein level). Highly expressed in dendritic cells, spleen and thymus. Detected in epidermal Langerhans cells. Detected in macrophages, liver and lung.PTM N-glycosylated.PTM Phosphorylated on tyrosine residues in response to beta-glucan binding.DISRUPTION PHENOTYPE Mice were born at the normal Mendelian ratio without obvious anatomical defects but are susceptible to infection with C.albicans (PubMed:17159984). They show impaired myeloid cell activation by fungal particles (PubMed:17159984). Deficient leukocytes display impaired responses to fungi, characterized by reduced inflammatory cell recruitment after fungal infection, resulting in substantially increased fungal burdens and enhanced fungal dissemination (PubMed:32358020). Mus musculus NCBI Taxonomy 10090 UniProt Q6QLQ4 Chain Coordinates 1 EQUAL 247 EQUAL Reactome DB_ID: 2186970 1 extracellular region GO 0005576 (1->3)-beta-D-glucan [ChEBI:37671] (1->3)-beta-D-glucan ChEBI 37671 Reactome Database ID Release 78 9824045 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824045 Reactome R-MMU-5607680 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607680.1 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: 9824049 1 1,3-beta-D-glucan:p-Y15-CLEC7A [plasma membrane] 1,3-beta-D-glucan:p-Y15-CLEC7A Reactome DB_ID: 9824047 1 O4'-phospho-L-tyrosine at 15 15 EQUAL O4'-phospho-L-tyrosine [MOD:00048] 1 EQUAL 247 EQUAL Reactome DB_ID: 2186970 1 Reactome Database ID Release 78 9824049 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824049 Reactome R-MMU-5607677 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607677.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9766388 UniProt:P05480 Src Src Src FUNCTION Non-receptor protein tyrosine kinase which is activated following engagement of many different classes of cellular receptors including immune response receptors, integrins and other adhesion receptors, receptor protein tyrosine kinases, G protein-coupled receptors as well as cytokine receptors. Participates in signaling pathways that control a diverse spectrum of biological activities including gene transcription, immune response, cell adhesion, cell cycle progression, apoptosis, migration, and transformation. Due to functional redundancy between members of the SRC kinase family, identification of the specific role of each SRC kinase is very difficult. SRC appears to be one of the primary kinases activated following engagement of receptors and plays a role in the activation of other protein tyrosine kinase (PTK) families. Receptor clustering or dimerization leads to recruitment of SRC to the receptor complexes where it phosphorylates the tyrosine residues within the receptor cytoplasmic domains. Plays an important role in the regulation of cytoskeletal organization through phosphorylation of specific substrates such as AFAP1. Phosphorylation of AFAP1 allows the SRC SH2 domain to bind AFAP1 and to localize to actin filaments. Cytoskeletal reorganization is also controlled through the phosphorylation of cortactin (CTTN) (Probable). When cells adhere via focal adhesions to the extracellular matrix, signals are transmitted by integrins into the cell resulting in tyrosine phosphorylation of a number of focal adhesion proteins, including PTK2/FAK1 and paxillin (PXN) (By similarity). In addition to phosphorylating focal adhesion proteins, SRC is also active at the sites of cell-cell contact adherens junctions and phosphorylates substrates such as beta-catenin (CTNNB1), delta-catenin (CTNND1), and plakoglobin (JUP). Another type of cell-cell junction, the gap junction, is also a target for SRC, which phosphorylates connexin-43 (GJA1). SRC is implicated in regulation of pre-mRNA-processing and phosphorylates RNA-binding proteins such as KHDRBS1 (Probable). Also plays a role in PDGF-mediated tyrosine phosphorylation of both STAT1 and STAT3, leading to increased DNA binding activity of these transcription factors (PubMed:9344858). Involved in the RAS pathway through phosphorylation of RASA1 and RASGRF1. Plays a role in EGF-mediated calcium-activated chloride channel activation (By similarity). Required for epidermal growth factor receptor (EGFR) internalization through phosphorylation of clathrin heavy chain (CLTC and CLTCL1) at 'Tyr-1477'. Involved in beta-arrestin (ARRB1 and ARRB2) desensitization through phosphorylation and activation of GRK2, leading to beta-arrestin phosphorylation and internalization. Has a critical role in the stimulation of the CDK20/MAPK3 mitogen-activated protein kinase cascade by epidermal growth factor (Probable). Might be involved not only in mediating the transduction of mitogenic signals at the level of the plasma membrane but also in controlling progression through the cell cycle via interaction with regulatory proteins in the nucleus (By similarity). Plays an important role in osteoclastic bone resorption in conjunction with PTK2B/PYK2. Both the formation of a SRC-PTK2B/PYK2 complex and SRC kinase activity are necessary for this function. Recruited to activated integrins by PTK2B/PYK2, thereby phosphorylating CBL, which in turn induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function (PubMed:14739300). Promotes energy production in osteoclasts by activating mitochondrial cytochrome C oxidase (PubMed:12615910). Phosphorylates DDR2 on tyrosine residues, thereby promoting its subsequent autophosphorylation. Phosphorylates RUNX3 and COX2 on tyrosine residues, TNK2 on 'Tyr-284' and CBL on 'Tyr-738'. Enhances DDX58/RIG-I-elicited antiviral signaling. Phosphorylates PDPK1 at 'Tyr-9', 'Tyr-373' and 'Tyr-376'. Phosphorylates BCAR1 at 'Tyr-226'. Phosphorylates CBLC at multiple tyrosine residues, phosphorylation at 'Tyr-341' activates CBLC E3 activity. Involved in anchorage-independent cell growth (By similarity). Required for podosome formation (PubMed:21525037). Mediates IL6 signaling by activating YAP1-NOTCH pathway to induce inflammation-induced epithelial regeneration (PubMed:25731159).ACTIVITY REGULATION Phosphorylation by CSK at Tyr-529 inhibits kinase activity. Inhibitory phosphorylation at Tyr-529 is enhanced by heme. Further phosphorylation by CDK1 partially reactivates CSK-inactivated SRC and facilitates complete reactivation by protein tyrosine phosphatase PTPRC. Integrin engagement stimulates kinase activity. Phosphorylation by PTK2/FAK1 enhances kinase activity. Butein and pseudosubstrate-based peptide inhibitors like CIYKYYF act as inhibitors. Phosphorylation at Tyr-418 increases kinase activity.SUBUNIT Part of a complex comprised of PTPRA, BCAR1, BCAR3 (via SH2 domain) and SRC; the formation of the complex is dependent on integrin mediated-tyrosine phosphorylation of PTPRA (PubMed:22801373). Interacts with CDCP1, TGFB1I1 and TOM1L2 (By similarity). Interacts with DDEF1/ASAP1 via its SH3 domain (PubMed:9819391). Interacts with CCPG1 (PubMed:17000758). Interacts with the cytoplasmic domain of MUC1, phosphorylates it and increases binding of MUC1 with beta-catenin (By similarity). Interacts with RALGPS1 via its SH3 domain (By similarity). Interacts with CAV2 (tyrosine phosphorylated form) (By similarity). Interacts (via the SH3 domain and the protein kinase domain) with ARRB1; the interaction is independent of the phosphorylation state of SRC C-terminus (By similarity). Interacts with FCAMR and PXN (By similarity). Interacts with ARRB2 (PubMed:19122674). Interacts with ARRB1 (By similarity). Interacts with SRCIN1 (By similarity). Interacts with NDFIP2 and more weakly with NDFIP1 (By similarity). Interacts with PIK3CA and/or PIK3C2B, PTK2/FAK1, ESR1 (dimethylated on arginine) and FAK (PubMed:14739300). Interacts (via SH2 and SH3 domain) with TNK2 (By similarity). Interacts (via protein kinase domain) with the tyrosine phosphorylated form of RUNX3 (via runt domain) (By similarity). Interacts with TRAF3 (via RING-type zinc finger domain) (By similarity). Interacts with DDX58, MAVS and TBK1 (By similarity). Interacts (via SH2 domain) with RACK1; the interaction is enhanced by tyrosine phosphorylation of RACK1 and inhibits SRC activity (By similarity). Interacts (via SH2 domain) with the 'Tyr-402' phosphorylated form of PTK2B/PYK2 (PubMed:14739300). Interacts (via SH2 domain) with FLT3 (tyrosine phosphorylated) (PubMed:16684964). Identified in a complex containing FGFR4, NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTTN (PubMed:11433297). Interacts with EPHB1; activates the MAPK/ERK cascade to regulate cell migration (PubMed:12925710). Interacts with ERBB2 and STAT1 (PubMed:7542762, PubMed:9344858). Interacts with PDGFRA (tyrosine phosphorylated) (PubMed:14644164). Interacts with CSF1R (PubMed:7681396). Interacts (via SH2 domain) with the 'Tyr-9' phosphorylated form of PDPK1 (By similarity). Interacts with DDR2 (By similarity). Interacts with AMOTL2; this interaction regulates the translocation of phosphorylated SRC to peripheral cell-matrix adhesion sites (By similarity). Interacts with DDR1 and DAB2 (PubMed:20093046). Interacts with TRAP1 (By similarity). Interacts with CBLC; the interaction is enhanced when SRC is phosphorylated at 'Tyr-424' (By similarity). Interacts with ARHGEF5 (PubMed:21525037). Interacts (via cytoplasmic domain) with CEACAM1 (via SH2 domain); this interaction is regulated by trans-homophilic cell adhesion (By similarity). Interacts with MPP2 (By similarity). Interacts with PRR7 (By similarity). Interacts (via kinase domain and to a lesser extent the SH2 domain) directly with PDLIM4; this interaction results in PTPN13-mediated dephosphorylation of this protein leading to its inactivation (By similarity). Interacts with P85 (PIK3R1 or PIK3R2) (By similarity). Interacts with HNRNPA2B1 (PubMed:31320558). Interacts with IL6ST/gp130 (By similarity). Interacts (via SH3 domain) with PELP1 in the presence of 17-beta-estradiol (By similarity).PTM Myristoylated at Gly-2, and this is essential for targeting to membranes.PTM Dephosphorylated at Tyr-529 by PTPRJ (By similarity). Phosphorylated on Tyr-529 by c-Src kinase (CSK). The phosphorylated form is termed pp60c-src. Dephosphorylated by PTPRJ at Tyr-418. Normally maintained in an inactive conformation with the SH2 domain engaged with Tyr-529, the SH3 domain engaged with the SH2-kinase linker, and Tyr-418 dephosphorylated. Dephosphorylation of Tyr-529 as a result of protein tyrosine phosphatase (PTP) action disrupts the intramolecular interaction between the SH2 domain and Tyr-529, Tyr-418 can then become autophosphorylated, resulting in SRC activation. Phosphorylation of Tyr-529 by CSK allows this interaction to reform, resulting in SRC inactivation. CDK5-mediated phosphorylation at Ser-74 targets SRC to ubiquitin-dependent degradation and thus leads to cytoskeletal reorganization. Phosphorylated by PTK2/FAK1; this enhances kinase activity. Phosphorylated by PTK2B/PYK2; this enhances kinase activity (By similarity). Upon activation of IL6ST by IL6, Tyr-418 is phosphorylated and Tyr-529 dephosphorylated (PubMed:25731159).PTM S-nitrosylation is important for activation of its kinase activity.PTM Ubiquitinated in response to CDK5-mediated phosphorylation. Ubiquitination mediated by CBLC requires SRC autophosphorylation at Tyr-418 and may lead to lysosomal degradation (By similarity).SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. SRC subfamily. UniProt P05480 2 EQUAL 536 EQUAL GO 0004713 GO molecular function Reactome Database ID Release 78 9766389 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766389 Reactome Database ID Release 78 9824051 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824051 Reactome R-MMU-5607750 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607750.1 The signalling abilities of CLEC7A (Dectin-1) depend on its cytoplasmic (immunoreceptor tyrosine based activation motif) ITAM-like motif. In contrast to traditional ITAM sequences which consists of dual YXXL sequences, CLEC7A's ITAM (hemi-ITAM) has only a single YXXL motif (Ariizumi et al. 2000). Despite its unusual ITAM, CLEC7A upon ligation with beta-glucan containing particles undergoes tyrosine phoshorylation by SRC kinases (Kerrigan & Brown 2010). 21525931 Pubmed 2011 Activation of the innate immune receptor Dectin-1 upon formation of a 'phagocytic synapse' Goodridge, Helen S Reyes, Christopher N Becker, Courtney A Katsumoto, Tamiko R Ma, Jun Wolf, Andrea J Bose, Nandita Chan, Anissa S H Magee, Andrew S Danielson, Michael E Weiss, Arthur Vasilakos, John P Underhill, David M Nature 472:471-5 20193029 Pubmed 2010 Syk-coupled C-type lectin receptors that mediate cellular activation via single tyrosine based activation motifs Kerrigan, Ann M Brown, Gordon D Immunol. Rev. 234:335-52 16341139 Pubmed 2006 Dectin-1: a signalling non-TLR pattern-recognition receptor Brown, Gordon D Nat. Rev. Immunol. 6:33-43 10779524 Pubmed 2000 Identification of a novel, dendritic cell-associated molecule, dectin-1, by subtractive cDNA cloning Ariizumi, K Shen, G L Shikano, S Xu, S Ritter, R Kumamoto, T Edelbaum, D Morita, A Bergstresser, P R Takashima, A J. Biol. Chem. 275:20157-67 15845454 Pubmed 2005 Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins Rogers, Neil C Slack, Emma C Edwards, Alexander D Nolte, Martijn A Schulz, Oliver Schweighoffer, Edina Williams, David L Gordon, Siamon Tybulewicz, Victor L Brown, Gordon D Reis e Sousa, C Immunity 22:507-17 inferred by electronic annotation IEA GO IEA p-Y753,Y759-PLCG2 translocates from cytosol to plasma membrane p-Y753,Y759-PLCG2 translocates from cytosol to plasma membrane This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9824061 1 UniProt:Q8CIH5 Plcg2 Plcg2 Plcg2 FUNCTION The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes. It is a crucial enzyme in transmembrane signaling.SUBUNIT Interacts (via SH2 domain) with CSF1R (tyrosine phosphorylated). Interacts constitutively with THEMIS2 (PubMed:27992403).PTM Phosphorylated on tyrosine residues by BTK and SYK; upon ligand-induced activation of a variety of growth factor receptors and immune system receptors. Phosphorylation leads to increased phospholipase activity (By similarity). Phosphorylated on tyrosine residues by CSF1R. UniProt Q8CIH5 O4'-phospho-L-tyrosine at 753 (in Homo sapiens) 753 EQUAL O4'-phospho-L-tyrosine at 759 (in Homo sapiens) 759 EQUAL 1 EQUAL 1265 EQUAL Reactome DB_ID: 9824007 1 O4'-phospho-L-tyrosine at 753 (in Homo sapiens) 753 EQUAL O4'-phospho-L-tyrosine at 759 (in Homo sapiens) 759 EQUAL 1 EQUAL 1265 EQUAL Reactome Database ID Release 78 9824063 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824063 Reactome R-MMU-5607755 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607755.1 Tyrosine-phosphorylated Phospholipase C-gamma 2 (PLCG2) translocates from the cytosol to the plasma membrane. At the membrane PLCG2 is in close proximity to phosphatidylinositol 4,5-bisphosphate (PIP2) and its other substrates generating the second messengers IP3 and DAG (Rhee 2001). This leads to the activation of CARD9-BCL10-MALT1/NF-kB signaling and stimulates calcineurin/NFAT signaling. 11606584 Pubmed 2001 Tyrosine residues in phospholipase Cgamma 2 essential for the enzyme function in B-cell signaling Rodriguez, R Matsuda, M Perisic, O Bravo, J Paul, A Jones, NP Light, Y Swann, K Williams, RL Katan, M J Biol Chem 276:47982-92 8972730 Pubmed 1996 Tyrosine phosphorylation and translocation of phospholipase C-gamma 2 in polymorphonuclear leukocytes treated with pervanadate Kawakami, N Shimohama, S Hayakawa, T Sumida, Y Fujimoto, S Biochim. Biophys. Acta 1314:167-74 11395409 Pubmed 2001 Regulation of phosphoinositide-specific phospholipase C Rhee, S G Annu. Rev. Biochem. 70:281-312 inferred by electronic annotation IEA GO IEA 3.1.4.11 p-Y753,Y759-PLCG2 hydrolyses PIP2 p-Y753,Y759-PLCG2 hydrolyses PIP2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 29356 1 water [ChEBI:15377] water ChEBI 15377 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: 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 Reactome DB_ID: 9824007 O4'-phospho-L-tyrosine at 753 (in Homo sapiens) 753 EQUAL O4'-phospho-L-tyrosine at 759 (in Homo sapiens) 759 EQUAL 1 EQUAL 1265 EQUAL GO 0004435 GO molecular function Reactome Database ID Release 78 9824008 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824008 Reactome Database ID Release 78 9824010 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824010 Reactome R-MMU-5607735 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607735.1 Following tyrosine phosphorylation, phospholipase C-gamma 2 (PLCG2) catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2 or PIP2] to inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). 7612269 Pubmed 1995 Significance of PIP2 hydrolysis and regulation of phospholipase C isozymes Lee, S B Rhee, S G Curr. Opin. Cell Biol. 7:183-9 inferred by electronic annotation IEA GO IEA CLEC7A (Dectin-1) induces NFAT activation CLEC7A (Dectin-1) induces NFAT activation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Activation of Calcineurin Activation of Calcineurin This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 74016 4 calcium(2+) [ChEBI:29108] calcium(2+) ChEBI 29108 Reactome DB_ID: 2025905 1 Calmodulin:Calcium [cytosol] Calmodulin:Calcium Reactome DB_ID: 9016924 1 UniProt:P0DP26 Calm1 Calm1 Calm Cam1 Cam Calm1 FUNCTION Calmodulin mediates the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding. Among the enzymes to be stimulated by the calmodulin-calcium complex are a number of protein kinases and phosphatases. Together with CCP110 and centrin, is involved in a genetic pathway that regulates the centrosome cycle and progression through cytokinesis. Is a regulator of voltage-dependent L-type calcium channels. Mediates calcium-dependent inactivation of CACNA1C. Positively regulates calcium-activated potassium channel activity of KCNN2. Forms a potassium channel complex with KCNQ1 and regulates electrophysiological activity of the channel via calcium-binding. Acts as a sensor to modulate the endomplasmic reticulum contacts with other organelles mediated by VMP1:ATP2A2 (By similarity).SUBUNIT Interacts with CEP97, CCP110, MYO1C, TTN/titin and SRY. Interacts with MYO10. Interacts with RRAD (By similarity). Interacts with USP6; the interaction is calcium dependent (By similarity). Interacts with CDK5RAP2. Interacts with SCN5A (By similarity). Interacts with FCHO1. Interacts with MIP in a 1:2 stoichiometry; the interaction with the cytoplasmic domains from two MIP subunits promotes MIP water channel closure. Interacts with ORAI1; this may play a role in the regulation of ORAI1-mediated calcium transport (By similarity). Interacts with RYR1 (PubMed:18650434). Interacts with MYO5A (PubMed:17151196). Interacts with IQCF1 (PubMed:25380116). Interacts with SYT7 (PubMed:24569478). Interacts with CEACAM1 (via cytoplasmic domain); this interaction is in a calcium dependent manner and reduces homophilic cell adhesion through dissociation of dimer (By similarity). Interacts with RYR2; regulates RYR2 calcium-release channel activity (PubMed:18650434). Interacts with PCP4; regulates calmodulin calcium-binding (By similarity). Interacts with the heterotetrameric KCNQ2 and KCNQ3 channel; the interaction is calcium-independent, constitutive and participates in the proper assembly of a functional heterotetrameric M channel (By similarity). Interacts with alpha-synuclein/SNCA (By similarity). Interacts with SLC9A1 in a calcium-dependent manner (By similarity). In the absence of Ca(+2), interacts with GIMAP4 (via IQ domain) (PubMed:16569770). Interacts with SCN8A; the interaction modulates the inactivation rate of SCN8A (PubMed:23942337). Interaction with KIF1A; the interaction is increased in presence of calcium and increases neuronal dense core vesicles motility (By similarity). Interacts with KCNN3 (By similarity). Interacts with KCNQ1 (via C-terminus); forms a heterooctameric structure (with 4:4 KCNQ1:CALM stoichiometry) in a calcium-independent manner (By similarity). Interacts with PIK3C3; the interaction modulates PIK3C3 kinase activity (By similarity).DOMAIN The N-terminal and C-terminal lobes of CALM bind to the C-terminus of KCNQ1 in a clamp-like conformation. Binding of CALM C-terminus to KCNQ1 is calcium-independent but is essential for assembly of the structure. Binding of CALM N-terminus to KCNQ1 is calcium-dependent and regulates electrophysiological activity of the channel.PTM Ubiquitination results in a strongly decreased activity.PTM Phosphorylation results in a decreased activity.MISCELLANEOUS This protein has four functional calcium-binding sites.SIMILARITY Belongs to the calmodulin family. UniProt P0DP26 2 EQUAL 149 EQUAL Reactome DB_ID: 74016 4 Reactome Database ID Release 78 2025905 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2025905 Reactome R-MMU-2025905 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-MMU-2025905.2 Reactome DB_ID: 9808011 1 Calcineurin (CaN) [cytosol] Calcineurin (CaN) Reactome DB_ID: 9808009 1 PPP3CA,B:Fe3+:Zn2+ [cytosol] PPP3CA,B:Fe3+:Zn2+ Reactome DB_ID: 29426 1 zinc(2+) [ChEBI:29105] zinc(2+) ChEBI 29105 Reactome DB_ID: 111736 1 iron(3+) [ChEBI:29034] iron(3+) Ferric ion ferric iron iron, ion (Fe(3+)) Fe3+ FE (III) ION Fe(III) Fe(3+) ChEBI 29034 Converted from EntitySet in Reactome Reactome DB_ID: 9808007 1 PPP3CA,B [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Ppp3ca [cytosol] Ppp3cb [cytosol] UniProt P63328 UniProt P48453 Reactome Database ID Release 78 9808009 