BioPAX pathway converted from "CLEC7A (Dectin-1) signaling" in the Reactome database.CLEC7A (Dectin-1) signalingThis 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>LEFT-TO-RIGHT2.7.10SRC kinase phosphorylates CLEC7A:1,3-beta-D-glucanSRC kinase phosphorylates Dectin-1:1,3-beta-D-glucanThis 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:1,3-beta-D-glucanReactome DB_ID: 9895056plasma membraneGENE ONTOLOGYGO:0005886zymosan1,3-beta-D-glucanphys-ent-participant74554(1->3)-beta-D-glucanphys-ent-participant74558Reactome DB_ID: 2186970extracellular regionGENE ONTOLOGYGO:0005576(1->3)-beta-D-glucan [ChEBI:37671](1->3)-beta-D-glucanChEBICHEBI:37671Reactome Database ID Release 752186970Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2186970ReactomeR-ALL-21869704Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2186970.4Reactomehttp://www.reactome.org1Clec7aCLEC7AB5BUZ1Reactome DB_ID: 9895054UniProt:B5BUZ1Clec7aRattus norvegicusNCBI Taxonomy10116UniProtB5BUZ11EQUAL247EQUALReactome Database ID Release 759895054Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895054ReactomeR-RNO-21306831Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2130683.11Reactome Database ID Release 759895056Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895056ReactomeR-RNO-56076801Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607680.1ATPAdenosine 5'-triphosphateATP(4-)Reactome DB_ID: 113592cytosolGENE ONTOLOGYGO:0005829ATP(4-) [ChEBI:30616]ATP(4-)ATPatpAdenosine 5'-triphosphateChEBICHEBI:30616Reactome Database ID Release 75113592Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113592ReactomeR-ALL-1135924Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113592.4COMPOUNDC00002additional informationMIMI:0361ADPAdenosine 5'-diphosphateADP(3-)Reactome DB_ID: 29370ADP(3-) [ChEBI:456216]ADP(3-)ADP5&apos;-O-[(phosphonatooxy)phosphinato]adenosineADP trianionChEBICHEBI:456216Reactome Database ID Release 7529370Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29370ReactomeR-ALL-293704Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29370.4COMPOUNDC000081,3-beta-D-glucan:p-Y15-CLEC7AReactome DB_ID: 98950611B5BUZ1phospho-Clec7ap-Y15-CLEC7AReactome DB_ID: 989505915EQUALO4'-phospho-L-tyrosineMODMOD:000481EQUAL247EQUALReactome Database ID Release 759895059Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895059ReactomeR-RNO-56076411Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607641.11Reactome Database ID Release 759895061Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895061ReactomeR-RNO-56076771Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607677.1ACTIVATIONSrcSRC-1Q9WUD9Reactome DB_ID: 9836664UniProt:Q9WUD9 SrcSrcFUNCTION 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 (By similarity). 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. 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. Promotes energy production in osteoclasts by activating mitochondrial cytochrome C oxidase (By similarity). Phosphorylates DDR2 on tyrosine residues, thereby promoting its subsequent autophosphorylation (PubMed:16186108). 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 (By similarity). Mediates IL6 signaling by activating YAP1-NOTCH pathway to induce inflammation-induced epithelial regeneration (By similarity).ACTIVITY REGULATION Phosphorylation by CSK at Tyr-530 inhibits kinase activity. Inhibitory phosphorylation at Tyr-530 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 (By similarity). Phosphorylation at Tyr-419 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 (By similarity). Interacts with DDEF1/ASAP1; via the SH3 domain (By similarity). Interacts with CCPG1 (By similarity). Identified in a complex containing FGFR4, NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTTN (By similarity). Interacts with ERBB2, STAT1 and PNN (By similarity). Interacts with CDCP1, PELP1, TGFB1I1 and TOM1L2 (By similarity). Interacts with the cytoplasmic domain of MUC1, phosphorylates it and increases binding of MUC1 with beta-catenin (By similarity). Interacts with RALGPS1; via the 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 (PubMed:10995467). Interacts with ARRB1 and ARRB2 (PubMed:10995467) (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 and ESR1 (dimethylated on arginine) (PubMed:8849729). Interacts with FASLG (By similarity). Interacts (via SH2 domain) with the 'Tyr-402' phosphorylated form of PTK2B/PYK2 (PubMed:8849729). Interacts (via SH2 domain) with FLT3 (tyrosine phosphorylated) (By similarity). 