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9808009 Reactome R-MMU-2025949 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-2025949.1 Reactome DB_ID: 2025929 1 UniProt:Q63810 Ppp3r1 Ppp3r1 Ppp3r1 Cnb FUNCTION Regulatory subunit of calcineurin, a calcium-dependent, calmodulin stimulated protein phosphatase. Confers calcium sensitivity.SUBUNIT Forms a complex composed of a calmodulin-dependent catalytic subunit (also known as calcineurin A) and a regulatory Ca(2+)-binding subunit (also known as calcineurin B) (PubMed:26794871). There are three catalytic subunits, each encoded by a separate gene (PPP3CA, PPP3CB, and PPP3CC) and two regulatory subunits which are also encoded by separate genes (PPP3R1 and PPP3R2). The regulatory subunit confers calcium sensitivity. Interacts with catalytic subunit PPP3CA/calcineurin A (PubMed:26794871). Interacts with catalytic subunit PPP3CB/calcineurin A (By similarity). Isoform 1 and isoform 2 interact with CIB1 (via C-terminal region); the interaction increases upon cardiomyocyte hypertrophy (PubMed:20639889).TISSUE SPECIFICITY Brain specific.MISCELLANEOUS This protein has four functional calcium-binding sites.SIMILARITY Belongs to the calcineurin regulatory subunit family. UniProt Q63810 2 EQUAL 170 EQUAL Reactome Database ID Release 78 9808011 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9808011 Reactome R-MMU-2025977 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-2025977.1 Reactome DB_ID: 9808064 1 Calcineurin:Calmodulin (CaN:CaM) [cytosol] Calcineurin:Calmodulin (CaN:CaM) Reactome DB_ID: 2025906 1 Ppp3r1:Calcium [cytosol] Ppp3r1:Calcium Reactome DB_ID: 74016 4 Reactome DB_ID: 2025929 1 2 EQUAL 170 EQUAL Reactome Database ID Release 78 2025906 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2025906 Reactome R-MMU-2025906 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-2025906.1 Reactome DB_ID: 9808062 1 PPP3CA,B:Calmodulin [cytosol] PPP3CA,B:Calmodulin Reactome DB_ID: 2025905 1 Reactome DB_ID: 9808009 1 Reactome Database ID Release 78 9808062 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9808062 Reactome R-MMU-2026003 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-2026003.1 Reactome Database ID Release 78 9808064 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9808064 Reactome R-MMU-2025947 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-2025947.1 Reactome Database ID Release 78 9814092 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9814092 Reactome R-MMU-2730872 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-2730872.1 Calcineurin (CaN), also called protein phosphatase 2B (PP2B), is a calcium/Calmodulin (CaM)-dependent serine/threonine protein phosphatase. It exists as a heterodimer consisting of CaM-binding catalytic subunit CaN A chain and a Ca+2 binding regulatory CaN B chain. At low calcium concentrations, CaN exists in an inactive state, where the autoinhibitory domain (AID) binds to the active-site cleft. Upon an increase in calcium concentration CaM binds to Ca+2 ions and gets activated. Active CaM binds to CaN regulatory domain (RD) and this causes release of the AID and activation of the phosphatase (Rumi-Masante et al. 2012). Binding of calcium to CaN B regulatory chain also causes a conformational change of the RD of CaN A chain (Yang & Klee 2000). 18296442 Pubmed 2008 The secondary structure of calcineurin regulatory region and conformational change induced by calcium/calmodulin binding Shen, Xianrong Li, Huiming Ou, Yan Tao, Wenbing Dong, Aichun Kong, Jilie Ji, C Yu, Shaoning J. Biol. Chem. 283:11407-13 11015619 Pubmed 2000 Calcineurin: form and function Rusnak, F Mertz, P Physiol. Rev. 80:1483-521 22100452 Pubmed 2012 Structural basis for activation of calcineurin by calmodulin Rumi-Masante, Julie Rusinga, Farai I Lester, Terrence E Dunlap, Tori B Williams, Todd D Dunker, A Keith Weis, David D Creamer, Trevor P J. Mol. Biol. 415:307-17 11123943 Pubmed 2000 Low affinity Ca2+-binding sites of calcineurin B mediate conformational changes in calcineurin A Yang, S A Klee, C B Biochemistry 39:16147-54 inferred by electronic annotation IEA GO IEA Calcineurin binds and dephosphorylates NFAT Calcineurin binds and dephosphorylates NFAT This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9808060 1 p-NFATC1,2,3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-Nfatc3 [cytosol] phospho-Nfatc2 [cytosol] phospho-Nfatc1 [cytosol] UniProt P97305 UniProt Q60591 UniProt O88942 Reactome DB_ID: 29356 1 Reactome DB_ID: 9808064 1 Reactome DB_ID: 29372 13 hydrogenphosphate [ChEBI:43474] hydrogenphosphate [PO3(OH)](2-) HYDROGENPHOSPHATE ION hydrogen phosphate [P(OH)O3](2-) HPO4(2-) phosphate INORGANIC PHOSPHATE GROUP ChEBI 43474 Reactome DB_ID: 9813979 1 NFAT:CaN:CaM [cytosol] NFAT:CaN:CaM Converted from EntitySet in Reactome Reactome DB_ID: 9813977 1 Dephosphorylated NFAT [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-Nfatc2 [cytosol] phospho-Nfatc1 [cytosol] phospho-Nfatc3 [cytosol] Reactome DB_ID: 9808064 1 Reactome Database ID Release 78 9813979 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9813979 Reactome R-MMU-2685705 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-2685705.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9808064 GO 0033192 GO molecular function Reactome Database ID Release 78 9813980 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9813980 Reactome Database ID Release 78 9813982 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9813982 Reactome R-MMU-2730849 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-2730849.1 Nuclear factor of activated T-cells (NFAT) is a transcription factor which induces genes responsible for cytokine production, for cell-cell interactions etc. NFAT transcription activity is modulated by calcium and Calcineurin concentration. In resting cells NFAT is phosphorylated and resides in the cytoplasm. Phosphorylation sites are located in NFAT's regulatory domain in three different serine rich motifs, termed SRR1, SP2 and SP. Upon stimulation, these serine residues are dephosphorylated by calcineurin, that thought to cause exposure of nuclear localization signal sequences triggering translocation of the dephosphorylated NFAT-CaN complex to the nucleus. Among all the phosphorylation sites one of the site in SRR-2 motif is not susceptable to dephosphorylation by CaN (Takeuchi et al. 2007, Hogan et al. 2003). 8631904 Pubmed 1996 Calcineurin binds the transcription factor NFAT1 and reversibly regulates its activity Loh, C Shaw, KT Carew, J Viola, JP Luo, C Perrino, BA Rao, A J Biol Chem 271:10884-91 8799126 Pubmed 1996 Interaction of calcineurin with a domain of the transcription factor NFAT1 that controls nuclear import Luo, C Shaw, KT Raghavan, A Aramburu, J Garcia-Cozar, F Perrino, BA Hogan, PG Rao, A Proc Natl Acad Sci U S A 93:8907-12 10860980 Pubmed 2000 A second calcineurin binding site on the NFAT regulatory domain Park, S Uesugi, M Verdine, GL Proc Natl Acad Sci U S A 97:7130-5 11030334 Pubmed 2000 Concerted dephosphorylation of the transcription factor NFAT1 induces a conformational switch that regulates transcriptional activity Okamura, H Aramburu, J García-Rodríguez, C Viola, JP Raghavan, A Tahiliani, M Zhang, X Qin, J Hogan, PG Rao, A Mol Cell 6:539-50 12975316 Pubmed 2003 Transcriptional regulation by calcium, calcineurin, and NFAT Hogan, Patrick G Chen, L Nardone, J Rao, Anjana Genes Dev. 17:2205-32 17502104 Pubmed 2007 Structure of the calcineurin-NFAT complex: defining a T cell activation switch using solution NMR and crystal coordinates Takeuchi, Koh Roehrl, Michael H A Sun, Zhen-Yu J Wagner, Gerhard Structure 15:587-97 inferred by electronic annotation IEA GO IEA Translocation of CaN:CaM:NFAT to nucleus Translocation of CaN:CaM:NFAT to nucleus This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9813979 1 Reactome DB_ID: 9814078 1 nucleoplasm GO 0005654 NFAT:CaN:CaM [nucleoplasm] NFAT:CaN:CaM Reactome DB_ID: 9814068 1 CaN:CaM:Ca2+ [nucleoplasm] CaN:CaM:Ca2+ Reactome DB_ID: 9814066 1 CaN catalytic alpha/beta:Zn++:Fe3+:CaM:Ca2+ [nucleoplasm] CaN catalytic alpha/beta:Zn++:Fe3+:CaM:Ca2+ Reactome DB_ID: 9005860 1 Calmodulin:Calcium [nucleoplasm] Calmodulin:Calcium Reactome DB_ID: 29496 4 Reactome DB_ID: 9016933 1 2 EQUAL 149 EQUAL Reactome Database ID Release 78 9005860 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9005860 Reactome R-MMU-9005860 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9005860.1 Reactome DB_ID: 9814064 1 CaN catalytic alpha/beta:Zn++:Fe3+ [nucleoplasm] CaN catalytic alpha/beta:Zn++:Fe3+ Reactome DB_ID: 2685584 1 Converted from EntitySet in Reactome Reactome DB_ID: 9814062 1 CaN-catalytic alpha/beta chains [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Ppp3ca [nucleoplasm] Ppp3cb [nucleoplasm] Reactome DB_ID: 200493 1 Reactome Database ID Release 78 9814064 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9814064 Reactome R-MMU-2685714 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-2685714.1 Reactome Database ID Release 78 9814066 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9814066 Reactome R-MMU-2685716 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-2685716.1 Reactome DB_ID: 9814056 1 CaN alpha regulatory:Ca2+ [nucleoplasm] CaN alpha regulatory:Ca2+ Reactome DB_ID: 29496 4 Reactome DB_ID: 9814054 1 2 EQUAL 170 EQUAL Reactome Database ID Release 78 9814056 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9814056 Reactome R-MMU-2685704 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-2685704.1 Reactome Database ID Release 78 9814068 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9814068 Reactome R-MMU-2685698 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-2685698.1 Converted from EntitySet in Reactome Reactome DB_ID: 9814076 1 Dephosphorylated NFATC1,2,3 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-Nfatc2 [nucleoplasm] phospho-Nfatc1 [nucleoplasm] phospho-Nfatc3 [nucleoplasm] Reactome Database ID Release 78 9814078 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9814078 Reactome R-MMU-2685690 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-2685690.1 Reactome Database ID Release 78 9814080 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9814080 Reactome R-MMU-2730867 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-2730867.1 Dephosphorylated NFAT-calcineurin (CaN) complex translocates to nucleus, where it activates transcription of several cytokine genes (e.g..IL2). inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 9862440 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9862440 Reactome R-MMU-5607763 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607763.1 CLEC7A (Dectin-1) signals through the classic calcineurin/NFAT pathway through Syk activation phospholipase C-gamma 2 (PLCG2) leading to increased soluble IP3 (inositol trisphosphate). IP3 is able to bind endoplasmic Ca2+ channels, resulting in an influx of Ca2+ into the cytoplasm. This increase in calcium concentration induces calcineurin activation and consequently, dephosphorylation of NFAT and its translocation into the nucleus, triggering gene transcription and extracellular release of Interleukin-2 (Plato et al. 2013, Goodridge et al. 2007, Mourao-Sa et al. 2011). 21728173 Pubmed 2011 CLEC-2 signaling via Syk in myeloid cells can regulate inflammatory responses Mourão-Sá, Diego Robinson, Matthew J Zelenay, Santiago Sancho, David Chakravarty, Probir Larsen, Rasmus Plantinga, Maud Van Rooijen, Nico Soares, Miguel P Lambrecht, Bart Reis e Sousa, C Eur. J. Immunol. 41:3040-53 22611159 Pubmed 2012 NFAT control of innate immunity Fric, Jan Zelante, Teresa Wong, Alicia Y W Mertes, Alexandra Yu, Hong-Bing Ricciardi-Castagnoli, Paola Blood 120:1380-9 17312158 Pubmed 2007 Dectin-1 stimulation by Candida albicans yeast or zymosan triggers NFAT activation in macrophages and dendritic cells Goodridge, Helen S Simmons, Randi M Underhill, David M J. Immunol. 178:3107-15 23570314 Pubmed 2013 C-type lectin-like receptors of the dectin-1 cluster: ligands and signaling pathways Plato, Anthony Willment, Janet A Brown, Gordon D Int. Rev. Immunol. 32:134-56 inferred by electronic annotation IEA GO IEA PKC-delta translocates to plasma membrane PKC-delta translocates to plasma membrane This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 112275 1 Reactome DB_ID: 9821206 1 UniProt:P28867 Prkcd UniProt P28867 O-phospho-L-threonine at 507 (in Homo sapiens) 507 EQUAL O-phospho-L-threonine [MOD:00047] O-phospho-L-serine at 645 (in Homo sapiens) 645 EQUAL O-phospho-L-serine [MOD:00046] O-phospho-L-serine at 664 (in Homo sapiens) 664 EQUAL 1 EQUAL 676 EQUAL Reactome DB_ID: 9824003 1 DAGs:p-T507,S645,S664-PRKCD [plasma membrane] DAGs:p-T507,S645,S664-PRKCD Reactome DB_ID: 112275 1 Reactome DB_ID: 9821206 1 O-phospho-L-threonine at 507 (in Homo sapiens) 507 EQUAL O-phospho-L-serine at 645 (in Homo sapiens) 645 EQUAL O-phospho-L-serine at 664 (in Homo sapiens) 664 EQUAL 1 EQUAL 676 EQUAL Reactome Database ID Release 78 9824003 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824003 Reactome R-MMU-5607700 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607700.1 Reactome Database ID Release 78 9824005 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824005 Reactome R-MMU-5607734 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607734.1 Protein kinase C-delta (PRKCD), activated upon CLEC7A (Dectin-1)-SYK signaling, phosphorylates CARD9 leading to NF-kB activation (Strasser et al. 2012) and complex formation between CARD9 and BCL10. CLEC6A (Dectin-2) and CLEC4E (Mincle) also induces intracellular signaling through PRKCD and CARD9-BCL10-MALT1 pathway. Similar to the CLEC7A responses, both CLEC6A and CLEC4E-induced interleukin 10 (IL10) and tumour necrotic factor (TNF) production were severely impaired in the absence of PRKCD (Strasser et al. 2012). PRKCD is a member of the Ca2+ independent and diacylglycerol (DAG) dependent novel PKC subfamily. PKC family members exist in an immature inactive conformation that requires post-translational modifications to achieve catalytic maturity. The catalytic maturation of PRKCD involves the auto-phosphorylation of Ser645 and the phosphorylation of Thr507 and Ser664 (Li et al. 1997, Keranen et al. 1995). These phosphorylations of activation loop residues act as a priming step that allows the catalytic maturation of PRKCD (Dutil et al. 1998). Fully phosphorylated and primed PRKCD localises to the cytosol with its pseudosubstrate occupying the substrate-binding cavity. Signals that cause the lipid hydrolysis recruit PKC to membranes. The C1 domain in PRKCD is a cysteine-rich compact structure, identified as the interaction site for DAG and phorbol ester. PRKCD preferentially translocates to the plasma membrane (Stahelin et al. 2004, Newton 2010). 15105418 Pubmed 2004 Mechanism of diacylglycerol-induced membrane targeting and activation of protein kinase Cdelta Stahelin, Robert V Digman, Michelle A Medkova, Martina Ananthanarayanan, Bharath Rafter, John D Melowic, Heather R Cho, Wonhwa J. Biol. Chem. 279:29501-12 8749392 Pubmed 1995 Protein kinase C is regulated in vivo by three functionally distinct phosphorylations Keranen, Lisa M Dutil, Erica M Newton, Alexandra C Curr. Biol. 5:1394-1403 22265677 Pubmed 2012 Syk kinase-coupled C-type lectin receptors engage protein kinase C-? to elicit Card9 adaptor-mediated innate immunity Strasser, Dominikus Neumann, Konstantin Bergmann, Hanna Marakalala, Mohlopheni J Guler, Reto Rojowska, Anna Hopfner, KP Brombacher, Frank Urlaub, Henning Baier, Gottfried Brown, Gordon D Leitges, Michael Ruland, Jürgen Immunity 36:32-42 9305920 Pubmed 1997 Identification of serine 643 of protein kinase C-delta as an important autophosphorylation site for its enzymatic activity Li, W Zhang, J Bottaro, D P Pierce, J H J. Biol. Chem. 272:24550-5 7499357 Pubmed 1995 Protein kinase C: structure, function, and regulation Newton, A C J. Biol. Chem. 270:28495-8 9889098 Pubmed 1998 Regulation of conventional protein kinase C isozymes by phosphoinositide-dependent kinase 1 (PDK-1) Dutil, Erica M Toker, Alex Newton, Alexandra C Curr. Biol. 8:1366-75 12473183 Pubmed 2002 Protein kinase C delta (PKC delta): activation mechanisms and functions Kikkawa, Ushio Matsuzaki, Hidenori Yamamoto, Toshiyoshi J. Biochem. 132:831-9 19934406 Pubmed 2010 Protein kinase C: poised to signal Newton, Alexandra C Am. J. Physiol. Endocrinol. Metab. 298:E395-402 inferred by electronic annotation IEA GO IEA PKC-delta is activated PKC-delta is activated This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9824003 1 Reactome DB_ID: 9824020 1 DAGs:active p-T507,S645,S664-PRKCD [plasma membrane] DAGs:active p-T507,S645,S664-PRKCD Reactome DB_ID: 112275 1 Reactome DB_ID: 9768941 1 O-phospho-L-threonine at 507 (in Homo sapiens) 507 EQUAL O-phospho-L-serine at 645 (in Homo sapiens) 645 EQUAL O-phospho-L-serine at 664 (in Homo sapiens) 664 EQUAL 1 EQUAL 676 EQUAL Reactome Database ID Release 78 9824020 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824020 Reactome R-MMU-5607689 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607689.1 Reactome Database ID Release 78 9824036 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824036 Reactome R-MMU-5607746 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607746.1 Membrane-bound PKC adopts an open conformation, in which the pseudosubstrate is released from the kinase domain, allowing downstream signaling (Newton 2010). inferred by electronic annotation IEA GO IEA PKC-delta phosphorylates CARD9 PKC-delta phosphorylates CARD9 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9824018 1 UniProt:A2AIV8 Card9 Card9 Card9 FUNCTION Adapter protein that plays a key role in innate immune response against fungi by forming signaling complexes downstream of C-type lectin receptors (PubMed:16862125, PubMed:20538615, PubMed:26679537, PubMed:29080677). CARD9-mediated signals are essential for antifungal immunity against a subset of fungi from the phylum Ascomycota (PubMed:16862125, PubMed:20538615, PubMed:24470469, PubMed:25621893, PubMed:26679537, PubMed:29080677, PubMed:32548948). Transduces signals in myeloid cells downstream of C-type lectin receptors CLEC7A (dectin-1), CLEC6A (dectin-2) and CLEC4E (Mincle), which detect pathogen-associated molecular pattern metabolites (PAMPs), such as fungal carbohydrates, and trigger CARD9 activation (PubMed:16862125, PubMed:20538615). Upon activation, CARD9 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 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:16862125, PubMed:20538615, PubMed:22265677, PubMed:29080677). CARD9 signaling in antigen-presenting cells links innate sensing of fungi to the activation of adaptive immunity and provides a cytokine milieu that induces the development and subsequent of interleukin 17-producing T helper (Th17) cells (PubMed:17450144, PubMed:24470469, PubMed:32358020). Also involved in activation of myeloid cells via classical ITAM-associated receptors and TLR: required for TLR-mediated activation of MAPK, while it is not required for TLR-induced activation of NF-kappa-B (PubMed:17486093). CARD9 can also be engaged independently of BCL10: forms a complex with RASGRF1 downstream of C-type lectin receptors, which recruits and activates HRAS, leading to ERK activation and the production of cytokines (PubMed:25267792). Acts as an important regulator of the intestinal commensal fungi (mycobiota) component of the gut microbiota (PubMed:27158904, PubMed:33548172). Plays an essential role in antifungal immunity against dissemination of gut fungi: acts by promoting induction of antifungal IgG antibodies response in CX3CR1(+) macrophages to confer protection against disseminated C.albicans or C.auris infection (PubMed:33548172). Also mediates immunity against other pathogens, such as certain bacteria, viruses and parasites; CARD9 signaling is however redundant with other innate immune responses (PubMed:17187069, PubMed:26679537, PubMed:29080677). In response to L.monocytogenes infection, required for the production of inflammatory cytokines activated by intracellular peptidoglycan: acts by connecting NOD2 recognition of peptidoglycan to downstream activation of MAP kinases (MAPK) without activating NF-kappa-B (PubMed:17187069).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 (By similarity). Activation downstream of C-type lectin receptors, by phosphorylation by PRKCD and/or ubiquitination by TRIM62, triggers disruption of the CARD domain-coiled coil interface, CARD9 homooligomerization and BCL10 recruitment, followed by activation of NF-kappa-B and MAP kinase p38 pathways (PubMed:22265677). Zinc-binding inhibits activation by stabilizing the CARD ground-state conformation and restricting its capacity to form BCL10-nucleating filaments (By similarity).SUBUNIT Monomer (By similarity). Homodimer; homodimerization is mediated by the CARD domain which forms an extensive interaction with the adjacent linker and coiled-coil regions; leads to an autoinhibited state (By similarity). Homomultimer; polymerizes following activation, forming a nucleating helical template that seeds BCL10-filament formation via a CARD-CARD interaction (By similarity). Interacts (via CARD domain) with BCL10 (via CARD domain); interaction takes place following CARD9 activation and polymerization, leading to the formation of a filamentous CBM complex assembly (PubMed:22265677). Component of a CBM complex (CARD9-BCL10, MALT1), composed of CARD9, BCL10 and MALT1 (PubMed:22265677). Interacts with RASGRF1 (By similarity). Interacts with NOD2 (via NACHT domain); interaction is direct (PubMed:17187069, PubMed:24960071). Interacts with RIPK2 (PubMed:17187069). Interacts with VHL; without leading to protein degradation (By similarity).TISSUE SPECIFICITY Specifically expressed in myeloid cells (PubMed:16862125, PubMed:17187069). Not expressed in non-lymphoid organs (PubMed:16862125, PubMed:17187069).DOMAIN The linker region, also named autoinhibitory interface, is required to prevent constitutive activation and maintain CARD9 in an autoinhibitory state. Disruption of this region triggers polymerization and activation, leading to formation of BCL10-nucleating filaments.PTM Phosphorylated at Thr-231 by PRKCD downstream of C-type lectin receptors activation: phosphorylation promotes interaction with BCL10, followed by activation of NF-kappa-B and MAP kinase p38 pathways (PubMed:22265677). Phosphorylated at Thr-531 and Thr-531 by CK2 following interaction with VHL, leading to inhibit the ability to activate NF-kappa-B (By similarity).PTM Ubiquitinated at Lys-125 via 'Lys-27'-linked ubiquitin by TRIM62 downstream of C-type lectin receptors activation; leading to CARD9 activation, followed by activation of NF-kappa-B and MAP kinase p38 pathways (By similarity). Deubiquitinated at Lys-125 by USP15, inhibiting CARD9 (By similarity).DISRUPTION PHENOTYPE Mice were born at the normal Mendelian ratio without obvious anatomical defects but display impaired innate immunity (PubMed:16862125, PubMed:17187069). In response to C.albicans infection, mice develop fungal infections, many of which target the central nervous system (CNS) (PubMed:26679537). All mice die within 5 days after infection by C.albicans whereas more than half of the control mice survive for more than 12 days (PubMed:16862125). Impaired zymosan-induced cytokine production (PubMed:16862125). No defects in adaptive immunity (PubMed:16862125). Mice show impaired recruitment of neutrophils in CNS after infection by C.albicans, an immune cell critical for antifungal host defense (PubMed:26679537). Mice are susceptible to pulmonary infection with C.neoformans and show decreased Th17-related immune response (PubMed:24470469). Mice are highly susceptible to phaeohyphomycosis following E.spinifera infection and show impaired antifungal immunity, characterized by reduced cytokine production and neutrophil recruitment (PubMed:29080677). Mice are susceptible to A.fumigatus and P.pneumonia infection (PubMed:25621893, PubMed:32548948). Mice are more susceptible to colitis and have an increased load of gut-resident fungi (mycobiota), causing gut fungal dysbiosis (PubMed:23732773, PubMed:27158904). Mice are unable to induce an efficient IgG antibody response against disseminated C.albicans infection (PubMed:33548172). Following infection by L.monocytogenes, mice fail to clear infection and show altered cytokine production (PubMed:17187069). UniProt A2AIV8 1 EQUAL 536 EQUAL Reactome DB_ID: 113592 1 Reactome DB_ID: 29370 1 Reactome DB_ID: 9823974 1 O-phospho-L-threonine at 231 (in Homo sapiens) 231 EQUAL 1 EQUAL 536 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9824020 GO 0004699 GO molecular function Reactome Database ID Release 78 9824021 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824021 Reactome Database ID Release 78 9824023 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824023 Reactome R-MMU-5607740 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607740.1 Activation of NF-kB signaling is a critical event downstream of CLEC7A (Dectin-1), CLEC6A (Dectin-2) (Bi et al. 2010) and CLEC4E (Mincle) (Yamasaki et al. 2008), requiring the adapter protein Caspase recruitment domain (CARD)-containing protein 9 (CARD9) in dendritic cells and in macrophages (Gross et al. 2006, Hara et al. 2007). CARD9 is analogous to CARD-containing MAGUK protein 1 (CARMA1), which mediates T-cell receptor (TCR) activation of NF-kB in lymphocytes. CARD9 is downstream of SYK and becomes phosphorylated by PRKCD (Protein kinase C-delta) phosphorylates CARD9 on Thr-231 (T231), which is required for the signal-induced association of CARD9 with B-cell lymphoma 10 (BCL10) and Mucosa-associated lymphoid tissue 1 (MALT1) and the subsequent recruitment of MAP3K transforming growth factor beta activated kinase 1 (TAK1), leading to activation of the NF-kB pathway (Strasser et al. 2012). A homozygous loss-of-function mutation in human CARD9 results in a premature termination codon (Gln295*). Patients with this mutation are highly susceptible to fungal infections (Glocker et al. 2009). 19359218 Pubmed 2009 CARD9 versus CARMA1 in innate and adaptive immunity Hara, Hiromitsu Saito, Takashi Trends Immunol. 30:234-42 19864672 Pubmed 2009 A homozygous CARD9 mutation in a family with susceptibility to fungal infections Glocker, Erik-Oliver Hennigs, Andre Nabavi, Mohammad Schäffer, Alejandro A Woellner, Cristina Salzer, Ulrich Pfeifer, Dietmar Veelken, Hendrik Warnatz, Klaus Tahami, Fariba Jamal, Sarah Manguiat, Annabelle Rezaei, Nima Amirzargar, Ali Akbar Plebani, Alessandro Hannesschläger, Nicole Gross, Olaf Ruland, Jürgen Grimbacher, Bodo N. Engl. J. Med. 361:1727-35 20538615 Pubmed 2010 CARD9 mediates dectin-2-induced IkappaBalpha kinase ubiquitination leading to activation of NF-kappaB in response to stimulation by the hyphal form of Candida albicans Bi, Liangkuan Gojestani, Sara Wu, Weihui Hsu, Yen-Michael S Zhu, Jiayuan Ariizumi, Kiyoshi Lin, Xin J. Biol. Chem. 285:25969-77 16862125 Pubmed 2006 Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity Gross, O Gewies, A Finger, K Schäfer, M Sparwasser, T Peschel, C Förster, I Ruland, J Nature 442:651-6 inferred by electronic annotation IEA GO IEA CARD9 oligomerizes CARD9 oligomerizes This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9823974 1 O-phospho-L-threonine at 231 (in Homo sapiens) 231 EQUAL 1 EQUAL 536 EQUAL Reactome DB_ID: 9824057 2 1 EQUAL 536 EQUAL Reactome DB_ID: 9823976 1 p-T231-CARD9 oligomer [plasma membrane] p-T231-CARD9 oligomer Reactome Database ID Release 78 9824059 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824059 Reactome R-MMU-5607753 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607753.1 Activated CARD9 localised in lipid rafts may self-associate with other CARD9 molecules (oligomerization). Residues 140-420 of CARD9 contain heptad repeats characteristic of coiled-coil structures that function in protein oligomerization (Bertin et al. 2000). 11053425 Pubmed 2000 CARD9 is a novel caspase recruitment domain-containing protein that interacts with BCL10/CLAP and activates NF-kappa B Bertin, J Guo, Y Wang, L Srinivasula, S M Jacobson, M D Poyet, J L Merriam, S Du, M Q Dyer, M J Robison, K E DiStefano, P S Alnemri, E S J. Biol. Chem. 275:41082-6 inferred by electronic annotation IEA GO IEA BCL10 binds CARD9 BCL10 binds CARD9 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 2685587 1 UniProt:Q9Z0H7 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:22265677). 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:22265677). 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 (By similarity). 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 (By similarity). Activated by CARD9 downstream of C-type lectin receptors; CARD9-mediated signals are essential for antifungal immunity (PubMed:22265677). Activated by CARD11 downstream of T-cell receptor (TCR) and B-cell receptor (BCR) (By similarity). Promotes apoptosis, pro-caspase-9 maturation and activation of NF-kappa-B via NIK and IKK (By similarity).SUBUNIT Homomultimer; homooligomerized following recruitment by CARD domain-containing proteins that form a nucleating helical template that recruits BCL10 via CARD-CARD interaction (By similarity). Self-associates by CARD-CARD interaction and interacts with other CARD-proteins such as CARD9, CARD10, CARD11 and CARD14 (PubMed:22265677, PubMed:22880103). Forms a complex with CARD14 and MALT1; resulting in the formation of a CBM (CARD14-BCL10-MALT1) complex (By similarity). Forms a complex with CARD11 and MALT1; resulting in the formation of a CBM (CARD11-BCL10-MALT1) complex (By similarity). Forms a complex with CARD9 and MALT1; resulting in the formation of a CBM (CARD9-BCL10-MALT1) complex (PubMed:22265677). Found in a membrane raft complex, at least composed of BCL10, CARD11, DPP4 and IKBKB (By similarity). Binds caspase-9 with its C-terminal domain (By similarity). Interacts with TRAF2 and BIRC2/c-IAP2 (By similarity). Interacts with PELI2 and SOCS3; these interactions may be mutually exclusive (PubMed:15213237).TISSUE SPECIFICITY Highly expressed in heart, brain, spleen, lung, liver, skeletal muscle, kidney and testis. Detected in developing brain, olfactory epithelium, tongue, whisker follicles, salivary gland, heart, lung, liver and intestinal epithelia of stage 15 embryos.PTM Phosphorylated by IKBKB/IKKB.PTM Ubiquitinated via both 'Lys-63'-linked and linear ('Met-1'-linked) polyubiquitin chains in response to T-cell receptor (TCR) activation. 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. 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. CARD11 is required for linear ubiquitination by HOIP by promoting the targeting of BCL10 to RNF31/HOIP.PTM Proteolytically cleaved by MALT1; required for T-cell activation. UniProt Q9Z0H7 1 EQUAL 233 EQUAL Reactome DB_ID: 9823976 1 Reactome DB_ID: 9823999 1 p-T231-CARD9 oligomer:BCL10 [plasma membrane] p-T231-CARD9 oligomer:BCL10 Reactome DB_ID: 2685587 1 1 EQUAL 233 EQUAL Reactome DB_ID: 9823976 1 Reactome Database ID Release 78 9823999 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823999 Reactome R-MMU-5607678 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607678.1 Reactome Database ID Release 78 9824001 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824001 Reactome R-MMU-5607733 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607733.1 B-cell lymphoma/leukemia 10 (BCL10) is the downstream signaling partner of CARD9 and it interacts selectively with the CARD activation domain of CARD9. BCL10 functions as an adaptor between the effector IKK complex and the proximal signaling complexes that interact with CARD9 (Bertin et al. 2000). inferred by electronic annotation IEA GO IEA BCL10 oligomerizes BCL10 oligomerizes This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9823999 1 Reactome DB_ID: 2685587 2 1 EQUAL 233 EQUAL Reactome DB_ID: 9823978 1 p-T231-CARD9:BCL10 oligomers [plasma membrane] p-T231-CARD9:BCL10 oligomers Reactome DB_ID: 9814011 1 BCL10 oligomer [cytosol] BCL10 oligomer Reactome DB_ID: 9823976 1 Reactome Database ID Release 78 9823978 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823978 Reactome R-MMU-5607676 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607676.1 Reactome Database ID Release 78 9824016 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824016 Reactome R-MMU-5607737 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607737.1 CARD interactions between CARD9 and BCL10 induce BCL10 oligomerization (through its CARD domain), required for oligomerization and activation of MALT1. 10187770 Pubmed 1999 CIPER, a novel NF kappaB-activating protein containing a caspase recruitment domain with homology to Herpesvirus-2 protein E10 Koseki, T Inohara, N Chen, S Carrio, R Merino, J Hottiger, M O Nabel, G J Nunez, G J. Biol. Chem. 274:9955-61 inferred by electronic annotation IEA GO IEA MALT1 binds BCL10 MALT1 binds BCL10 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9823978 1 Reactome DB_ID: 9771352 1 UniProt:Q2TBA3 Malt1 Malt1 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 (By similarity). Mediates BCL10 cleavage: MALT1-dependent BCL10 cleavage plays an important role in T-cell antigen receptor-induced integrin adhesion (By similarity). Involved in the induction of T helper 17 cells (Th17) differentiation (By similarity). Cleaves RC3H1 and ZC3H12A in response to T-cell receptor (TCR) stimulation which releases their cooperatively repressed targets to promote Th17 cell differentiation (PubMed:25282160). Also mediates cleavage of N4BP1 in T-cells following TCR-mediated activation, leading to N4BP1 inactivation. May also have ubiquitin ligase activity: binds to TRAF6, inducing TRAF6 oligomerization and activation of its ligase activity (By similarity).SUBUNIT Homooligomer; forms oligomers which bind to TRAF6. Forms a complex with CARD14 and MALT1; resulting in the formation of a CBM (CARD14-BCL10-MALT1) complex. Forms a complex with CARD11 and MALT1; resulting in the formation of a CBM (CARD11-BCL10-MALT1) complex (By similarity). Forms a complex with CARD9 and MALT1; resulting in the formation of a CBM (CARD9-BCL10-MALT1) complex (PubMed:22265677).SIMILARITY Belongs to the peptidase C14B family. UniProt Q2TBA3 1 EQUAL 824 EQUAL Reactome DB_ID: 9824012 1 p-T231-CARD9:BCL10 oligomers:MALT1 [plasma membrane] p-T231-CARD9:BCL10 oligomers:MALT1 Reactome DB_ID: 9823978 1 Reactome DB_ID: 9771352 1 1 EQUAL 824 EQUAL Reactome Database ID Release 78 9824012 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824012 Reactome R-MMU-5607682 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607682.1 Reactome Database ID Release 78 9824034 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824034 Reactome R-MMU-5607744 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607744.1 Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is the main downstream target of BCL10. MALT1 interacts directly with BCL10 and this interaction involves a short stretch of amino acids that follow the BCL10 CARD motif (amino acids 107–119 of human BCL10) and the two immunoglobulin-like domains of MALT1 (Uren et al. 2000, Lucas et al. 2001). 11262391 Pubmed 2001 Bcl10 and MALT1, independent targets of chromosomal translocation in malt lymphoma, cooperate in a novel NF-kappa B signaling pathway Lucas, P C Yonezumi, M Inohara, N McAllister-Lucas, L M Abazeed, M E Chen, F F Yamaoka, S Seto, M Nunez, G J. Biol. Chem. 276:19012-9 11090634 Pubmed 2000 Identification of paracaspases and metacaspases: two ancient families of caspase-like proteins, one of which plays a key role in MALT lymphoma Uren, A G O'Rourke, K Aravind, L A Pisabarro, MT Seshagiri, S Koonin, EV Dixit, V M Mol. Cell 6:961-7 inferred by electronic annotation IEA GO IEA MALT1 oligomerizes MALT1 oligomerizes This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9771352 2 1 EQUAL 824 EQUAL Reactome DB_ID: 9824012 1 Reactome DB_ID: 9823980 1 p-T231-CARD9:BCL10:MALT1 oligomers [plasma membrane] p-T231-CARD9:BCL10:MALT1 oligomers Reactome DB_ID: 9823978 1 Reactome DB_ID: 9814013 1 MALT1 oligomer [cytosol] MALT1 oligomer Reactome Database ID Release 78 9823980 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823980 Reactome R-MMU-5607696 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607696.1 Reactome Database ID Release 78 9824014 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824014 Reactome R-MMU-5607736 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607736.1 After binding BCL10, MALT1 also undergoes oligomerization. Like traditional caspases, MALT1 also becomes activated through the formation of oligomers. Once the CARD9-BCL10-MALT1 (CBM) signalosome is assembled, MALT1 functions as the effector protein and mediates activation of the IKK complex (McAllister-Lucas & Lucas 2008). 18285772 Pubmed 2008 Finally, MALT1 is a protease! McAllister-Lucas, Linda M Lucas, Peter C Nat. Immunol. 9:231-3 24074955 Pubmed 2013 Structural architecture of the CARMA1/Bcl10/MALT1 signalosome: nucleation-induced filamentous assembly Qiao, Qi Yang, Chenghua Zheng, Chao Fontán, Lorena David, Liron Yu, Xiong Bracken, Clay Rosen, Monica Melnick, Ari Egelman, Edward H Wu, H Mol. Cell 51:766-79 21966355 Pubmed 2011 Oligomeric structure of the MALT1 tandem Ig-like domains Qiu, Liyan Dhe-Paganon, Sirano PLoS ONE 6:e23220 inferred by electronic annotation IEA GO IEA TRAF6 binds MALT1 oligomers TRAF6 binds MALT1 oligomers This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9823980 1 Reactome DB_ID: 9763826 1 UniProt:P70196-1 Traf6 Traf6 Traf6 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 (By similarity). 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 (By similarity). Homooligomer (By similarity). 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 (By similarity). Associates with NGFR, TNFRSF17, IRAK2, IRAK3, PELI2, PELI3, RIPK2, MAP3K1, MAP3K5, MAP3K14, CSK, TRAF, TRAF-interacting protein TRIP and TNF receptor associated protein TDP2. Binds UBE2V1. Interacts with MAVS/IPS1. Interacts with TAX1BP1 (By similarity). Interacts with IL17R. Interacts with SQSTM1 bridging NTRK1 and NGFR. Forms a ternary complex with SQSTM1 and PRKCZ. Interacts with IL1RL1. Interacts with AJUBA (By similarity). Interacts with TRAFD1. Interacts with TICAM2. Interacts with ZFAND5. Interacts with ARRB1 and ARRB2 (By similarity). 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) (By similarity). Interacts (via TRAF domains) with DYNC2I2 (via WD domains). Interacts with RBCK1 (By similarity). Interacts with LIMD1 (via LIM domains). Interacts with RSAD2/viperin. Interacts with IFIT3 (via N-terminus) (By similarity). Interacts (via C-terminus) with EIF2AK2/PKR (via the kinase catalytic domain). Interacts with CARD14 (By similarity). Interacts with CD40 and MAP3K8; the interaction is required for ERK activation. Interacts with TICAM1 and this interaction is enhanced in the presence of WDFY1 (By similarity). Interacts with TANK; this interaction increases in response to DNA damage (By similarity). Interacts with USP10; this interaction increases in response to DNA damage (By similarity). Interacts with ZC3H12A; this interaction increases in response to DNA damage and is stimulated by TANK (By similarity). Interacts with WDFY3 (PubMed:27330028). Interacts with TRIM13 (By similarity). Interacts with GPS2 (PubMed:22424771). Interacts (via C-terminus) with SASH1 (By similarity). Interacts with LRRC19 (By similarity). Interacts with IL17RA AND TRAF3IP2. Interacts with TOMM70 (By similarity).TISSUE SPECIFICITY Highly expressed in brain, lung, liver, skeletal muscle, and kidney; lower expression in heart, spleen, and testis.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-461 with SUMO1.PTM Polyubiquitinated on Lys-124 by TRAF3IP2; after cell stimulation with IL17A (By similarity). Polyubiquitinated; 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-kappa-B signaling upon DNA damage. LRRC19 induces 'Lys-63' ubiquitination (PubMed:25026888).DISRUPTION PHENOTYPE Abrogation of IL-1-induced activation of NF-kappa-B, MAPK8/JNK and MAPK14/p38. Animals appear normal at birth but become smaller after one week. Show runting, failure of tooth eruption and die after three weeks. Exhibit severe osteopetrosis, thymic atrophy, lymph node deficiency, splenomegaly, and have alopecia and lack sweat glands.SIMILARITY Belongs to the TNF receptor-associated factor family. A subfamily. UniProt P70196-1 1 EQUAL 522 EQUAL Reactome DB_ID: 9824038 1 p-T231-CARD9:BCL10:MALT1 oligomers:TRAF6 [plasma membrane] p-T231-CARD9:BCL10:MALT1 oligomers:TRAF6 Reactome DB_ID: 9823980 1 Reactome DB_ID: 9763826 1 1 EQUAL 522 EQUAL Reactome Database ID Release 78 9824038 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824038 Reactome R-MMU-5607701 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607701.1 Reactome Database ID Release 78 9824040 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824040 Reactome R-MMU-5607747 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607747.1 TRAF6 (tumor necrosis factor receptor-associated factor 6) is a RING (really interesting new gene) domain ubiquitin (Ub) ligase that mediates NF-kB activation by regulating the ubiquitination of transforming growth factor beta-activated kinase (TAK1) and IkB kinase (IKK). TRAF6 has been implicated as downstream effector of MALT1. MALT1 binds to TRAF6 through two putative C-terminal TRAF6-binding motifs (Sun et al. 2004). Gorjestani et al. demonstrate that TRAF6 and TAK1 are required for C-type lectin receptor-induced NF-kB activation and play critical roles in anti-fungal innate immune responses (Gorjestani et al. 2012). 23148225 Pubmed 2012 Tumor necrosis factor receptor-associated factor 6 (TRAF6) and TGF?