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 with EPHB1; activates the MAPK/ERK cascade to regulate cell migration (By similarity). Interacts with FCAMR (By similarity). Interacts with PDGFRA (tyrosine phosphorylated) (By similarity). Interacts with CSF1R (By similarity). Interacts with DDR1 (By similarity). Interacts (via SH2 domain) with the 'Tyr-9' phosphorylated form of PDPK1 (By similarity). Interacts with AMOTL2; this interaction promotes the translocation of phosphorylated SRC to peripheral cell-matrix adhesion sites (By similarity). Interacts with DDR2 and DAB2 (PubMed:11884411, PubMed:12473651, PubMed:16186108). Interacts with TRAP1 (By similarity). Interacts with CBLC; the interaction is enhanced when SRC is phosphorylated at Tyr-419 (By similarity). Interacts with ARHGEF5 (By similarity). Interacts (via cytoplasmic domain) with CEACAM1 (via SH2 domain); this interaction is regulated by trans-homophilic cell adhesion (PubMed:19948503). 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 (By similarity). Interacts with IL6ST/gp130 (By similarity).TISSUE SPECIFICITY Isoform 2 is expressed in the brain with highest expression in the pyramidal layers of the hippocampus and the granular layer of the dentate gyrus and moderate expression in cortical regions, with higher levels in the superficial layers than in the deep layers. Isoform 2 may be neuron-specific. Isoform 1 is expressed at very low levels in the forebrain.PTM Myristoylated at Gly-2, and this is essential for targeting to membranes.PTM Dephosphorylated at Tyr-530 by PTPRJ. Phosphorylated on Tyr-530 by c-Src kinase (CSK). The phosphorylated form is termed pp60c-src (By similarity). Dephosphorylated by PTPRJ at Tyr-419. Normally maintained in an inactive conformation with the SH2 domain engaged with Tyr-530, the SH3 domain engaged with the SH2-kinase linker, and Tyr-419 dephosphorylated. Dephosphorylation of Tyr-530 as a result of protein tyrosine phosphatase (PTP) action disrupts the intramolecular interaction between the SH2 domain and Tyr-530, Tyr-419 can then become autophosphorylated, resulting in SRX activation. Phosphorylation of Tyr-530 by CSK allows this interaction to reform, resulting in SRC inactivation. CDK5-mediated phosphorylation at Ser-75 targets SRC to ubiquitin-dependent degradation and thus leads to cytoskeletal reorganization. Phosphorylated by PTK2/FAK1; this enhances kinase activity (By similarity). Phosphorylated by PTK2B/PYK2; this enhances kinase activity. Upon activation of IL6ST by IL6, Tyr-419 is phosphorylated and Tyr-530 dephosphorylated (By similarity).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-419 and may lead to lysosomal degradation (By similarity).SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. SRC subfamily.UniProtQ9WUD92EQUAL536EQUALReactome Database ID Release 759836664Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9836664ReactomeR-RNO-650431Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-65043.1GENE ONTOLOGYGO:0004713gene ontology term for cellular functionMIMI:0355Same Catalyst ActivityReactome Database ID Release 759836665Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9836665Reactome Database ID Release 759895063Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895063ReactomeR-RNO-56077501Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607750.1The 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).21525931Pubmed2011Activation of the innate immune receptor Dectin-1 upon formation of a 'phagocytic synapse'Goodridge, Helen SReyes, Christopher NBecker, Courtney AKatsumoto, Tamiko RMa, JunWolf, Andrea JBose, NanditaChan, Anissa S HMagee, Andrew SDanielson, Michael EWeiss, ArthurVasilakos, John PUnderhill, David MNature 472:471-520193029Pubmed2010Syk-coupled C-type lectin receptors that mediate cellular activation via single tyrosine based activation motifsKerrigan, Ann MBrown, Gordon DImmunol. Rev. 234:335-5215845454Pubmed2005Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectinsRogers, Neil CSlack, Emma CEdwards, Alexander DNolte, Martijn ASchulz, OliverSchweighoffer, EdinaWilliams, David LGordon, SiamonTybulewicz, Victor LBrown, Gordon DReis e Sousa, CImmunity 22:507-1710779524Pubmed2000Identification of a novel, dendritic cell-associated molecule, dectin-1, by subtractive cDNA cloningAriizumi, KShen, G LShikano, SXu, SRitter, RKumamoto, TEdelbaum, DMorita, ABergstresser, P RTakashima, AJ. Biol. Chem. 275:20157-6716341139Pubmed2006Dectin-1: a signalling non-TLR pattern-recognition receptorBrown, Gordon DNat. Rev. Immunol. 