-activated kinase 1 (TAK1) play essential roles in the C-type lectin receptor signaling in response to Candida albicans infection Gorjestani, Sara Darnay, BG Lin, Xin J. Biol. Chem. 287:44143-50 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 inferred by electronic annotation IEA GO IEA TRAF6 oligomerizes TRAF6 oligomerizes This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9824038 1 Reactome DB_ID: 9763826 2 1 EQUAL 522 EQUAL Reactome DB_ID: 9824053 1 p-T231-CARD9:BCL10:MALT1:TRAF6 oligomers [plasma membrane] p-T231-CARD9:BCL10:MALT1:TRAF6 oligomers Reactome DB_ID: 9814131 1 TRAF6 oligomer [cytosol] TRAF6 oligomer Reactome DB_ID: 9823980 1 Reactome Database ID Release 78 9824053 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824053 Reactome R-MMU-5607674 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607674.1 Reactome Database ID Release 78 9824055 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824055 Reactome R-MMU-5607751 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607751.1 The MALT1 oligomers bound to TRAF6 induce TRAF6 oligomerization and activate TRAF6 E3 ubiquitin ligase activity (Sun et al. 2004). inferred by electronic annotation IEA GO IEA 6.3.2.19 TRAF6 oligomer autoubiquitinates TRAF6 oligomer autoubiquitinates This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9764075 1 UBE2N:UBE2V1 [cytosol] UBE2N:UBE2V1 Reactome DB_ID: 9764069 1 UniProt:P61089 Ube2n UniProt P61089 1 EQUAL 152 EQUAL Reactome DB_ID: 9764073 1 UniProt:Q9CZY3 Ube2v1 UniProt Q9CZY3 2 EQUAL 147 EQUAL Reactome Database ID Release 78 9764075 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764075 Reactome R-MMU-202463 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-202463.1 Reactome DB_ID: 113592 1 Reactome DB_ID: 9824053 1 Reactome DB_ID: 9764139 1 K63polyUb [cytosol] K63polyUb Reactome DB_ID: 9764075 1 Reactome DB_ID: 111294 1 diphosphate(3-) [ChEBI:33019] diphosphate(3-) ChEBI 33019 Reactome DB_ID: 76577 1 adenosine 5'-monophosphate(2-) [ChEBI:456215] adenosine 5'-monophosphate(2-) Adenosine-5-monophosphate(2-) AMP 5'-O-phosphonatoadenosine AMP dianion AMP(2-) Adenosine-5-monophosphate dianion ChEBI 456215 Reactome DB_ID: 9823984 1 p-T231-CARD9:BCL10:MALT1:K63polyUb-TRAF6 oligomers [plasma membrane] p-T231-CARD9:BCL10:MALT1:K63polyUb-TRAF6 oligomers Reactome DB_ID: 9823982 1 K63polyUb-TRAF6 oligomer [cytosol] K63polyUb-TRAF6 oligomer Reactome DB_ID: 9823980 1 Reactome Database ID Release 78 9823984 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823984 Reactome R-MMU-5607675 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607675.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9824053 GO 0004842 GO molecular function Reactome Database ID Release 78 9824064 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824064 Reactome Database ID Release 78 9824066 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824066 Reactome R-MMU-5607756 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607756.1 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 also known as TRIKA1 (TRAF6-regulated IKK activator 1)) 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 (Deng et al. 2000, Lamothe et al. 2007). 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. 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 11057907 Pubmed 2000 Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain Deng, L Wang, C Spencer, E Yang, L Braun, A You, J Slaughter, C Pickart, C Chen, ZJ Cell 103:351-61 inferred by electronic annotation IEA GO IEA TRIKA2 binds K63polyUb-TRAF6 oligomer TRIKA2 binds K63polyUb-TRAF6 oligomer This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9764094 1 TAK1 complex [cytosol] TAK1 complex Converted from EntitySet in Reactome Reactome DB_ID: 9764092 1 TAB2,TAB3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Tab2 [cytosol] Tab3 [cytosol] UniProt Q99K90 UniProt Q571K4 Reactome DB_ID: 9764080 1 UniProt:Q62073 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) (PubMed:10748100, PubMed:16157589, PubMed:21183079, PubMed:29291351). 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 (PubMed:16157589, PubMed:8533096, PubMed:29291351). MAP3K7 activates also IKBKB and MAPK8/JNK1 in response to TRAF6 signaling and mediates BMP2-induced apoptosis (PubMed:10748100). 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 (By similarity). 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 (PubMed:28842570).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 (By similarity). Binds both upstream activators and downstream substrates in multimolecular complexes (By similarity). Interacts with TAB1/MAP3K7IP1, TAB2/MAP3K7IP2 and TAB3/MAP3K7IP3 (By similarity). Identified in the TRIKA2 complex composed of MAP3K7/TAK1, TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2 (By similarity). Interacts with PPM1L and PPM1B/PP2CB (PubMed:12556533). Interaction with PP2A and PPP6C leads to its repressed activity (By similarity). Interacts with TRAF6 and TAB1/MAP3K7IP1; during IL-1 signaling (By similarity). Interacts with TAOK1 and TAOK2; interaction with TAOK2 interferes with MAP3K7 interaction with IKKA, thus preventing NF-kappa-B activation (By similarity). Interacts with DYNC2I2 (via WD domains) (By similarity). Interacts with CYLD and RBCK1 (PubMed:17548520). Interacts with TGFBR1; induces MAP3K7/TAK1 activation by TRAF6 (By similarity). Interacts with MAPK8IP1 and SMAD6 (PubMed:10748100, PubMed:17709393). Interacts with isoform 1 of VRK2 (PubMed:17709393). Interacts with DAB2; the interaction is induced by TGF-beta stimulation and may mediate TGF-beta stimulated JNK activation (By similarity). Interacts with TRIM5 (By similarity). Part of a complex containing ITCH, NDFIP1 and MAP3K7 (PubMed:25632008). Interacts with PLEKHM1 (via N- and C-terminus) (PubMed:27777970). Interacts with TRIM8 (By similarity). Found in a complex with SH3RF1, RAC2, MAP2K7/MKK7, MAPK8IP1/JIP1, MAPK8/JNK1 and MAPK9/JNK2 (PubMed:27084103). Interacts with SASH1 (By similarity). Interacts with RIPK1 (PubMed:31519887).PTM Association with TAB1/MAP3K7IP1 promotes autophosphorylation 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 Thr-187 by PP2A and PPP6C leads to inactivation (By similarity).PTM 'Lys-48'-linked polyubiquitination at Lys-72 is induced by TNFalpha, and leads to proteasomal degradation (PubMed:16157589). Undergoes 'Lys-48'-linked polyubiquitination catalyzed by ITCH (PubMed:25632008). 'Lys-63'-linked polyubiquitination at Lys-158 by TRIM8 does not lead to proteasomal degradation but contributes to autophosphorylation and activation. Deubiquitinated by CYLD, a protease that selectively cleaves 'Lys-63'-linked ubiquitin chains (PubMed:17548520, PubMed:29291351).SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily. UniProt Q62073 1 EQUAL 606 EQUAL Reactome DB_ID: 9764083 1 UniProt:Q8CF89 Tab1 Tab1 Map3k7ip1 Tab1 FUNCTION May be an important signaling intermediate between TGFB receptors and MAP3K7/TAK1. May play an important role in mammalian embryogenesis.SUBUNIT Interacts with XIAP and BIRC7. Interacts with TRAF6 and MAP3K7; during IL-1 signaling. Identified in the TRIKA2 complex composed of MAP3K7, TAB1 and TAB2 (By similarity).PTM Monoubiquitinated.CAUTION Lacks several key residues involved in metal-binding and catalytic activity, therefore has lost phosphatase activity. UniProt Q8CF89 1 EQUAL 504 EQUAL Reactome Database ID Release 78 9764094 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764094 Reactome R-MMU-446878 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-446878.1 Reactome DB_ID: 9823984 1 Reactome DB_ID: 9824068 1 p-T231-CARD9:BCL10:MALT1:K63polyUb-TRAF6 oligomers:TRIKA2 [plasma membrane] p-T231-CARD9:BCL10:MALT1:K63polyUb-TRAF6 oligomers:TRIKA2 Reactome DB_ID: 9764094 1 Reactome DB_ID: 9823984 1 Reactome Database ID Release 78 9824068 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824068 Reactome R-MMU-5607672 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607672.1 Reactome Database ID Release 78 9824073 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824073 Reactome R-MMU-5607759 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607759.1 K-63 linked polyubiquitin (pUb) chain on TRAF6 provides a scaffold to recruit downstream effector molecules to activate NF-kB. Transforming growth factor beta-associated kinase 1 (TAK1) is a member of the mitogen-activated protein kinase (MAPK) kinase kinase family that is shown to be an essential intermediate that transmits the upstream signals from the receptor complex to the downstream MAPKs and to the NF-kB pathway (Broglie et al. 2009). As a member of the MAP3K family, TAK1 is unique in that its activity requires its binding proteins TAK1-binding protein 1 (TAB1), TAB2 and TAB3. TAB1 acts as the kinase subunit of the TAK1 complex, aiding in the autophosphorylation of TAK1, whereas TAB2 and its homologue TAB3, acts as an adaptor of TAK1 that facilitate the assembly of TAK1 complex to TRAF6 (Takaesu et al. 2000, Ishitani et al. 2003). This protein kinase complex containing the kinase subunit TAK1 and the regulatory subunits TAB1 and TAB2/TAB3 is also known as TRIKA2 (TRAF6-regulated IKK activator 2) (Adhikari et al. 2007). 19955178 Pubmed 2010 Transforming growth factor beta-activated kinase 1 (TAK1) kinase adaptor, TAK1-binding protein 2, plays dual roles in TAK1 signaling by recruiting both an activator and an inhibitor of TAK1 kinase in tumor necrosis factor signaling pathway Broglie, Peter Matsumoto, Kunihiro Akira, Shizuo Brautigan, David L Ninomiya-Tsuji, Jun J. Biol. Chem. 285:2333-9 17496917 Pubmed 2007 Ubiquitin-mediated activation of TAK1 and IKK Adhikari, A Xu, M Chen, ZJ Oncogene 26:3214-26 15327770 Pubmed 2004 TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains Kanayama, A Seth, RB Sun, L Ea, CK Hong, M Shaito, A Chiu, YH Deng, L Chen, ZJ Mol Cell 15:535-48 14633987 Pubmed 2003 Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling Ishitani, T Takaesu, G Ninomiya-Tsuji, J Shibuya, H Gaynor, RB Matsumoto, K EMBO J 22:6277-88 17158449 Pubmed 2007 TAK1-dependent signaling requires functional interaction with TAB2/TAB3 Besse, A Lamothe, B Campos, AD Webster, WK Maddineni, U Lin, SC Wu, H Darnay, BG J Biol Chem 282:3918-28 10882101 Pubmed 2000 TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway Takaesu, G Kishida, S Hiyama, A Yamaguchi, K Shibuya, H Irie, K Ninomiya-Tsuji, J Matsumoto, K Mol Cell 5:649-58 inferred by electronic annotation IEA GO IEA 6.3.2.19 K63polyUb-TRAF6 ubiquitinates TAK1 K63polyUb-TRAF6 ubiquitinates TAK1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9764075 1 Reactome DB_ID: 113592 1 Reactome DB_ID: 9824068 1 Reactome DB_ID: 9764139 1 Reactome DB_ID: 9764075 1 Reactome DB_ID: 111294 1 Reactome DB_ID: 76577 1 Reactome DB_ID: 9823986 1 p-T231-CARD9:BCL10:MALT1:K63polyUb-TRAF6 oligomers:TAB1:TAB2/TAB3:K63polyUb-34,158-TAK1 [plasma membrane] p-T231-CARD9:BCL10:MALT1:K63polyUb-TRAF6 oligomers:TAB1:TAB2/TAB3:K63polyUb-34,158-TAK1 Reactome DB_ID: 9823984 1 Reactome DB_ID: 9823970 1 TAB1:TAB2/TAB3:K63polyUb-34,158-TAK1 [cytosol] TAB1:TAB2/TAB3:K63polyUb-34,158-TAK1 Converted from EntitySet in Reactome Reactome DB_ID: 9764092 1 Reactome DB_ID: 9764083 1 1 EQUAL 504 EQUAL Reactome DB_ID: 9823968 1 ubiquitinylated lysine (K63polyUb [cytosol]) at 34 (in Homo sapiens) 34 EQUAL ubiquitinylated lysine [MOD:01148] ubiquitinylated lysine (K63polyUb [cytosol]) at 158 (in Homo sapiens) 158 EQUAL 1 EQUAL 606 EQUAL Reactome Database ID Release 78 9823970 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823970 Reactome R-MMU-5607691 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607691.1 Reactome Database ID Release 78 9823986 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823986 Reactome R-MMU-5607695 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607695.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9824068 Reactome Database ID Release 78 9824069 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824069 Reactome Database ID Release 78 9824071 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824071 Reactome R-MMU-5607757 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607757.1 TAK1-binding protein 2 (TAB2), or its homologue TAB3, binds preferentially to K63-linked polyubiquitin chains in TRAF6 and links TRAF6 (TNF receptor-associated factor 6) to TAK1 (Transforming growth factor beta-associated kinase 1). TRAF6 ubiquitinates TAK1 on K34 and K158 and this triggers conformational changes in TAK1 that lead to autophosphorylation and activation (Fan et al. 2010, Hamidi et al. 2011). 22069318 Pubmed 2012 Polyubiquitination of transforming growth factor ? (TGF?)-associated kinase 1 mediates nuclear factor-?B activation in response to different inflammatory stimuli Hamidi, Anahita von Bulow, Verena Hamidi, Rosita Winssinger, Nicolas Barluenga, Sofia Heldin, Carl-Henrik Landström, Marene J. Biol. Chem. 287:123-33 20038579 Pubmed 2010 Lysine 63-linked polyubiquitination of TAK1 at lysine 158 is required for tumor necrosis factor alpha- and interleukin-1beta-induced IKK/NF-kappaB and JNK/AP-1 activation Fan, Yihui Yu, Yang Shi, Yi Sun, Wenjing Xie, Min Ge, Ningling Mao, Renfang Chang, Alex Xu, Gufeng Schneider, Michael D Zhang, H Fu, Songbin Qin, J Yang, Jianhua J. Biol. Chem. 285:5347-60 inferred by electronic annotation IEA GO IEA 2.7.11 K63polyUb-TAK1 autophosphorylates K63polyUb-TAK1 autophosphorylates This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 4 Reactome DB_ID: 9823986 1 Reactome DB_ID: 29370 4 Reactome DB_ID: 9823994 1 p-T231-CARD9:BCL10:MALT1:K63polyUb-TRAF6 oligomers:TAB1:TAB2/TAB3:K63polyUb-34,158-p3Y,1S-TAK1 [plasma membrane] p-T231-CARD9:BCL10:MALT1:K63polyUb-TRAF6 oligomers:TAB1:TAB2/TAB3:K63polyUb-34,158-p3Y,1S-TAK1 Reactome DB_ID: 9823984 1 Reactome DB_ID: 9823992 1 TAB1:TAB2,TAB3:K63polyUb-34,158-p-T178,184,187,S192-TAK1 [cytosol] TAB1:TAB2,TAB3:K63polyUb-34,158-p-T178,184,187,S192-TAK1 Converted from EntitySet in Reactome Reactome DB_ID: 9764092 1 Reactome DB_ID: 9764083 1 1 EQUAL 504 EQUAL Reactome DB_ID: 9823990 1 ubiquitinylated lysine (K63polyUb [cytosol]) at 34 (in Homo sapiens) 34 EQUAL ubiquitinylated lysine (K63polyUb [cytosol]) at 158 (in Homo sapiens) 158 EQUAL O-phospho-L-threonine at 178 (in Homo sapiens) 178 EQUAL O-phospho-L-threonine at 184 (in Homo sapiens) 184 EQUAL O-phospho-L-threonine at 187 187 EQUAL O-phospho-L-serine at 192 (in Homo sapiens) 192 EQUAL 1 EQUAL 606 EQUAL Reactome Database ID Release 78 9823992 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823992 Reactome R-MMU-5607683 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607683.1 Reactome Database ID Release 78 9823994 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823994 Reactome R-MMU-5607673 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607673.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9823986 GO 0004674 GO molecular function Reactome Database ID Release 78 9823995 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823995 Reactome Database ID Release 78 9823997 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823997 Reactome R-MMU-5607732 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607732.1 TAK1-binding protein 1 (TAB1) is a TAK1-interacting protein and induces TAK1 (Transforming growth factor beta-associated kinase 1) kinase activity through promoting autophosphorylation of key serine/threonine sites of the kinase activation loop. There are four phosphorylation sites in the activation loop and analysis of these site mutants indicate that autophosphorylation of S192, is followed by sequential phosphorylation of T178, T187, and finally T184 (Scholz et al. 2010). 20538596 Pubmed 2010 Autoactivation of transforming growth factor beta-activated kinase 1 is a sequential bimolecular process Scholz, Roland Sidler, Corinne L Thali, Ramon F Winssinger, Nicolas Cheung, Peter C F Neumann, D J. Biol. Chem. 285:25753-66 inferred by electronic annotation IEA GO IEA 2.7.11 K63polyUb-p-3T,1S-TAK1 phosphorylates IKK-beta K63polyUb-p-3T,1S-TAK1 phosphorylates IKK-beta This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9764054 1 CHUK:IKBKB:IKBKG [cytosol] CHUK:IKBKB:IKBKG Reactome DB_ID: 9764052 1 UniProt:O88351 Ikbkb UniProt O88351 1 EQUAL 756 EQUAL Reactome DB_ID: 9763953 1 UniProt:O88522 Ikbkg UniProt O88522 1 EQUAL 419 EQUAL Reactome DB_ID: 9764050 1 UniProt:Q60680 Chuk UniProt Q60680 1 EQUAL 745 EQUAL Reactome Database ID Release 78 9764054 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764054 Reactome R-MMU-168113 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-168113.1 Reactome DB_ID: 113592 2 Reactome DB_ID: 29370 2 Reactome DB_ID: 9771380 1 p-S177,S181-IKKB:IKKA:NEMO [cytosol] p-S177,S181-IKKB:IKKA:NEMO Reactome DB_ID: 9763953 1 1 EQUAL 419 EQUAL Reactome DB_ID: 9764050 1 1 EQUAL 745 EQUAL Reactome DB_ID: 9763965 1 O-phospho-L-serine at 177 (in Homo sapiens) 177 EQUAL O-phospho-L-serine at 181 (in Homo sapiens) 181 EQUAL 1 EQUAL 756 EQUAL Reactome Database ID Release 78 9771380 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9771380 Reactome R-MMU-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-MMU-202513.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9823994 Reactome Database ID Release 78 9824030 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824030 Reactome Database ID Release 78 9824032 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824032 Reactome R-MMU-5607742 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607742.1 In humans, 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 S177 and S181 (S176 and S180 in IKK alpha) in the activation loop and thus activate the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation. 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 20300203 Pubmed 2010 The IKK complex, a central regulator of NF-kappaB activation Israel, A Cold Spring Harb Perspect Biol 2:a000158 11460167 Pubmed 2001 TAK1 is a ubiquitin-dependent kinase of MKK and IKK Wang, C Deng, L Hong, M Akkaraju, GR Inoue, J Chen, ZJ Nature 412:346-51 17047224 Pubmed 2006 Regulation and function of IKK and IKK-related kinases Hacker, H Karin, M Sci STKE 2006:re13 11325957 Pubmed 2001 Persistent activation of NF-kappa B by the tax transforming protein involves chronic phosphorylation of IkappaB kinase subunits IKKbeta and IKKgamma Carter, R S Geyer, B C Xie, M Acevedo-Suárez, C A Ballard, D W J. Biol. Chem. 276:24445-8 inferred by electronic annotation IEA GO IEA 6.3.2.19 Ubiquitination of NEMO by TRAF6 Ubiquitination of NEMO by TRAF6 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9764075 1 Reactome DB_ID: 9764139 1 Reactome DB_ID: 9771380 1 Reactome DB_ID: 9764075 1 Reactome DB_ID: 9771405 1 p-S177,S181-IKKB:IKKA:pUb-NEMO [cytosol] p-S177,S181-IKKB:IKKA:pUb-NEMO Reactome DB_ID: 9764050 1 1 EQUAL 745 EQUAL Reactome DB_ID: 9771403 1 ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 321 (in Homo sapiens) 321 EQUAL ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 325 (in Homo sapiens) 325 EQUAL ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 326 (in Homo sapiens) 326 EQUAL ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at unknown position 1 EQUAL 419 EQUAL Reactome DB_ID: 9763965 1 O-phospho-L-serine at 177 (in Homo sapiens) 177 EQUAL O-phospho-L-serine at 181 (in Homo sapiens) 181 EQUAL 1 EQUAL 756 EQUAL Reactome Database ID Release 78 9771405 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9771405 Reactome R-MMU-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-MMU-202562.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9771360 Ub-TRAF6 trimer bound to CBM complex [plasma membrane] Ub-TRAF6 trimer bound to CBM complex Reactome DB_ID: 9771356 1 MALT1 trimer bound to Bcl10 and CARMA1 trimer [plasma membrane] MALT1 trimer bound to Bcl10 and CARMA1 trimer Reactome DB_ID: 9771354 1 MALT1 trimer [cytosol] MALT1 trimer Reactome DB_ID: 9771352 3 1 EQUAL 824 EQUAL Reactome Database ID Release 78 9771354 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9771354 Reactome R-MMU-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-MMU-202487.1 Reactome DB_ID: 9771349 1 Bcl10 trimer bound to CARMA1 trimer [plasma membrane] Bcl10 trimer bound to CARMA1 trimer Reactome DB_ID: 9771347 3 phosphorylated residue at unknown position phosphorylated residue [MOD:00696] 1 EQUAL 233 EQUAL Reactome DB_ID: 9771341 1 CARMA1 trimer [plasma membrane] CARMA1 trimer Reactome DB_ID: 9771054 1 PDK1:PIP2,PIP3 [plasma membrane] PDK1:PIP2,PIP3 Reactome DB_ID: 9758215 1 UniProt:Q9Z2A0 Pdpk1 UniProt Q9Z2A0 1 EQUAL 556 EQUAL 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] ChEBI 16618 ChEBI 16152 Reactome Database ID Release 78 9771054 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9771054 Reactome R-MMU-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-MMU-202311.1 Reactome DB_ID: 9771334 3 UniProt:Q8CIS0 Card11 Card11 Card11 Carma1 FUNCTION Adapter protein that plays a key role in adaptive immune response by transducing the activation of NF-kappa-B downstream of T-cell receptor (TCR) and B-cell receptor (BCR) engagement (PubMed:12356734, PubMed:12154356, PubMed:16356855). 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:12356734, PubMed:12154356, PubMed:16356855). 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 (By similarity). Its binding to DPP4 induces T-cell proliferation and NF-kappa-B activation in a T-cell receptor/CD3-dependent manner (By similarity). Promotes linear ubiquitination of BCL10 by promoting the targeting of BCL10 to RNF31/HOIP (By similarity). Stimulates the phosphorylation of BCL10 (By similarity). Also activates the TORC1 signaling pathway (By similarity).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 (By similarity). 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 (PubMed:16356855).SUBUNIT Homodimer; disulfide-linked (By similarity). Homomultimer; polymerizes following activation, forming a nucleating helical template that seeds BCL10-filament formation via a CARD-CARD interaction (By similarity). 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:22880103). Component of a CBM complex (CARD11-BCL10-MALT1) complex involved in NF-kappa-B activation (By similarity). Found in a membrane raft complex, at least composed of BCL10, CARD11, DPP4 and IKBKB (By similarity). Interacts (via PDZ domain) with DPP4 (via cytoplasmic tail) (By similarity).DOMAIN The linker region, also named autoinhibitory interface, is less inhibitory on its own than that of CARD9. The linker region together with the inhibitory domain (ID) are required to prevent constitutive activation and maintain CARD11 in an autoinhibitory state. Disruption of the inhibitory domain (ID) region triggers polymerization and activation, leading to formation of BCL10-nucleating filaments.PTM Phosphorylation at Ser-564, Ser-649 and Ser-657 by PRKCB and PRKCQ leads to a shift from an inactive to an active form that activates the NF-kappa-B signaling.DISRUPTION PHENOTYPE Impaired activation of NF-kappa-B downstream of T-cell receptor (TCR), leading to defects in interleukin-2 (IL2) production. UniProt Q8CIS0 O-phospho-L-serine at 552 (in Homo sapiens) 552 EQUAL 1 EQUAL 1154 EQUAL Reactome Database ID Release 78 9771341 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9771341 Reactome R-MMU-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-MMU-202445.1 Reactome Database ID Release 78 9771349 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9771349 Reactome R-MMU-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-MMU-202475.1 Reactome Database ID Release 78 9771356 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9771356 Reactome R-MMU-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-MMU-202468.1 Reactome DB_ID: 9764065 3 ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 124 (in Homo sapiens) 124 EQUAL 1 EQUAL 522 EQUAL Reactome Database ID Release 78 9771360 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9771360 Reactome R-MMU-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-MMU-202456.1 Reactome Database ID Release 78 9771406 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9771406 Reactome Database ID Release 78 9771408 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9771408 Reactome R-MMU-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-MMU-202534.1 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). 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 inferred by electronic annotation IEA GO IEA 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 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 2 Reactome DB_ID: 9768307 1 IkB(alpha):NF-kB complex [cytosol] IkB(alpha):NF-kB complex Reactome DB_ID: 9763931 1 UniProt:Q9Z1E3 Nfkbia UniProt Q9Z1E3 1 EQUAL 317 EQUAL Reactome DB_ID: 9768248 1 NFKB1(1-433):RELA [cytosol] NFKB1(1-433):RELA Reactome DB_ID: 9763919 1 UniProt:P25799 Nfkb1 UniProt P25799 1 EQUAL 433 EQUAL Reactome DB_ID: 9763915 1 UniProt:Q04207 Rela UniProt Q04207 1 EQUAL 551 EQUAL Reactome Database ID Release 78 9768248 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9768248 Reactome R-MMU-194043 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-194043.1 Reactome Database ID Release 78 9768307 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9768307 Reactome R-MMU-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-MMU-193938.1 Reactome DB_ID: 29370 2 Reactome DB_ID: 9771410 1 p-S32,36-IkB-alpha:NF-kB complex [cytosol] p-S32,36-IkB-alpha:NF-kB complex Reactome DB_ID: 9768248 1 Reactome DB_ID: 9763943 1 O-phospho-L-serine at 32 (in Homo sapiens) 32 EQUAL O-phospho-L-serine at 36 (in Homo sapiens) 36 EQUAL 1 EQUAL 317 EQUAL Reactome Database ID Release 78 9771410 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9771410 Reactome R-MMU-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-MMU-5607671.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9771405 Reactome Database ID Release 78 9771411 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9771411 Reactome Database ID Release 78 9771413 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9771413 Reactome R-MMU-202541 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-202541.1 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) 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 inferred by electronic annotation IEA GO IEA 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 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9771410 1 Converted from EntitySet in Reactome Reactome DB_ID: 9788366 4 K48-Ub [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Uba52 [cytosol] Rps27a [cytosol] Ubb [cytosol] UniProt P62984 UniProt P62983 UniProt P0CG49 Converted from EntitySet in Reactome Reactome DB_ID: 9823957 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 P61080 UniProt P62838 Reactome DB_ID: 9795243 1 CUL1:FBXW11:SKP1 [cytosol] CUL1:FBXW11:SKP1 Reactome DB_ID: 5610356 1 UniProt:Q5SRY7 Fbxw11 Fbxw11 Btrcp2 Fbw1b Fbxw11 Fbxw1b FUNCTION Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Probably recognizes and binds to phosphorylated target proteins. SCF(FBXW11) mediates the ubiquitination of phosphorylated CTNNB1 and participates in Wnt signaling regulation. SCF(FBXW11) mediates the ubiquitination of phosphorylated NFKBIA, which degradation frees the associated NFKB1 to translocate into the nucleus and to activate transcription. SCF(FBXW11) mediates the ubiquitination of IFNAR1. SCF(FBXW11) mediates the ubiquitination of CEP68; this is required for centriole separation during mitosis (By similarity). Involved in the oxidative stress-induced a ubiquitin-mediated decrease in RCAN1. Mediates the degradation of CDC25A induced by ionizing radiation in cells progressing through S phase and thus may function in the intra-S-phase checkpoint. Has an essential role in the control of the clock-dependent transcription via degradation of phosphorylated PER1 and phosphorylated PER2. SCF(FBXW11) mediates the ubiquitination of CYTH1, and probably CYTH2 (By similarity).SUBUNIT Self-associates. Component of the SCF(FBXW11) complex formed of CUL1, SKP1, RBX1 and a FBXW11 dimer. Interacts with BTRC, BST2, PER1, RCAN1 and USP47. Interacts with phosphorylated ubiquitination substrates CTNNB1, NFKBIA, IFNAR1, PER1 and PER2; the interaction requires the phosphorylation of the two serine residues in the substrates' destruction motif D-S-G-X(2,3,4)-S. Interacts with TRIM21. Interacts with PER3. Interacts with phosphorylated ubiquitination substrate CEP68 (By similarity). Interacts with INAVA (By similarity). Interacts with REST (By similarity).INDUCTION Expression is negatively regulated by Wnt/beta-catenin pathway.DOMAIN The N-terminal D domain mediates homodimerization. UniProt Q5SRY7 1 EQUAL 542 EQUAL Reactome DB_ID: 9765206 1 UniProt:Q9WTX6 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. 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. 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(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:10097128, PubMed:12140560, PubMed:16880526, PubMed:23452855, PubMed:23452856). 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 (By similarity). Component of the SCF(BTRC) complex, composed of SKP1, CUL1 and BTRC (PubMed:10097128, PubMed:11735228). This complex binds phosphorylated NFKBIA (PubMed:10097128). 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. 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 (By similarity). Interacts with FBXW8 (PubMed:16880526). Interacts with RNF7 (By similarity). Interacts with CUL7; the interaction seems to be mediated by FBXW8 (PubMed:16880526). Interacts with TRIM21 (By similarity). Interacts with COPS2 (PubMed:11967155). Interacts with DCUN1D1 and UBE2M. Interacts with DCUN1D3. Interacts with DCUN1D4 (By similarity). Identified in a complex with RBX1 and GLMN (By similarity). 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. Interacts (when neddylated) with ARIH1; leading to activate the E3 ligase activity of ARIH1. Interacts with COPS9. Interacts with UBXN1 (By similarity). Interacts with KAT7, probably as part of an SCF complex; the interaction mediates KAT7 ubiquitination (PubMed:23319590). Interacts with NOTCH2 (By similarity). Part of a complex that contains DCUN1D5, CUL1 and RBX1; this interaction is bridged by CUL1 (By similarity). Interacts (unneddylated form) with DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5; these interactions promote the cullin neddylation (By similarity).SUBUNIT (Microbial infection) Interacts with murine cytomegalovirus M48.TISSUE SPECIFICITY Embryo fibroblasts and embryo preadipocytes.PTM Neddylated; which enhances the ubiquitination activity of SCF. Deneddylated via its interaction with the COP9 signalosome (CSN) complex.PTM (Microbial infection) Deneddylated by murine cytomegalovirus M48 leading to a S-phase-like environment that is required for efficient replication of the viral genome.SIMILARITY Belongs to the cullin family. UniProt Q9WTX6 1 EQUAL 776 EQUAL Reactome DB_ID: 9765204 1 UniProt:Q9WTX5 Skp1 Skp1 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. 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 (By similarity).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Interacts with KDM2B, forming heterodimers (By similarity). The KDM2B-SKP1 heterodimeric complex interacts with the PCGF1-BCORL heterodimeric complex to form a homotetrameric polycomb repression complex 1 (PRC1.1) (By similarity). 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. Component of the SCF(FBXW15) complex containing FBXW15 (PubMed:23319590). Interacts with CEP68 (By similarity). Interacts with FBXW15 (PubMed:23319590). Interacts with NOTCH2 (By similarity). The SKP1-KDM2A and SKP1-KDM2B complexes interact with UBB (By similarity).PTM Undergoes autophagy-mediated degradation in the liver in a time-dependent manner.SIMILARITY Belongs to the SKP1 family. UniProt Q9WTX5 2 EQUAL 163 EQUAL Reactome Database ID Release 78 9795243 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9795243 Reactome R-MMU-1168592 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-1168592.1 Reactome DB_ID: 9823942 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: 9768248 1 Reactome DB_ID: 9823940 1 O-phospho-L-serine at 32 (in Homo sapiens) 32 EQUAL O-phospho-L-serine at 36 (in Homo sapiens) 36 EQUAL ubiquitinylated lysine (K48polyUb [cytosol]) at 21 (in Homo sapiens) 21 EQUAL ubiquitinylated lysine (K48polyUb [cytosol]) at 22 (in Homo sapiens) 22 EQUAL 1 EQUAL 317 EQUAL Reactome Database ID Release 78 9823942 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823942 Reactome R-MMU-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-MMU-5607697.1 Converted from EntitySet in Reactome Reactome DB_ID: 9823957 1 Reactome DB_ID: 9795243 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9795243 Reactome Database ID Release 78 9823958 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823958 Reactome Database ID Release 78 9823960 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823960 Reactome R-MMU-5607728 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607728.1 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). 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 inferred by electronic annotation IEA GO IEA 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 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9823942 1 Reactome DB_ID: 9768248 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9751524 26S proteasome [cytosol] 26S proteasome Reactome DB_ID: 1236853 1 UniProt:P28076 Psmb9 Psmb9 Lmp2 Ring12 Psmb9 FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides. Contributes to NFKBIA degradation and subsequently NFKB1 generation.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Component of the immunoproteasome, where it displaces the equivalent housekeeping subunit PSMB6. Component of the spermatoproteasome, a form of the proteasome specifically found in testis. Interacts with NCOA1, NCOA2 and NCOA3.TISSUE SPECIFICITY Detected in liver (at protein level). Expressed at high levels in the thymus, spleen, lung, heart and liver. Expressed at moderate levels in the kidney.INDUCTION Up-regulated by interferon gamma (at protein level). Up-regulated by IRF1. Up-regulated by heat shock treatment. Down-regulated by EGR1 in neuronal cells.PTM Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.DISRUPTION PHENOTYPE Depletion of LMP2 by RNAi suppresses expression and activities of the matrix metalloproteinase MMP2 and MMP9 by blocking the transfer of active NF-kappa-B heterodimers into the nucleus.SIMILARITY Belongs to the peptidase T1B family. UniProt P28076 21 EQUAL 219 EQUAL Reactome DB_ID: 1236868 1 UniProt:O70435 Psma3 Psma3 Psma3 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). Binds to the C-terminus of CDKN1A and thereby mediates its degradation. Negatively regulates the membrane trafficking of the cell-surface thromboxane A2 receptor (TBXA2R) isoform 2.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 (PubMed:16857966, PubMed:22341445). Interacts with AURKB. Interacts with CDKN1A. Interacts with MDM2 and RB1. Interacts with the C-terminus of TBXA2R isoform 2. Interacts with DNAJB2.TISSUE SPECIFICITY Detected in liver (at protein level).SIMILARITY Belongs to the peptidase T1A family. UniProt O70435 2 EQUAL 255 EQUAL Reactome DB_ID: 9751430 1 UniProt:O88685 Psmc3 UniProt O88685 1 EQUAL 439 EQUAL Reactome DB_ID: 9751517 1 UniProt:Q9CWH6 Psma8 Psma8 Psma7l Psma8 FUNCTION Component of the spermatoproteasome, a proteasome specifically found in testis that promotes acetylation-dependent degradation of histones, thereby participating actively to the exchange of histones during spermatogenesis (PubMed:23706739, PubMed:31358751, PubMed:31437213). The proteasome is a protein complexe that degrades unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds (Probable). Required for 20S core proteasome assembly, essential for the degradation of meiotic proteins RAD51 and RPA1 at late prophase I and the progression of meiosis I during spermatogenesis (PubMed:31358751). Localizes to the synaptonemal complex, a 'zipper'-like structure that holds homologous chromosome pairs in synapsis during meiotic prophase I (PubMed:31437213).SUBUNIT Component of the outer alpha-ring of the 20S proteasome core which is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure (PubMed:23706739, PubMed:31358751). The catalytic chamber with the active sites is on the inside of the barrel (Probable). Interacts with canonical subunits of the spermatoproteasome, including proteasome activators PSME4 (also called PA200) and PSME3 (also called PA28-gamma) (PubMed:31437213). Interacts with proteasome-interacting proteins chaperones including CCT6B and CCT2, ubiquitin ligases (TRIP12, NEDD4, TRIM36 and RAD18), and ubiquitin specific proteases such as USP9X, USP34, USP5 and USP47 (PubMed:31437213). Interacts with meiotic proteins cyclin dependent kinase CDK1 and the ATPase TRIP13 as well as proteins of the synaptonemal complex SIX6OS1 and SYCE3 (PubMed:31437213).DEVELOPMENTAL STAGE In testes, expressed in spermatocytes at the pachytene stage (weakly in early pachynema and strongly in late pachynema), and its expression persisted thereafter throughout spermatogenesis.DISRUPTION PHENOTYPE Knockout mice were obtained according to the expected Mendelian ratios and showed no obvious phenotypes with respect to viability and development; however males show infertility (PubMed:31358751, PubMed:31437213). PSMA8-null spermatocytes exhibit delayed M-phase entry and are finally arrested at this stage, resulting in male infertility (PubMed:31358751, PubMed:31437213).SIMILARITY Belongs to the peptidase T1A family.CAUTION Predicted to have endopeptidase activity (By similarity). However, as it is located in the outer alpha-ring, it is suggested to lack catalytic activity and preferentially interact with regulatory complexes such as PSME4/PA200. UniProt Q9CWH6 1 EQUAL 256 EQUAL Reactome DB_ID: 9751426 1 UniProt:P46471 Psmc2 UniProt P46471 2 EQUAL 433 EQUAL Reactome DB_ID: 9751393 1 UniProt:O35593 Psmd14 UniProt O35593 1 EQUAL 310 EQUAL Reactome DB_ID: 9751498 1 UniProt:P97371 Psme1 UniProt P97371 1 EQUAL 249 EQUAL Reactome DB_ID: 9751412 1 UniProt:O55234 Psmb5 Psmb5 Psmb5 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 (PubMed:16857966, PubMed:22341445). Directly interacts with POMP (By similarity). Interacts with ABCB1 and TAP1 (By similarity).TISSUE SPECIFICITY Expressed in uterus at the embryo implantation site.INDUCTION Up-regulated in embryonic fibroblasts and neuroblastoma cells by antioxidants through the Nrf2-ARE pathway (at protein level). Up-regulated by the antioxidant dithiolethione (D3T) in liver, small intestine and brain (at protein level). Down-regulated under lithium treatment.SIMILARITY Belongs to the peptidase T1B family. UniProt O55234 60 EQUAL 263 EQUAL Reactome DB_ID: 9751506 1 UniProt:P61290 Psme3 UniProt P61290 2 EQUAL 254 EQUAL Reactome DB_ID: 1236811 1 UniProt:O35955 Psmb10 Psmb10 Psmb10 Lmp10 Mecl1 FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides. Plays a role in determining the T-cell repertoire for an antiviral T-cell response.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Component of the immunoproteasome, where it displaces the equivalent housekeeping subunit PSMB7. Component of the spermatoproteasome, a form of the proteasome specifically found in testis.TISSUE SPECIFICITY Detected in liver (at protein level).INDUCTION Up-regulated by interferon gamma (at protein level). Up-regulated by IRF1.PTM Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.DISRUPTION PHENOTYPE Impaired response of cytotoxic T-lymphocyte (CTL) to dominant epitopes of lymphocytic choriomeningitis virus (LCMV).SIMILARITY Belongs to the peptidase T1B family. UniProt O35955 40 EQUAL 273 EQUAL Reactome DB_ID: 9751422 1 UniProt:P62192 Psmc1 UniProt P62192 2 EQUAL 440 EQUAL Reactome DB_ID: 1236802 1 UniProt:Q9R1P4 Psma1 Psma1 Psma1 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).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 (PubMed:16857966). Interacts with NOTCH3 (By similarity). Interacts with ZFAND1 (By similarity).TISSUE SPECIFICITY Detected in liver (at protein level).INDUCTION Up-regulated in liver tumor tissues. Up-regulated by the antioxidant dithiolethione (D3T) in liver, lung and colon (at the protein level).PTM C-terminal extension is partially cleaved off by limited proteolysis leading to a conversion of the proteasome from its latent into its active form.SIMILARITY Belongs to the peptidase T1A family. UniProt Q9R1P4 1 EQUAL 263 EQUAL Reactome DB_ID: 9751470 1 UniProt:P14685 Psmd3 UniProt P14685 1 EQUAL 534 EQUAL Reactome DB_ID: 9751520 1 UniProt:Q8BG41 Psmb11 Psmb11 Psmb11 FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. Incorporated instead of PSMB5 or PSMB8, this unit reduces the chymotrypsin-like activity of the proteasome. Plays a pivotal role in development of CD8-positive T-cells.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Incorporated instead of PSMB5 and PSMB8.TISSUE SPECIFICITY Expressed exclusively in cortical thymic epithelial cells.DISRUPTION PHENOTYPE Displays defective development of CD8-positive T-cells in the thymus.SIMILARITY Belongs to the peptidase T1B family. UniProt Q8BG41 50 EQUAL 300 EQUAL Reactome DB_ID: 1236795 1 UniProt:Q9R1P1 Psmb3 Psmb3 Psmb3 FUNCTION Non-catalytic 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).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.TISSUE SPECIFICITY Detected in liver (at protein level).SIMILARITY Belongs to the peptidase T1B family. UniProt Q9R1P1 2 EQUAL 205 EQUAL Reactome DB_ID: 9751405 1 UniProt:O09061 Psmb1 Psmb1 Psmb1 FUNCTION Non-catalytic 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).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 (PubMed:16857966, PubMed:22341445). Interacts with SERPINB2 (By similarity). Interacts with RFPL4A (PubMed:12525704).TISSUE SPECIFICITY Detected in liver (at protein level).SIMILARITY Belongs to the peptidase T1B family. UniProt O09061 29 EQUAL 241 EQUAL Reactome DB_ID: 1236775 1 UniProt:P70195 Psmb7 Psmb7 Psmb7 Mmc14 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, PSMB7 displays a trypsin-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.INDUCTION Up-regulated by the antioxidant dithiolethione (D3T) in colon (at protein level).SIMILARITY Belongs to the peptidase T1B family. UniProt P70195 44 EQUAL 277 EQUAL Reactome DB_ID: 9751490 1 UniProt:Q9CX56 Psmd8 UniProt Q9CX56 1 EQUAL 350 EQUAL Reactome DB_ID: 9751446 1 UniProt:Q3TXS7 Psmd1 UniProt Q3TXS7 1 EQUAL 953 EQUAL Reactome DB_ID: 9751458 1 UniProt:Q9D8W5 Psmd12 UniProt Q9D8W5 2 EQUAL 456 EQUAL Reactome DB_ID: 1236800 1 UniProt:P49722 Psma2 Psma2 Psma2 Lmpc3 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).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.TISSUE SPECIFICITY Detected in liver (at protein level).PTM Phosphorylated on tyrosine residues; which may be important for nuclear import.SIMILARITY Belongs to the peptidase T1A family. UniProt P49722 2 EQUAL 234 EQUAL Reactome DB_ID: 9751442 1 UniProt:P62334 Psmc6 UniProt P62334 1 EQUAL 389 EQUAL Reactome DB_ID: 1236864 1 UniProt:P28063 Psmb8 Psmb8 Lmp7 Mc13 Psmb8 FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides. May participate in the inflammatory response pathway. Required for adipocyte differentiation (PubMed:21881205, PubMed:22341445, PubMed:8066463). May be involved in the generation of spliced peptides resulting from the ligation of two separate proteasomal cleavage products that are not contiguous in the parental protein (By similarity).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Component of the immunoproteasome, where it displaces the equivalent housekeeping subunit PSMB5. Component of the spermatoproteasome, a form of the proteasome specifically found in testis. Directly interacts with POMP. Interacts with TAP1.TISSUE SPECIFICITY Detected in liver (at protein level). Expressed in spleen, thymus, lung, liver, heart and, at a very low level, in kidney. Not expressed in brain nor testis.INDUCTION Up-regulated by interferon gamma (at protein level). Up-regulated by IRF1. Down-regulated in spleen by deoxynivalenol (DON), a mycotoxin that alters immune functions. Down-regulated by the selective inhibitor PR-957. Up-regulated by heat shock treatment. Down-regulated by EGR1 in neuronal cells.PTM Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.POLYMORPHISM The allele, LMP7k/LMP7s/LMPf/LMP7r/LMPcas4/LMPg7 found in strains NMRI, B10.BR, SJL, A.CA, B10.RIII, B10.cas4 and NOD may be post-translationally modified. Allele LMP7q is found in strain DBA/1J.SIMILARITY Belongs to the peptidase T1B family. UniProt P28063 73 EQUAL 276 EQUAL Reactome DB_ID: 9751466 1 UniProt:Q8VDM4 Psmd2 UniProt Q8VDM4 1 EQUAL 908 EQUAL Reactome DB_ID: 9751510 1 UniProt:Q8BHL8 Psmf1 UniProt Q8BHL8 1 EQUAL 271 EQUAL Reactome DB_ID: 1236823 1 UniProt:Q9QUM9 Psma6 Psma6 Psma6 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).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 (PubMed:16857966, PubMed:22341445). Interacts with ALKBH4 (By similarity).TISSUE SPECIFICITY Detected in liver (at protein level).INDUCTION Up-regulated in liver tumor tissues (at protein level).SIMILARITY Belongs to the peptidase T1A family. UniProt Q9QUM9 1 EQUAL 246 EQUAL Reactome DB_ID: 9751502 1 UniProt:P97372 Psme2 UniProt P97372 2 EQUAL 239 EQUAL Reactome DB_ID: 1236839 1 UniProt:Q9R1P0 Psma4 Psma4 Psma4 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).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 (PubMed:16857966, PubMed:22341445).TISSUE SPECIFICITY Detected in liver (at protein level).SIMILARITY Belongs to the peptidase T1A family. UniProt Q9R1P0 1 EQUAL 261 EQUAL Reactome DB_ID: 9751522 1 Ghost homologue of SHFM1 [cytosol] Ghost homologue of SHFM1 Reactome DB_ID: 1236756 1 UniProt:Q9R1P3 Psmb2 Psmb2 Psmb2 FUNCTION Non-catalytic 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).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.TISSUE SPECIFICITY Detected in liver (at protein level).SIMILARITY Belongs to the peptidase T1B family. UniProt Q9R1P3 1 EQUAL 201 EQUAL Reactome DB_ID: 9751462 1 UniProt:Q9WVJ2 Psmd13 UniProt Q9WVJ2 1 EQUAL 376 EQUAL Reactome DB_ID: 9751478 1 UniProt:Q8BJY1 Psmd5 UniProt Q8BJY1 2 EQUAL 504 EQUAL Reactome DB_ID: 9751434 1 UniProt:P54775 Psmc4 UniProt P54775 1 EQUAL 418 EQUAL Reactome DB_ID: 9751486 1 UniProt:P26516 Psmd7 UniProt P26516 1 EQUAL 324 EQUAL Reactome DB_ID: 9751482 1 UniProt:Q99JI4 Psmd6 UniProt Q99JI4 1 EQUAL 389 EQUAL Reactome DB_ID: 9751450 1 UniProt:Q9Z2X2 Psmd10 UniProt Q9Z2X2 1 EQUAL 226 EQUAL Reactome DB_ID: 9751415 1 UniProt:Q60692 Psmb6 Psmb6 Psmb6 Lmp19 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-hydrolyzing 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.INDUCTION Up-regulated by the antioxidant dithiolethione (D3T) in liver, lung and small intestine (at protein level).SIMILARITY Belongs to the peptidase T1B family. UniProt Q60692 35 EQUAL 239 EQUAL Reactome DB_ID: 9751494 1 UniProt:Q9CR00 Psmd9 UniProt Q9CR00 1 EQUAL 223 EQUAL Reactome DB_ID: 1236877 1 UniProt:Q9Z2U1 Psma5 Psma5 Psma5 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).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 (PubMed:16857966, PubMed:22341445). PSMA5 interacts directly with the PSMG1-PSMG2 heterodimer which promotes 20S proteasome assembly (By similarity).TISSUE SPECIFICITY Detected in liver (at protein level).SIMILARITY Belongs to the peptidase T1A family. UniProt Q9Z2U1 1 EQUAL 241 EQUAL Reactome DB_ID: 9751438 1 UniProt:P62196 Psmc5 UniProt P62196 2 EQUAL 406 EQUAL Reactome DB_ID: 9751454 1 UniProt:Q8BG32 Psmd11 UniProt Q8BG32 2 EQUAL 422 EQUAL Reactome DB_ID: 9751474 1 UniProt:O35226 Psmd4 UniProt O35226 1 EQUAL 377 EQUAL Reactome DB_ID: 9751514 1 UniProt:Q5SSW2 Psme4 UniProt Q5SSW2 1 EQUAL 1843 EQUAL Reactome DB_ID: 9751402 1 UniProt:Q9Z2U0 Psma7 Psma7 Psma7 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).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 (PubMed:16857966, PubMed:22341445). PSMA7 interacts directly with the PSMG1-PSMG2 heterodimer which promotes 20S proteasome assembly (By similarity). Interacts with HIF1A (By similarity). Interacts with RAB7A (By similarity). Interacts with PRKN (By similarity). Interacts with ABL1 and ABL2 (By similarity). Interacts with EMAP2 (By similarity). Interacts with MAVS (By similarity).TISSUE SPECIFICITY Detected in liver (at protein level).INDUCTION Up-regulated in liver tumor tissues.PTM Phosphorylation by ABL1 or ABL2 leads to an inhibition of proteasomal activity and cell cycle transition blocks.SIMILARITY Belongs to the peptidase T1A family. UniProt Q9Z2U0 1 EQUAL 248 EQUAL Reactome DB_ID: 1236812 1 UniProt:P99026 Psmb4 Psmb4 Lmp3 Psmb4 FUNCTION Non-catalytic 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). SMAD1/OAZ1/PSMB4 complex mediates the degradation of the CREBBP/EP300 repressor SNIP1.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 (PubMed:16857966, PubMed:22341445). Forms a ternary complex with SMAD1 and OAZ1 before PSMB4 is incorporated into the 20S proteasome (By similarity). Interacts with PRPF19 (By similarity).TISSUE SPECIFICITY Detected in liver (at protein level).INDUCTION Up-regulated in liver tumor tissues (at protein level).SIMILARITY Belongs to the peptidase T1B family. UniProt P99026 46 EQUAL 264 EQUAL Reactome Database ID Release 78 9751524 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9751524 Reactome R-MMU-68819 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-68819.1 GO 0004175 GO molecular function Reactome Database ID Release 78 9751525 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9751525 Reactome Database ID Release 78 9823944 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823944 Reactome R-MMU-5607724 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607724.1 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. 9362451 Pubmed 1997 The carboxy-terminus of I kappaB alpha determines susceptibility to degradation by the catalytic core of the proteasome Kroll, M Conconi, M Desterro, M J Marin, A Thomas, D Friguet, B Hay, R T Virelizier, J L Arenzana-Seisdedos, F Rodriguez, M S Oncogene 15:1841-50 24854014 Pubmed 2014 Structural Basis for the Ubiquitin-Linkage Specificity and deISGylating activity of SARS-CoV papain-like protease Ratia, Kiira Kilianski, Andrew Báez-Santos, Yahira M Baker, Susan C Mesecar, A PLoS Pathog 10:e1004113 27203180 Pubmed 2016 Recognition of Lys48-Linked Di-ubiquitin and Deubiquitinating Activities of the SARS Coronavirus Papain-like Protease Békés, Miklós van der Heden van Noort, Gerbrand J Ekkebus, Reggy Ovaa, Huib Huang, TT Lima, Christopher D Mol Cell 62:572-85 inferred by electronic annotation IEA GO IEA NFKB1:RELA translocates from the cytosol to the nucleus NFKB1:RELA translocates from the cytosol to the nucleus Released NF-kB complex is transported to the nucleus This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9768248 1 Reactome DB_ID: 9768250 1 NFKB1(1-433):RELA [nucleoplasm] NFKB1(1-433):RELA Reactome DB_ID: 9764019 1 1 EQUAL 551 EQUAL Reactome DB_ID: 9764013 1 1 EQUAL 433 EQUAL Reactome Database ID Release 78 9768250 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9768250 Reactome R-MMU-194047 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-194047.1 Reactome Database ID Release 78 9814112 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9814112 Reactome R-MMU-2730894 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-2730894.1 The released NF-kB transcription factor (p50/p65) with unmasked nuclear localization signal (NLS) moves in to the nucleus. Once in the nucleus, NF-kB binds DNA and regulate the expression of genes encoding cytokines, cytokine receptors, and apoptotic regulators. 17072321 Pubmed 2006 Introduction to NF-kappaB: players, pathways, perspectives Gilmore, T D Oncogene 25:6680-4 inferred by electronic annotation IEA GO IEA Dectin-1 mediated noncanonical NF-kB signaling Dectin-1 mediated noncanonical NF-kB signaling This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Activation of NIK Activation of NIK This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9780422 1 UniProt:Q9WUL6 Map3k14 UniProt Q9WUL6 1 EQUAL 947 EQUAL Reactome DB_ID: 9780422 1 1 EQUAL 947 EQUAL Reactome Database ID Release 78 9823914 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823914 Reactome R-MMU-5607721 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607721.1 The catalytic activity of NF-kB-inducing kinase (NIK) is regulated by structural conformation rather than by phosphorylation events. Under normal conditions NIK may be present in an autoinhibited state in which its constitutively active kinase domain is shielded by the N-terminal inhibitory element and upon receptor induction NIK kinase domain adopts an active conformation, in agreement with its catalytic activity. This catalytically competent conformation is maintained by an N-terminal extension prior to the kinase domain rather than through a phosphorylation event (Liu et al. 2012). NIK, also known as MAP3K14 (MAPK kinase kinase 14), is a serine/threonine kinase in the MAP3K family (Malinin et al. 1997). In unstimulated cells NIK associates with a complex composed of TNF receptor-associated factor 2 (TRAF2), TRAF3 and cellular inhibitor of apoptosis 1 (cIAP1) and cIAP2. This molecular interaction with TRAF-cIAP complex appears to target NIK for ubiquitination and proteasomal degradation. In response to receptor stimulation, TRAF2 or TRAF3, or both are targeted for proteasomal degradation by cIAP-mediated ubiquitination, which triggers the release and stabilization of NIK (Razani et al. 2010). 22718757 Pubmed 2012 Structure of the nuclear factor ?B-inducing kinase (NIK) kinase domain reveals a constitutively active conformation Liu, Jinsong Sudom, Athena Min, Xiaoshan Cao, Z Gao, Xiong Ayres, Merrill Lee, Fei Cao, Ping Johnstone, Sheree Plotnikova, Olga Walker, Nigel Chen, Guoqing Wang, Zhulun J. Biol. Chem. 287:27326-34 9020361 Pubmed 1997 MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1 Malinin, N L Boldin, M P Kovalenko, A V Wallach, D Nature 385:540-4 20501937 Pubmed 2010 Negative feedback in noncanonical NF-kappaB signaling modulates NIK stability through IKKalpha-mediated phosphorylation Razani, Bahram Zarnegar, Brian Ytterberg, AJ Shiba, Travis Dempsey, Paul W Ware, Carl F Loo, Joseph A Cheng, Genhong Sci Signal 3:ra41 20501935 Pubmed 2010 Controlling the fate of NIK: a central stage in noncanonical NF-kappaB signaling Sun, Shao-Cong Sci Signal 3:pe18 inferred by electronic annotation IEA GO IEA 2.7.11 Active NIK phosphorylates IKKA dimer Active NIK phosphorylates IKKA dimer This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 4 Reactome DB_ID: 9780422 1 1 EQUAL 947 EQUAL Reactome DB_ID: 9823916 1 IKKA dimer [cytosol] IKKA dimer Reactome DB_ID: 9764050 2 1 EQUAL 745 EQUAL Reactome Database ID Release 78 9823916 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823916 Reactome R-MMU-5607705 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607705.1 Reactome DB_ID: 29370 4 Reactome DB_ID: 9823902 1 Active NIK:p-S176,180-IKKA dimer [cytosol] Active NIK:p-S176,180-IKKA dimer Reactome DB_ID: 9823900 1 p-S176,S180-IKKA dimer [cytosol] p-S176,S180-IKKA dimer Reactome DB_ID: 9763959 2 O-phospho-L-serine at 176 (in Homo sapiens) 176 EQUAL O-phospho-L-serine at 180 (in Homo sapiens) 180 EQUAL 1 EQUAL 745 EQUAL Reactome Database ID Release 78 9823900 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823900 Reactome R-MMU-5607702 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607702.1 Reactome DB_ID: 9780422 1 1 EQUAL 947 EQUAL Reactome Database ID Release 78 9823902 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823902 Reactome R-MMU-5607681 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607681.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9780422 1 EQUAL 947 EQUAL Reactome Database ID Release 78 9823917 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823917 Reactome Database ID Release 78 9823919 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823919 Reactome R-MMU-5607722 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607722.1 Accumulated NF-kB-inducing kinase (NIK) activates I kappa-B kinase alpha (IKKA) by directly phosphorylating the Ser176 and Ser180 with in the activation loop of IKKA. This phoshorylation is required for IKKA activity (Ling et al. 1998). Besides activating IKKA, NIK also serves as a docking molecule recruiting IKKA to p100 (Xiao et al. 2004). 15140882 Pubmed 2004 Induction of p100 processing by NF-kappaB-inducing kinase involves docking IkappaB kinase alpha (IKKalpha) to p100 and IKKalpha-mediated phosphorylation Xiao, Gutian Fong, Abraham Sun, Shao-Cong J. Biol. Chem. 279:30099-105 9520446 Pubmed 1998 NF-kappaB-inducing kinase activates IKK-alpha by phosphorylation of Ser-176 Ling, L Cao, Z Goeddel, DV Proc Natl Acad Sci U S A 95:3792-7 11520989 Pubmed 2001 Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway Senftleben, U Cao, Y Xiao, G Greten, F R Krähn, G Bonizzi, G Chen, Y Hu, Y Fong, A Sun, S C Karin, M Science 293:1495-9 inferred by electronic annotation IEA GO IEA p100:RELB binds active NIK:p-IKKA dimer p100:RELB binds active NIK:p-IKKA dimer This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9823902 1 Reactome DB_ID: 9823908 1 p100:RELB [cytosol] p100:RELB Reactome DB_ID: 9823906 1 UniProt:Q04863 Relb UniProt Q04863 1 EQUAL 579 EQUAL Reactome DB_ID: 9820009 1 UniProt:Q9WTK5 Nfkb2 UniProt Q9WTK5 1 EQUAL 900 EQUAL Reactome Database ID Release 78 9823908 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823908 Reactome R-MMU-5607703 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607703.1 Reactome DB_ID: 9823910 1 Active NIK:p-S176,180-IKKA dimer:p100:RELB [cytosol] Active NIK:p-S176,180-IKKA dimer:p100:RELB Reactome DB_ID: 9823902 1 Reactome DB_ID: 9823908 1 Reactome Database ID Release 78 9823910 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823910 Reactome R-MMU-5607690 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607690.1 Reactome Database ID Release 78 9823912 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823912 Reactome R-MMU-5607720 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607720.1 NFKB2 (also known as p100) is a member of the NF-kB family of transcription factors. It is synthesised as large precursor with an N-terminal RHD (Rel homology domain) and a C-terminal series of ankyrin repeats that masks the nuclear localization signal of NFKB2/p100 localising it to the cytosol. In resting cells, p100 is associated with RELB (Transcription factor RelB) in the cytosol. Upon cell stimulation, the IkB-like C terminus of p100 is proteolyzed, resulting in RELB-p52 dimers that translocate to the nucleus (Senftleben et al. 2001, Hayden & Ghosh 2004). IKKA (I kappa-B kinase alpha) does not associate directly with p100 but in the presence of NIK (NF-kB-inducing kinase), IKKA stably binds to p100. Serine residues 866 and 870 of p100 are essential for the recruitment of IKKA to p100 by NIK. This interaction is required for p100 phosphorylation and subsequent processing by IKKA (Xiao et al. 2001, 2004). 11239468 Pubmed 2001 NF-kappaB-inducing kinase regulates the processing of NF-kappaB2 p100 Xiao, G Harhaj, E W Sun, S C Mol. Cell 7:401-9 inferred by electronic annotation IEA GO IEA 2.7.11 Active NIK:p-S176,180-IKKA dimer phosphorylates p100:RELB Active NIK:p-S176,180-IKKA dimer phosphorylates p100:RELB This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9823910 1 Reactome DB_ID: 113592 7 Reactome DB_ID: 29370 7 Reactome DB_ID: 9823932 1 Active NIK:p-S176,180-IKKA dimer:p-7S-p100:RELB [cytosol] Active NIK:p-S176,180-IKKA dimer:p-7S-p100:RELB Reactome DB_ID: 9823902 1 Reactome DB_ID: 9823930 1 p-7S-p100:RELB [cytosol] p-7S-p100:RELB Reactome DB_ID: 9823906 1 1 EQUAL 579 EQUAL Reactome DB_ID: 9823928 1 O-phospho-L-serine at 99 (in Homo sapiens) 99 EQUAL O-phospho-L-serine at 108 (in Homo sapiens) 108 EQUAL O-phospho-L-serine at 115 (in Homo sapiens) 115 EQUAL O-phospho-L-serine at 123 (in Homo sapiens) 123 EQUAL O-phospho-L-serine at 866 (in Homo sapiens) 866 EQUAL O-phospho-L-serine at 870 (in Homo sapiens) 870 EQUAL O-phospho-L-serine at 872 (in Homo sapiens) 872 EQUAL 1 EQUAL 900 EQUAL Reactome Database ID Release 78 9823930 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823930 Reactome R-MMU-5607686 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607686.1 Reactome Database ID Release 78 9823932 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823932 Reactome R-MMU-5607698 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607698.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9823910 Reactome Database ID Release 78 9823953 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823953 Reactome Database ID Release 78 9823955 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823955 Reactome R-MMU-5607726 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607726.1 After being recruited into the NIK (NFkB-inducing kinase) complex, activated IKKA (I kappaB kinase alpha) phosphorylates serine residues 99, 108, 115, 123, 866, 870 and 872 located in both N- and C-terminal regions of NFKB2/p100. The phosphorylation of these specific serines is the prerequisite for ubiquitination and subsequent processing of p100. The C-terminal serine residues create a binding site for beta-TRCP (beta-transducinrepeat-containing protein), a ubiquitin E3 ligase (Xiao et al. 2001 & 2004, Liang et al. 2006). 16303288 Pubmed 2006 beta-TrCP binding and processing of NF-kappaB2/p100 involve its phosphorylation at serines 866 and 870 Liang, Chunyang Zhang, Minying Sun, Shao-Cong Cell. Signal. 18:1309-17 inferred by electronic annotation IEA GO IEA SCF-beta-TRCP binds p-7S-p100 in active NIK:p-S176,180-IKKA dimer:p-7S-p100:RELB SCF-beta-TRCP binds p-7S-p100 in active NIK:p-S176,180-IKKA dimer:p-7S-p100:RELB This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9823932 1 Reactome DB_ID: 9795243 1 Reactome DB_ID: 9823934 1 Active NIK:p-176,S180-IKKA dimer:p-7S-p100:SCF-beta-TRCP [cytosol] Active NIK:p-176,S180-IKKA dimer:p-7S-p100:SCF-beta-TRCP Reactome DB_ID: 9823932 1 Reactome DB_ID: 9795243 1 Reactome Database ID Release 78 9823934 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823934 Reactome R-MMU-5607693 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607693.1 Reactome Database ID Release 78 9823936 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823936 Reactome R-MMU-5607723 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607723.1 Phosphorylated C-terminal serines 866, 870 and 872 in NFKB2 creates binding site for beta-TRCP (beta-transducin repeat-containing protein), the receptor subunit of a SCF-type of E3 ubiquitin ligase, SCF beta-TRCP (Liang et al. 2006). The SKP1-CUL1-F-box (SCF) ubiquitin E3 ligase superfamily is the largest family of cullin-RING ligases, with interchangeable F-box proteins orchestrating the trafficking proteins for ubiquitination and degradation (Weathington & Mallampalli 2013). Beta-TRCP is an F-box protein that contains two domains, an F-box motif that binds SKP1 and allows assembly into SKP1-CUL1 complexes and a second protein-protein interaction domain that interacts with phosphorylated serines in NFKB2 (Bai et al. 1996, Skowyra et al. 1997, Patton et al. 1998). 23680451 Pubmed 2013 New insights on the function of SCF ubiquitin E3 ligases in the lung Weathington, Nathaniel M Mallampalli, Rama K Cell. Signal. 25:1792-8 9499404 Pubmed 1998 Cdc53 is a scaffold protein for multiple Cdc34/Skp1/F-box proteincomplexes that regulate cell division and methionine biosynthesis in yeast Patton, E E Willems, A R Sa, D Kuras, L Thomas, D Craig, K L Tyers, M Genes Dev. 12:692-705 8706131 Pubmed 1996 SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box Bai, C Sen, P Hofmann, K Ma, L Goebl, M Harper, JW Elledge, S J Cell 86:263-74 9346238 Pubmed 1997 F-box proteins are receptors that recruit phosphorylated substrates to the SCF ubiquitin-ligase complex Skowyra, D Craig, K L Tyers, M Elledge, S J Harper, JW Cell 91:209-19 15340381 Pubmed 2004 The SCF ubiquitin ligase: insights into a molecular machine Cardozo, Timothy Pagano, Michele Nat. Rev. Mol. Cell Biol. 5:739-51 inferred by electronic annotation IEA GO IEA 6.3.2.19 SCF-beta-TRCP ubiquitinates p-7S-p100:RELB in active NIK:p-176,S180-IKKA dimer:p-7S-p100:SCF-beta-TRCP SCF-beta-TRCP ubiquitinates p-7S-p100:RELB in active NIK:p-176,S180-IKKA dimer:p-7S-p100:SCF-beta-TRCP This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9823934 1 Reactome DB_ID: 9793276 1 UniProt:Q8C878 Uba3 UniProt Q8C878 1 EQUAL 463 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9788366 4 Reactome DB_ID: 9818822 1 UniProt:P61082 Ube2m UniProt P61082 Inter-chain Crosslink via S-(glycyl)-L-cysteine (Cys-Gly) at 111 and 76 (in Homo sapiens) 111 EQUAL S-(glycyl)-L-cysteine (Cys-Gly) ChEBI 24411 modification N-acetyl-L-methionine at 1 (in Homo sapiens) 1 EQUAL N-acetyl-L-methionine [MOD:00058] 1 EQUAL 183 EQUAL Reactome DB_ID: 9823949 1 K48-polyUb-p-7S-p100:RELB [cytosol] K48-polyUb-p-7S-p100:RELB Reactome DB_ID: 9823906 1 1 EQUAL 579 EQUAL Reactome DB_ID: 9823947 1 O-phospho-L-serine at 99 (in Homo sapiens) 99 EQUAL O-phospho-L-serine at 108 (in Homo sapiens) 108 EQUAL O-phospho-L-serine at 115 (in Homo sapiens) 115 EQUAL O-phospho-L-serine at 123 (in Homo sapiens) 123 EQUAL O-phospho-L-serine at 866 (in Homo sapiens) 866 EQUAL O-phospho-L-serine at 870 (in Homo sapiens) 870 EQUAL O-phospho-L-serine at 872 (in Homo sapiens) 872 EQUAL ubiquitinylated lysine (K48polyUb [cytosol]) at 855 (in Homo sapiens) 855 EQUAL 1 EQUAL 900 EQUAL Reactome Database ID Release 78 9823949 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823949 Reactome R-MMU-5607694 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607694.1 Reactome DB_ID: 9793276 1 1 EQUAL 463 EQUAL Reactome DB_ID: 9823902 1 Reactome DB_ID: 9818822 1 Inter-chain Crosslink via S-(glycyl)-L-cysteine (Cys-Gly) at 111 and 76 (in Homo sapiens) 111 EQUAL N-acetyl-L-methionine at 1 (in Homo sapiens) 1 EQUAL 1 EQUAL 183 EQUAL Reactome DB_ID: 9795243 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9823934 Reactome Database ID Release 78 9823950 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823950 Reactome Database ID Release 78 9823952 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823952 Reactome R-MMU-5607725 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607725.1 Ubiquitination of p100 is very specific. Lysine residue K855 has been identified as the anchoring site for ubiquitin and required for signaling mediated processing of p100 to p52. In the presence of SCF-beta-TRCP E3 ligase the ubiquitin (Ub) conjugated to E2 (E2-Ub thioester) is attached to p100 at K855 (Amir et al. 2004). Several rounds of ubiquitin conjugation can produce long chains of ubiquitin moieties (polyubiquitylation), the first of which is covalently bound to p100. At this point the polyubiquitylated p100 is committed to association with, and unfolding and processing by, the 26S proteasome (Pickart & Cohen 2004).<br>Efficient ubiquitination of phosphorylated p100 by SCF-beta-TRCP E3 ligase also requires the presence of the components of the NEDD8 pathway: UBA3 (NEDD8-activating enzyme E1 catalytic subunit), UBC12 (NEDD8-conjugating enzyme Ubc12 (E2)), NEDD8 (Neural precursor cell expressed developmentally down-regulated protein 8). NEDD8 binds and promotes a conformational change in CUL1 that may result in efficient formation of an E2-E3 complex, thus stimulating SCF complexes activity (Kawakami et al. 2001, Morimoto et al. 2000, Read et al. 2000). 11483504 Pubmed 2001 NEDD8 recruits E2-ubiquitin to SCF E3 ligase Kawakami, T Chiba, T Suzuki, T Iwai, K Yamanaka, K Minato, N Suzuki, H Shimbara, N Hidaka, Yuji Osaka, F Omata, M Tanaka, K EMBO J. 20:4003-12 10772955 Pubmed 2000 Modification of cullin-1 by ubiquitin-like protein Nedd8 enhances the activity of SCF(skp2) toward p27(kip1) Morimoto, M Nishida, T Honda, R Yasuda, H Biochem. Biophys. Res. Commun. 270:1093-6 10713156 Pubmed 2000 Nedd8 modification of cul-1 activates SCF(beta(TrCP))-dependent ubiquitination of IkappaBalpha Read, M A Brownell, J E Gladysheva, T B Hottelet, M Parent, L A Coggins, M B Pierce, J W Podust, VN Luo, R S Chau, V Palombella, V J Mol. Cell. Biol. 20:2326-33 14676825 Pubmed 2004 Mechanism of processing of the NF-kappa B2 p100 precursor: identification of the specific polyubiquitin chain-anchoring lysine residue and analysis of the role of NEDD8-modification on the SCF(beta-TrCP) ubiquitin ligase Amir, Ruthie E Haecker, Hans Karin, M Ciechanover, Aaron Oncogene 23:2540-7 14990998 Pubmed 2004 Proteasomes and their kin: proteases in the machine age Pickart, Cecile M Cohen, Robert E Nat. Rev. Mol. Cell Biol. 5:177-87 inferred by electronic annotation IEA GO IEA 26S proteasome processes p-7S-p100:RELB to form p52:RELB 26S proteasome processes p-7S-p100:RELB to form p52:RELB This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9823949 1 Reactome DB_ID: 9823962 1 p52:RELB [cytosol] p52:RELB Reactome DB_ID: 9823906 1 1 EQUAL 579 EQUAL Reactome DB_ID: 9763923 1 1 EQUAL 454 EQUAL Reactome Database ID Release 78 9823962 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823962 Reactome R-MMU-5607699 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607699.1 Converted from EntitySet in Reactome Reactome DB_ID: 9751385 4 Ub [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Rps27a [cytosol] Ubiquitin (Uba52) [cytosol] Ubiquitin (Ubb 1) [cytosol] Ubiquitin (Ubb 4) [cytosol] Ubb [cytosol] Ubiquitin (Ubb 3) [cytosol] Ubiquitin (Pps27a) [cytosol] Ubiquitin (Ubb 2) [cytosol] PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9751524 Reactome Database ID Release 78 9823964 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823964 Reactome R-MMU-5607731 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607731.1 Once polyubiquitinated, the precursor p100 undergoes 26S proteasome mediated processing to form the mature p52 NF-kB subuunit. Different from complete degradation of other IkB proteins, the proteasome-mediated degradation of p100 only leads to loss of their C-terminal ankyrin repeat regions, leaving intact N-termini, p52 respectively (Amir et al. 2004). inferred by electronic annotation IEA GO IEA p52:RELB translocates from cytosol to nucleus p52:RELB translocates from cytosol to nucleus This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9823962 1 Reactome DB_ID: 9824027 1 p52:RELB [nucleoplasm] p52:RELB Reactome DB_ID: 9824025 1 1 EQUAL 579 EQUAL Reactome DB_ID: 9764015 1 1 EQUAL 454 EQUAL Reactome Database ID Release 78 9824027 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824027 Reactome R-MMU-5607679 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607679.1 Reactome Database ID Release 78 9824029 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824029 Reactome R-MMU-5607741 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607741.1 Following 26S-proteasomal processing, NFKB2 p52:RELB dimer is translocated from cytosol into the nucleus where it stimulates expression of target genes (Lin & Karin 2003). Dectin-1 induced RELB-p52 triggers the transcription of chemokines C-C motif chemokine 17 (CCL17) and CCL22 and repression of interleukin 12B (IL12B) transcription (Gringhuis et al. 2009). 19122653 Pubmed 2009 Dectin-1 directs T helper cell differentiation by controlling noncanonical NF-kappaB activation through Raf-1 and Syk Gringhuis, Sonja I den Dunnen, Jeroen Litjens, Manja van der Vlist, Michiel Wevers, Brigitte Bruijns, Sven C M Geijtenbeek, Teunis B H Nat. Immunol. 10:203-13 12654254 Pubmed 2003 NF-kappaB in cancer: a marked target Lin, Anning Karin, M Semin. Cancer Biol. 13:107-14 8921937 Pubmed 1996 Differential nuclear localization of p50, p52, and RelB proteins in human accessory cells of the immune response in situ Feuillard, J Körner, M Israël, A Vassy, J Raphael, M Eur. J. Immunol. 26:2547-51 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 9862632 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9862632 Reactome R-MMU-5607761 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607761.1 In addition to the activation of canonical NF-kB subunits, activation of SYK pathway by Dectin-1 leads to the induction of the non-canonical NF-kB pathway, which mediates the nuclear translocation of RELB-p52 dimers through the successive activation of NF-kB-inducing kinase (NIK) and IkB kinase-alpha (IKKa) (Geijtenbeek & Gringhuis 2009, Gringhuis et al. 2009). Noncanonical activity tends to build more slowly and remain sustained several hours longer than does the activation of canonical NF-kB. The noncanonical NF-kB pathway is characterized by the post-translational processing of NFKB2 (Nuclear factor NF-kappa-B) p100 subunit to the mature p52 subunit. This subsequently leads to nuclear translocation of p52:RELB (Transcription factor RelB) complexes to induce cytokine expression of some genes (C-C motif chemokine 17 (CCL17) and CCL22) and transcriptional repression of others (IL12B) (Gringhuis et al. 2009, Geijtenbeek & Gringhuis 2009, Plato et al. 2013). 19521399 Pubmed 2009 Signalling through C-type lectin receptors: shaping immune responses Geijtenbeek, Teunis B H Gringhuis, Sonja I Nat. Rev. Immunol. 9:465-79 19302050 Pubmed 2009 Regulation and function of NF-kappaB transcription factors in the immune system Vallabhapurapu, Sivakumar Karin, M Annu. Rev. Immunol. 27:693-733 inferred by electronic annotation IEA GO IEA CLEC7A/inflammasome pathway CLEC7A/inflammasome pathway This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Caspase-8 binds MALT Caspase-8 binds MALT This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9760018 1 active caspase-8 [cytosol] active caspase-8 Reactome DB_ID: 9760016 2 Caspase-8 dimer [cytosol] Caspase-8 dimer Reactome DB_ID: 9760014 1 UniProt:O89110 Casp8 UniProt O89110 385 EQUAL 479 EQUAL Reactome DB_ID: 9760012 1 217 EQUAL 374 EQUAL Reactome Database ID Release 78 9760016 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9760016 Reactome R-MMU-139950 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-139950.1 Reactome Database ID Release 78 9760018 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9760018 Reactome R-MMU-2562550 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-2562550.1 Reactome DB_ID: 9771352 1 1 EQUAL 824 EQUAL Reactome DB_ID: 9827113 1 MALT1:active caspase-8 [cytosol] MALT1:active caspase-8 Reactome DB_ID: 9760018 1 Reactome DB_ID: 9771352 1 1 EQUAL 824 EQUAL Reactome Database ID Release 78 9827113 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9827113 Reactome R-MMU-5660654 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5660654.1 Reactome Database ID Release 78 9827122 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9827122 Reactome R-MMU-5660665 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5660665.1 After CLEC7A (dectin-1) triggering, MALT1 and caspase-8 associate to form BCL10-MALT1-Caspase-8 complex. MALT1 has a crucial dual role in the expression of IL1B by CLEC7A. It is involved in the transcription of IL1B by activating NF-kB and the other role in processing of pro-IL1B by mediating the formation and activation of a MALT1-caspase8-ASC (adaptor protein apoptosis-associated speck-like protein containing a CARD) complex (Gringhuis et al. 2012). The paracaspase domain of MALT1, in a protease-independent manner, induces caspase-8 activation through direct association (Kawadler et al. 2008). 18691973 Pubmed 2008 The paracaspase MALT1 controls caspase-8 activation during lymphocyte proliferation Kawadler, Holli Gantz, Mary A Riley, James L Yang, X Mol. Cell 31:415-21 22267217 Pubmed 2012 Dectin-1 is an extracellular pathogen sensor for the induction and processing of IL-1? via a noncanonical caspase-8 inflammasome Gringhuis, Sonja I Kaptein, Tanja M Wevers, Brigitte A Theelen, Bart van der Vlist, Michiel Boekhout, Teun Geijtenbeek, Teunis B H Nat. Immunol. 13:246-54 inferred by electronic annotation IEA GO IEA ASC binds Caspase-8 complex ASC binds Caspase-8 complex This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9787752 1 UniProt:Q9EPB4 Pycard Pycard Asc Pycard FUNCTION Functions as key mediator in apoptosis and inflammation. Promotes caspase-mediated apoptosis involving predominantly caspase-8 and also caspase-9 in a probable cell type-specific manner. Involved in activation of the mitochondrial apoptotic pathway, promotes caspase-8-dependent proteolytic maturation of BID independently of FADD in certain cell types and also mediates mitochondrial translocation of BAX and activates BAX-dependent apoptosis coupled to activation of caspase-9, -2 and -3. Involved in macrophage pyroptosis, a caspase-1-dependent inflammatory form of cell death and is the major constituent of the ASC pyroptosome which forms upon potassium depletion and rapidly recruits and activates caspase-1. In innate immune response believed to act as an integral adapter in the assembly of the inflammasome which activates caspase-1 leading to processing and secretion of proinflammatory cytokines. The function as activating adapter in different types of inflammasomes is mediated by the pyrin and CARD domains and their homotypic interactions. Required for recruitment of caspase-1 to inflammasomes containing certain pattern recognition receptors, such as NLRP2, NLRP3, AIM2 and probably IFI16. In the NLRP1 and NLRC4 inflammasomes seems not be required but facilitates the processing of procaspase-1. In cooperation with NOD2 involved in an inflammasome activated by bacterial muramyl dipeptide leading to caspase-1 activation. May be involved in DDX58-triggered proinflammatory responses and inflammasome activation. In collaboration with AIM2 which detects cytosolic double-stranded DNA may also be involved in a caspase-1-independent cell death that involves caspase-8. In adaptive immunity may be involved in maturation of dendritic cells to stimulate T-cell immunity and in cytoskeletal rearrangements coupled to chemotaxis and antigen uptake may be involved in post-transcriptional regulation of the guanine nucleotide exchange factor DOCK2; the latter function is proposed to involve the nuclear form. Also involved in transcriptional activation of cytokines and chemokines independent of the inflammasome; this function may involve AP-1, NF-kappa-B, MAPK and caspase-8 signaling pathways. For regulation of NF-kappa-B activating and inhibiting functions have been reported. Modulates NF-kappa-B induction at the level of the IKK complex by inhibiting kinase activity of CHUK and IKBK. Proposed to compete with RIPK2 for association with CASP1 thereby down-regulating CASP1-mediated RIPK2-dependent NF-kappa-B activation and activating interleukin-1 beta processing. Modulates host resistance to DNA virus infection, probably by inducing the cleavage of and inactivating CGAS in presence of cytoplasmic double-stranded DNA (PubMed:28314590).SUBUNIT Self-associates; enforced oligomerization induces apoptosis, NF-kappa-B regulation and interleukin-1 beta secretion (By similarity). Homooligomers can form disk-like particles of approximately 12 nm diameter and approximately 1 nm height (By similarity). Component of several inflammasomes containing one pattern recognition receptor/sensor, such as NLRP2, NLRP3, NLRC4, AIM2, MEFV or NOD2, and probably NLRC4, NLRP12 or IFI16 (By similarity). Major component of the ASC pyroptosome, a 1-2 um supramolecular assembly (one per macrophage cell) which consists of oligomerized PYCARD dimers and CASP1 (By similarity). Interacts with CASP1 (precursor form); the interaction induces activation of CASP1 leading to the processing of interleukin-1 beta; PYCARD competes with RIPK2 for binding to CASP1 (By similarity). Interacts with NLRP3; the interaction requires the homooligomerization of NLRP3 (By similarity). Interacts with NLRP2, NLRC4, MEFV, CARD16, AIM2, IFI16, NOD2, DDX58, RIPK2, PYDC1, PYDC2, NLRP10, CHUK, IKBKB and BAX (By similarity). Interacts with CASP8 (PubMed:22555457).TISSUE SPECIFICITY Expressed in small intestine, colon, thymus, spleen, brain, heart, skeletal muscle, kidney, lung and liver.DEVELOPMENTAL STAGE Strongly expressed at 9.5 dpc in the telencephalon, thalamic areas of the diencephalon, heart and liver.DOMAIN The CARD domain mediates interaction with CASP1 and NLRC4.DOMAIN The pyrin domain mediates homotypic interactions with pyrin domains of proteins such as of NLRP3, PYDC1, PYDC2 and AIM2.PTM Phosphorylated.DISRUPTION PHENOTYPE Increased resistance to endotoxic shock and severe defects in caspase-1 activation and interleukin-1 beta and interleukin-18 production in macrophages in response to several pro-inflammatory molecules (PubMed:15190255, PubMed:15507117). Mutants are resitant to vaccinia virus (VACV) but not vesicular somatitis virus (VSV) infection. They show lower viral loads in the lungs compared to wild type mice, they produce higher levels of type I IFN, IL6 and RSAD2/Viperin after VCAV INFECTION (PubMed:28314590). UniProt Q9EPB4 1 EQUAL 195 EQUAL Reactome DB_ID: 9827113 1 Reactome DB_ID: 9827115 1 MALT1 oligomers:active caspase-8:ASC [cytosol] MALT1 oligomers:active caspase-8:ASC Reactome DB_ID: 9787752 1 1 EQUAL 195 EQUAL Reactome DB_ID: 9827113 1 Reactome Database ID Release 78 9827115 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9827115 Reactome R-MMU-5660653 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5660653.1 Reactome Database ID Release 78 9827117 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9827117 Reactome R-MMU-5660662 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5660662.1 ASC (adaptor protein apoptosis-associated speck-like protein containing a CARD) is a pro-apoptotic protein containing a pyrin domain (PD) and a caspase-recruitment domain (CARD). ASC with its PD domain physically interacts with caspase-8. Formation of the MALT1–caspase-8 complex is a prerequisite for the association of caspase-8 with ASC. ASC is necessary for the recruitment of pro-IL1B into the proximity of activated caspase-8 (Gringhuis et al. 2012). 12646168 Pubmed 2003 ASC is an activating adaptor for NF-kappa B and caspase-8-dependent apoptosis Masumoto, Junya Dowds, Theresa A Schaner, Philip Chen, Felicia F Ogura, Yasunori Li, Mu Zhu, Li Katsuyama, Tsutomu Sagara, Junji Taniguchi, Shun'ichiro Gumucio, Deborah L Núñez, Gabriel Inohara, Naohiro Biochem. Biophys. Res. Commun. 303:69-73 inferred by electronic annotation IEA GO IEA 3.4.22.41 3.4.22.40 3.4.22.34 3.4.22.8 3.4.22.28 3.4.22.16 3.4.22.27 3.4.22.38 3.4.22.1 3.4.22.15 3.4.22.14 Caspase-8 cleaves IL1B precursor Caspase-8 cleaves IL1B precursor This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9785067 1 UniProt:P10749 Il1b UniProt P10749 1 EQUAL 269 EQUAL Reactome DB_ID: 9785073 1 117 EQUAL 269 EQUAL Reactome DB_ID: 9785079 1 1 EQUAL 116 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9827115 GO 0004197 GO molecular function Reactome Database ID Release 78 9827118 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9827118 Reactome Database ID Release 78 9827120 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9827120 Reactome R-MMU-5660663 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5660663.1 Interleukin-1beta (IL1B) is secreted as inactive precursor, and the processing of pro-IL1B depends on cleavage by proteases. Active caspase-8 inflammasome is capable of cleaving the 31-kDa inactive IL1B precursor form into the bioactive 17-kDa IL1B. 1574116 Pubmed 1992 A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes Thornberry, NA Bull, HG Calaycay, JR Chapman, KT Howard, AD Kostura, MJ Miller, Douglas K Molineaux, SM Weidner, JR Aunins, J Nature 356:768-74 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 9862722 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9862722 Reactome R-MMU-5660668 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5660668.1 Antifungal immunity through the induction of T-helper 17 cells (TH17) responses requires the production of mature, active interleukin-1beta (IL1B). CLEC7A (dectin-1) through the SYK route induces activation of NF-kB and transcription of the gene encoding pro-IL1B via the CARD9-BCL10-MALT1 complex as well as the formation and activation of a MALT1-caspase-8-ASC complex that mediated the processing of pro-IL1B. The inactive precursor pro-IL1B has to be processed into mature bioactive form of IL1B and is usually mediated by inflammatory cysteine protease caspase-1. Gringhuis et al. showed that CLEC7A mediated processing of IL1B occurs through two distinct mechanisms: CLEC7A triggering induced a primary noncanonical caspase-8 inflammasome for pro-IL1B processing that was independent of caspase-1 activity, whereas some fungi triggered a second additional mechanism that required activation of the NLRP3/caspase 1 inflammasome. Unlike the canonical caspase-1 inflammasome, CLEC7A mediated noncanonical caspase-8-dependent inflammasome is independent of pathogen internalization. CLEC7A/inflammasome pathway enables the host immune system to mount a protective TH17 response against fungi and bacterial infection (Gringhuis et al. 2012, Cheng et al. 2011). 21531876 Pubmed 2011 The dectin-1/inflammasome pathway is responsible for the induction of protective T-helper 17 responses that discriminate between yeasts and hyphae of Candida albicans Cheng, Shih-Chin van de Veerdonk, Frank L Lenardon, Megan Stoffels, Monique Plantinga, Theo Smeekens, Sanne Rizzetto, Lisa Mukaremera, Liliane Preechasuth, Kanya Cavalieri, Duccio Kanneganti, Thirumala Devi van der Meer, Jos W M Kullberg, Bart Jan Joosten, Leo A B Gow, Neil A R Netea, Mihai G J. Leukoc. Biol. 90:357-66 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 9861322 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9861322 Reactome R-MMU-5607764 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5607764.1 CLEC7A (also known as Dectin-1) is a pattern-recognition receptor (PRR) expressed by myeloid cells (macrophages, dendritic cells and neutrophils) that detects pathogens by binding to beta-1,3-glucans in fungal cell walls and triggers direct innate immune responses to fungal and bacterial infections. CLEC7A belongs to thetype-II C-type lectin receptor (CLR) family that can mediate its own intracellular signaling. Upon binding particulate beta-1,3-glucans, CLEC7A mediates intracellular signalling through its cytoplasmic immunoreceptor tyrosine-based activation motif (ITAM)-like motif (Brown 2006). CLEC7A signaling can induce the production of various cytokines and chemokines, including tumour-necrosis factor (TNF), CXC-chemokine ligand 2 (CXCL2, also known as MIP2), interleukin-1beta (IL-1b), IL-2, IL-10 and IL-12 (Brown et al. 2003), it also triggers phagocytosis and stimulates the production of reactive oxygen species (ROS), thus contributing to microbial killing (Gantner et al. 2003, Herre et al. 2004, Underhill et al. 2005, Goodridge at al. 2011, Reid et al. 2009). These cellular responses mediated by CLEC7A rely on both Syk-dependent and Syk-independent signaling cascades. The pathways leading to the Syk-dependent activation of NF-kB can be categorised into both canonical and non-canonical routes (Gringhuis et al. 2009). Activation of the canonical NF-kB pathway is essential for innate immunity, whereas activation of the non-canonical pathway is involved in lymphoid organ development and adaptive immunity (Plato et al. 2013). 19223162 Pubmed 2009 Pattern recognition: recent insights from Dectin-1 Reid, Delyth M Gow, Neil A R Brown, Gordon D Curr. Opin. Immunol. 21:30-7 12719478 Pubmed 2003 Dectin-1 mediates the biological effects of beta-glucans Brown, Gordon D Herre, Jurgen Williams, David L Willment, Janet A Marshall, Andrew S J Gordon, Siamon J. Exp. Med. 197:1119-24 15956283 Pubmed 2005 Dectin-1 activates Syk tyrosine kinase in a dynamic subset of macrophages for reactive oxygen production Underhill, David M Rossnagle, Eddie Lowell, Clifford A Simmons, Randi M Blood 106:2543-50 12719479 Pubmed 2003 Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2 Gantner, Benjamin N Simmons, Randi M Canavera, Scott J Akira, Shizuo Underhill, David M J. Exp. Med. 197:1107-17 14698225 Pubmed 2004 Dectin-1 and its role in the recognition of beta-glucans by macrophages Herre, Jürgen Gordon, Siamon Brown, Gordon D Mol. Immunol. 40:869-76 inferred by electronic annotation IEA GO IEA Dectin-2 family Dectin-2 family This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> CLEC4D binds mycobacterial trehalose-6,6'-dimycolate (TDM) CLEC4D binds mycobacterial trehalose-6,6'-dimycolate (TDM) This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9824810 1 CLEC4D:FCER1G dimer [plasma membrane] CLEC4D:FCER1G dimer Reactome DB_ID: 9824808 1 UniProt:Q9Z2H6 Clec4d UniProt Q9Z2H6 1 EQUAL 215 EQUAL Reactome DB_ID: 9759803 1 FCERIG dimer [plasma membrane] FCERIG dimer Reactome DB_ID: 5621125 2 UniProt:P20491 Fcer1g Fcer1g Fcer1g Fce1g FUNCTION Adapter protein containing an immunoreceptor tyrosine-based activation motif (ITAM) that transduces activation signals from various immunoreceptors. As a component of the high-affinity immunoglobulin E (IgE) receptor, mediates allergic inflammatory signaling in mast cells (PubMed:14764707). As a constitutive component of interleukin-3 receptor complex, selectively mediates interleukin 4/IL4 production by basophils, priming T-cells toward effector T-helper 2 subset (PubMed:19098920). Associates with pattern recognition receptors CLEC4D and CLEC4E to form a functional signaling complex in myeloid cells. Binding of mycobacterial trehalose 6,6'-dimycolate (TDM) to this receptor complex leads to phosphorylation of ITAM, triggering activation of SYK, CARD9 and NF-kappa-B, consequently driving maturation of antigen-presenting cells and shaping antigen-specific priming of T-cells toward effector T-helper 1 and T-helper 17 cell subtypes (PubMed:23602766) (Probable). May function cooperatively with other activating receptors. Functionally linked to integrin beta-2/ITGB2-mediated neutrophil activation (PubMed:17086186). Also involved in integrin alpha-2/ITGA2-mediated platelet activation (PubMed:9171347).SUBUNIT IgE Fc receptor is a tetramer of an alpha chain, a beta chain, and two disulfide linked gamma chains. Associates with FCGR1A; forms a functional signaling complex (By similarity). Associates with CLEC6A (PubMed:17050534). Interacts with CLEC4E (PubMed:23602766, PubMed:18776906). Interacts (via ITAM domain) with SYK (via SH2 domains); activates SYK, enabling integrin-mediated activation of neutrophils and macrophages (PubMed:17086186). Interacts with CSF2RB and recruits SYK in response to IL3 stimulation; this interaction is direct (PubMed:19098920). Interacts with CD300LH; the interaction may be indirect (PubMed:20817736). Interacts with CD300LD (PubMed:20817736). Interacts with TARM1 (By similarity).TISSUE SPECIFICITY Expressed in mast cells (at protein level) (PubMed:14764707). Expressed in basophils (at protein level) (PubMed:19098920).DISRUPTION PHENOTYPE Knockout mice are resistant to IgE-mediated systemic anaphylaxis.SIMILARITY Belongs to the CD3Z/FCER1G family. UniProt P20491 19 EQUAL 86 EQUAL Reactome Database ID Release 78 9759803 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759803 Reactome R-MMU-210223 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-210223.1 Reactome Database ID Release 78 9824810 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824810 Reactome R-MMU-5621148 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5621148.1 Reactome DB_ID: 5621138 1 trehalose 6,6'-dimycolate [ChEBI:82624] trehalose 6,6'-dimycolate ChEBI 82624 Reactome DB_ID: 9824812 1 CLEC4D:FCER1G dimer:TDM [plasma membrane] CLEC4D:FCER1G dimer:TDM Reactome DB_ID: 9824810 1 Reactome DB_ID: 5621138 1 Reactome Database ID Release 78 9824812 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824812 Reactome R-MMU-5621151 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5621151.1 Reactome Database ID Release 78 9824814 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824814 Reactome R-MMU-5621353 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5621353.1 CLEC4D (Macrophage C-type lectin (MCL)) is a member of the C-type lectin that recognises mycobacterial trehalose-6,6'-dimycolate (TDM) or cord factor likely to arise from gene duplication of CLEC4E (also called Minicle). CLEC4D is constitutively expressed on myeloid cells. It couples with FCERG (High affinity immunoglobulin epsilon receptor subunit gamma) and acts as an activating receptor (Miyake et al. 2013). 23602766 Pubmed 2013 C-type lectin MCL is an FcR?-coupled receptor that mediates the adjuvanticity of mycobacterial cord factor Miyake, Yasunobu Toyonaga, Kenji Mori, Daiki Kakuta, S Hoshino, Yoshihiko Oyamada, Akiko Yamada, Hisakata Ono, Ken-Ichiro Suyama, Mikita Iwakura, Y Yoshikai, Yasunobu Yamasaki, Sho Immunity 38:1050-62 inferred by electronic annotation IEA GO IEA CLEC4E binds alpha-mannan and trehalose-6-6'-dimycolate CLEC4E binds alpha-mannan and trehalose-6-6'-dimycolate This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9824816 1 CLEC4E:FCER1G dimer [plasma membrane] CLEC4E:FCER1G dimer Reactome DB_ID: 9824785 1 UniProt:Q9R0Q8 Clec4e UniProt Q9R0Q8 1 EQUAL 219 EQUAL Reactome DB_ID: 9759803 1 Reactome Database ID Release 78 9824816 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824816 Reactome R-MMU-5621137 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5621137.1 Converted from EntitySet in Reactome Reactome DB_ID: 9038391 1 TDM,alpha-mannan [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity alpha-mannan [plasma membrane] TDM [plasma membrane] ChEBI 28808 Reactome DB_ID: 9824818 1 CLEC4E:FCER1G dimer:TDM,alpha-mannan [plasma membrane] CLEC4E:FCER1G dimer:TDM,alpha-mannan Reactome DB_ID: 9824816 1 Converted from EntitySet in Reactome Reactome DB_ID: 9038391 1 Reactome Database ID Release 78 9824818 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824818 Reactome R-MMU-5621144 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5621144.1 Reactome Database ID Release 78 9824820 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824820 Reactome R-MMU-5621354 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5621354.1 CLEC4E (also called Mincle or CLECSF9) is a C-type lectin receptor (CLR) expressed in activated macrophages and dendritic cells (DCs) in response to several inflammatory stimuli, including LPS, TNF, IL6, IFN-gamma and cellular stresses (Matsumoto et al. 1999). Like the other activating receptors in the Dectin-2 family, CLEC4E is coupled with the FCERG (High affinity immunoglobulin epsilon receptor subunit gamma) to transduce intracellular signalling (Yamasaki et al. 2008). CLEC4E possesses a typical carbohydrate recognition domain (CRD) containing an EPN (Glu-Pro-Asn) motif which is capable of recognising several types of carbohydrates, particularly those containing alpha-mannose. CLEC4E can recognise fungal (Candida albicans and Malassezia), mycobacterial (trehalose-6,6?-dimycolate (TDM)) and necrotic cell ligands implicating this receptor in anti-microbial immunity and homeostasis (Schoenen et al. 2010, Yamasaki et al. 2009, Graham & Brown. 2009). 19665392 Pubmed 2009 The Dectin-2 family of C-type lectins in immunity and homeostasis Graham, Lisa M Brown, Gordon D Cytokine 48:148-55 19171887 Pubmed 2009 C-type lectin Mincle is an activating receptor for pathogenic fungus, Malassezia Yamasaki, Sho Matsumoto, Makoto Takeuchi, O Matsuzawa, Tetsuhiro Ishikawa, Eri Sakuma, Machie Tateno, Hiroaki Uno, Jun Hirabayashi, Jun Mikami, Yuzuru Takeda, Kiyoshi Akira, Shizuo Saito, Takashi Proc. Natl. Acad. Sci. U.S.A. 106:1897-902 18776906 Pubmed 2008 Mincle is an ITAM-coupled activating receptor that senses damaged cells Yamasaki, Sho Ishikawa, Eri Sakuma, Machie Hara, Hiromitsu Ogata, Koji Saito, Takashi Nat. Immunol. 9:1179-88 20164423 Pubmed 2010 Cutting edge: Mincle is essential for recognition and adjuvanticity of the mycobacterial cord factor and its synthetic analog trehalose-dibehenate Schoenen, Hanne Bodendorfer, Barbara Hitchens, Kelly Manzanero, Silvia Werninghaus, Kerstin Nimmerjahn, Falk Agger, Else Marie Stenger, Steffen Andersen, Peter Ruland, Jürgen Brown, Gordon D Wells, Christine Lang, Roland J. Immunol. 184:2756-60 10528209 Pubmed 1999 A novel LPS-inducible C-type lectin is a transcriptional target of NF-IL6 in macrophages Matsumoto, M Tanaka, T Kaisho, T Sanjo, H Copeland, N G Gilbert, D J Jenkins, N A Akira, S J. Immunol. 163:5039-48 18490740 Pubmed 2008 The macrophage-inducible C-type lectin, mincle, is an essential component of the innate immune response to Candida albicans Wells, Christine A Salvage-Jones, Judith A Li, Xin Hitchens, Kelly Butcher, Suzanne Murray, Rachael Z Beckhouse, Anthony G Lo, Yu-Lan-Sandra Manzanero, Silvia Cobbold, Christian Schroder, K Ma, Bo Orr, Sally Stewart, Lauren Lebus, Daniel Sobieszczuk, Peter Hume, David A Stow, Jennifer Blanchard, Helen Ashman, Robert B J. Immunol. 180:7404-13 inferred by electronic annotation IEA GO IEA 2.7.10 LYN and FYN phosphorylate FCER1G in CLEC6A:FCERG and CLEC4E:FCERG LYN and FYN phosphorylate FCER1G in CLEC6A:FCERG and CLEC4E:FCERG This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9824826 1 pathogens:CLEC6A,CLEC4E:FCER1G dimer [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: 113592 2 Reactome DB_ID: 29370 2 Converted from EntitySet in Reactome Reactome DB_ID: 9824798 1 pathogens:CLEC6A,CLEC4E:p-Y65,Y76-FCER1G dimer [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: 9824828 FYN, LYN [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Fyn [cytosol] Lyn [cytosol] UniProt P39688 UniProt P25911 Reactome Database ID Release 78 9824829 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824829 Reactome Database ID Release 78 9824831 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824831 Reactome R-MMU-5621355 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5621355.1 Ligation of CLEC6A (C-type lectin domain family 6 member A/Dectin-2) and CLEC4E (Mincle) with their appropriate ligands trigger the tyrosine phosphorylation of the immune receptor tyrosine-based activation motif (ITAM) in the cytoplasmic tail of FCER1G chain. Tyrosine Y65 and Y76 in the ITAM are phosphorylated and this phosphorylation is mediated by Src kinases Lyn and Fyn (Sato et al. 2006, Yamasaki et al. 2008, Quek et al. 1998). 11110698 Pubmed 2000 Fyn and Lyn phosphorylate the Fc receptor gamma chain downstream of glycoprotein VI in murine platelets, and Lyn regulates a novel feedback pathway Quek, L S Pasquet, J M Hers, I Cornall, R Knight, G Barnes, M Hibbs, M L Dunn, A R Lowell, C A Watson, S P Blood 96:4246-53 17050534 Pubmed 2006 Dectin-2 is a pattern recognition receptor for fungi that couples with the Fc receptor gamma chain to induce innate immune responses Sato, Kota Yang, Xiao-li Yudate, Tatsuo Chung, Jin-Sung Wu, Jianming Luby-Phelps, Kate Kimberly, Robert P Underhill, David Cruz, Ponciano D Ariizumi, Kiyoshi J. Biol. Chem. 281:38854-66 inferred by electronic annotation IEA GO IEA SYK binds to p-Y65,Y76-FCER1G SYK binds to p-Y65,Y76-FCER1G This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9824798 1 Reactome DB_ID: 9759903 1 UniProt:P48025 Syk Syk ptk72 Syk Sykb FUNCTION Non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immunoreceptors like the B-cell receptor (BCR). Regulates several biological processes including innate and adaptive immunity, cell adhesion, osteoclast maturation, platelet activation and vascular development. Assembles into signaling complexes with activated receptors at the plasma membrane via interaction between its SH2 domains and the receptor tyrosine-phosphorylated ITAM domains. The association with the receptor can also be indirect and mediated by adapter proteins containing ITAM or partial hemITAM domains. The phosphorylation of the ITAM domains is generally mediated by SRC subfamily kinases upon engagement of the receptor. More rarely signal transduction via SYK could be ITAM-independent. Direct downstream effectors phosphorylated by SYK include VAV1, PLCG1, PI-3-kinase, LCP2 and BLNK. Initially identified as essential in B-cell receptor (BCR) signaling, it is necessary for the maturation of B-cells most probably at the pro-B to pre-B transition. Activated upon BCR engagement, it phosphorylates and activates BLNK an adapter linking the activated BCR to downstream signaling adapters and effectors. It also phosphorylates and activates PLCG1 and the PKC signaling pathway. It also phosphorylates BTK and regulates its activity in B-cell antigen receptor (BCR)-coupled signaling. In addition to its function downstream of BCR plays also a role in T-cell receptor signaling. Plays also a crucial role in the innate immune response to fungal, bacterial and viral pathogens. It is for instance activated by the membrane lectin CLEC7A. Upon stimulation by fungal proteins, CLEC7A together with SYK activates immune cells inducing the production of ROS. Also activates the inflammasome and NF-kappa-B-mediated transcription of chemokines and cytokines in presence of pathogens. Regulates neutrophil degranulation and phagocytosis through activation of the MAPK signaling cascade. Required for the stimulation of neutrophil phagocytosis by IL15 (By similarity). Also mediates the activation of dendritic cells by cell necrosis stimuli. Also involved in mast cells activation. Involved in interleukin-3/IL3-mediated signaling pathway in basophils (PubMed:19098920). Also functions downstream of receptors mediating cell adhesion. Relays for instance, integrin-mediated neutrophils and macrophages activation and P-selectin receptor/SELPG-mediated recruitment of leukocytes to inflammatory loci. Plays also a role in non-immune processes. It is for instance involved in vascular development where it may regulate blood and lymphatic vascular separation. It is also required for osteoclast development and function. Functions in the activation of platelets by collagen, mediating PLCG2 phosphorylation and activation. May be coupled to the collagen receptor by the ITAM domain-containing FCER1G. Also activated by the membrane lectin CLEC1B that is required for activation of platelets by PDPN/podoplanin. Involved in platelet adhesion being activated by ITGB3 engaged by fibrinogen. Together with CEACAM20, enhances production of the cytokine CXCL8/IL-8 via the NFKB pathway and may thus have a role in the intestinal immune response (PubMed:26195794).ACTIVITY REGULATION Autoinhibited. Intramolecular binding of the interdomains A and B (also called linker region) to parts of the catalytic domain keep the catalytic center in an inactive conformation. The phosphorylation of the interdomains or the binding of the SH2 domains with dually phosphorylated ITAM domains on transmembrane proteins disrupt those intramolecular interactions allowing the kinase domain to adopt an active conformation. The phosphorylation of SYK and of the ITAM domains which is responsible for SYK activation is essentially mediated by SRC subfamily kinases, like LYN, upon transmembrane receptors engagement. May also be negatively regulated by PTPN6 through dephosphorylation (By similarity). Downstream signaling adapters and intermediates like BLNK or RHOH may mediate positive and/or negative feedback regulation. Negatively regulated by CBL and CBLB through ubiquitination and probable degradation. Phosphorylates SH3BP2 which in turn may regulate SYK through LYN (By similarity).SUBUNIT Interacts with LYN; phosphorylates SYK. Interacts with RHOH (phosphorylated); regulates mast cells activation. Interacts with NFAM1 (phosphorylated); probably involved in BCR signaling. Interacts with VAV1 (via SH2 domain); phosphorylates VAV1 upon BCR activation (By similarity). Interacts with GAB2 (phosphorylated); probably involved in IgE Fc receptor signaling. Interacts (via its SH2 domains) with CD79A (via its phosphorylated ITAM domain); the interaction stimulates SYK autophosphorylation and activation. Interacts (via SH2 domains) with FCER1G (via ITAM domain); activates SYK and mediates neutrophils and macrophages integrin-mediated activation. Interaction with FCER1G in basophils triggers IL3-induced IL4 production (PubMed:19098920). Interacts with ITGB2 and FGR; involved in ITGB2 downstream signaling. Interacts with ITGB3; upon activation by ITGB3 promotes platelet adhesion (By similarity). Interacts (via SH2 domains) with TYROBP (via ITAM domain); involved in neutrophils and macrophages integrin-mediated activation. Interacts with MSN and SELPLG; mediates the selectin-dependent activation of SYK by SELPLG (By similarity). Interacts with BLNK (via SH2 domain). Interacts (via the second SH2 domain) with USP25 (via C-terminus); phosphorylates USP25 and regulates USP25 intracellular levels (By similarity). Interacts (via SH2 domains) with CLEC1B (dimer) (By similarity). Interacts with CLEC7A; participates in leukocyte activation in presence of fungal pathogens. Interacts (phosphorylated) with SLA; may regulate SYK through CBL recruitment (By similarity). Interacts with YWHAG; attenuates BCR-induced membrane translocation and activation of SYK (By similarity). Interacts (via SH2 domains) with GCSAM; the interaction increases after B-cell receptor stimulation, resulting in enhanced SYK autophosphorylation and activity (By similarity). Interacts with TNS2; leading to the phosphorylation of SYK (By similarity). Interacts with FLNA (via filamin repeat 5); docks SYK to the plasma membrane (By similarity). Interacts with CEACAM1; lipopolysaccharide activated neutrophils induce phosphorylation of SYK resulting in the formation of a complex including TLR4 and the phosphorylated form of SYK and CEACAM1, which in turn, recruits PTPN6 that dephosphorylates SYK, reducing the production of reactive oxygen species (ROS) and lysosome disruption, leading to a reduction of the inflammasome activity (PubMed:22496641). Interacts (via SH2 domains) with CEACAM20 (phosphorylated form); the interaction further enhances CEACAM20 phosphorylation (PubMed:26195794). Interacts with IL15RA (By similarity).DOMAIN The SH2 domains mediate the interaction of SYK with the phosphorylated ITAM domains of transmembrane proteins. Some proteins like CLEC1B have a partial ITAM domain (also called hemITAM) containing a single YxxL motif. The interaction with SYK requires CLEC1B homodimerization (By similarity).PTM Autophosphorylated. Phosphorylated on tyrosine residues by LYN following receptors engagement. Phosphorylation on Tyr-317 creates a binding site for CBL, an adapter protein that serves as a negative regulator of BCR-stimulated calcium ion signaling. Phosphorylation at Tyr-342 creates a binding site for VAV1 (By similarity). Phosphorylation on Tyr-342 and Tyr-346 enhances the phosphorylation and activation of phospholipase C-gamma and the early phase of calcium ion mobilization via a phosphoinositide 3-kinase-independent pathway (By similarity). Phosphorylated on tyrosine residues in response to IL15 (By similarity). Phosphorylation on Ser-291 is very common, it peaks 5 minutes after BCR stimulation, and creates a binding site for YWHAG (By similarity). Phosphorylation at Tyr-624 creates a binding site for BLNK (By similarity). Dephosphorylated by PTPN6 (By similarity).PTM Ubiquitinated by CBLB after BCR activation; which promotes proteasomal degradation.DISRUPTION PHENOTYPE Embryos display severe systemic hemorrhage and mice are not viable dying perinatally. While T-cells development is not affected, the development of B-cells is impaired most probably at the pro-B to pre-B transition and mice lack mature B-cells.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. SYK/ZAP-70 subfamily. UniProt P48025 1 EQUAL 635 EQUAL Reactome DB_ID: 9824838 1 pathogens:CLEC6A,CLEC4E:p-Y65,Y76-FCER1G dimer:SYK [plasma membrane] pathogens:CLEC6A,CLEC4E:p-Y65,Y76-FCER1G dimer:SYK Converted from EntitySet in Reactome Reactome DB_ID: 9824798 1