6:33-43inferred from electronic annotationEVIDENCE CODEECO:0000203LEFT-TO-RIGHTp-Y753,Y759-PLCG2 translocates from cytosol to plasma membraneThis 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>P24135phospho-Plcg2p-Y753,Y759-PLCG2Reactome DB_ID: 9895073UniProt:P24135 Plcg2Plcg2FUNCTION 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).PTM Phosphorylated on tyrosine residues by CSF1R (By similarity). Phosphorylated on tyrosine residues by BTK and SYK; upon ligand-induced activation of a variety of growth factor receptors and immune system receptors. Phosphorylation leads to increased phospholipase activity (By similarity).UniProtP24135753EQUAL759EQUAL1EQUAL1265EQUALReactome Database ID Release 759895073Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895073ReactomeR-RNO-56076311Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607631.1P24135phospho-Plcg2p-Y753,Y759-PLCG2Reactome DB_ID: 98950171EQUAL1265EQUALReactome Database ID Release 759895017Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895017ReactomeR-RNO-56076401Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607640.1Reactome Database ID Release 759895075Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895075ReactomeR-RNO-56077551Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607755.1Tyrosine-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.11606584Pubmed2001Tyrosine residues in phospholipase Cgamma 2 essential for the enzyme function in B-cell signalingRodriguez, RMatsuda, MPerisic, OBravo, JPaul, AJones, NPLight, YSwann, KWilliams, RLKatan, MJ Biol Chem 276:47982-928972730Pubmed1996Tyrosine phosphorylation and translocation of phospholipase C-gamma 2 in polymorphonuclear leukocytes treated with pervanadateKawakami, NShimohama, SHayakawa, TSumida, YFujimoto, SBiochim. Biophys. Acta 1314:167-7411395409Pubmed2001Regulation of phosphoinositide-specific phospholipase CRhee, S GAnnu. Rev. Biochem. 70:281-312LEFT-TO-RIGHT3.1.4.11p-Y753,Y759-PLCG2 hydrolyses PIP2This 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>H2OwaterReactome DB_ID: 29356water [ChEBI:15377]waterChEBICHEBI:15377Reactome Database ID Release 7529356Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29356ReactomeR-ALL-293565Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29356.5COMPOUNDC00001PIP2PI(4,5)P21-phosphatidyl-1D-myo-inositol 4,5-bisphosphatePhosphatidylinositol-4,5-bisphosphate1-phosphatidyl-1D-myo-inositol 4,5- bisphosphateReactome DB_ID: 1798561-phosphatidyl-1D-myo-inositol 4,5-bisphosphate [ChEBI:18348]1-phosphatidyl-1D-myo-inositol 4,5-bisphosphatePIP2ChEBICHEBI:18348Reactome Database ID Release 75179856Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=179856ReactomeR-ALL-1798563Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-179856.3COMPOUNDC04637IP3I(1,4,5)P31D-myo-inositol 1,4,5-trisphosphateD-myo-Inositol 1,4,5-trisphosphateInositol 1,4,5-trisphosphatephosphatidylinositol 1,4,5-trisphosphateReactome DB_ID: 1145201D-myo-inositol 1,4,5-trisphosphate [ChEBI:16595]1D-myo-inositol 1,4,5-trisphosphateChEBICHEBI:16595Reactome Database ID Release 75114520Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=114520ReactomeR-ALL-1145203Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-114520.3COMPOUNDC01245DAGDAGsdiacylglycerolsdiglycerideReactome DB_ID: 112275diglyceride [ChEBI:18035]diglycerideChEBICHEBI:18035Reactome Database ID Release 75112275Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=112275ReactomeR-ALL-1122753Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-112275.3COMPOUNDC00165ACTIVATIONGENE ONTOLOGYGO:0004435Reactome Database ID Release 759895018Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895018Reactome Database ID Release 759895020Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895020ReactomeR-RNO-56077351Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607735.1Following 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).7612269Pubmed1995Significance of PIP2 hydrolysis and regulation of phospholipase C isozymesLee, S BRhee, S GCurr. Opin. Cell Biol. 7:183-9CLEC7A (Dectin-1) induces NFAT activationThis 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>LEFT-TO-RIGHTActivation of CalcineurinThis 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>CALM1:4xCa2+Reactome DB_ID: 9829357Ca2+Calciumcalcium(2+)Reactome DB_ID: 74016calcium(2+) [ChEBI:29108]calcium(2+)ChEBICHEBI:29108Reactome Database ID Release 7574016Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74016ReactomeR-ALL-740163Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-74016.3COMPOUNDC000764Calm3CALM1P0DP31Reactome DB_ID: 9823564UniProt:P0DP31Calm3UniProtP0DP312EQUAL149EQUALReactome Database ID Release 759823564Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823564ReactomeR-RNO-90167071Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-9016707.11Reactome Database ID Release 759829357Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9829357ReactomeR-RNO-742941Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-74294.14Calcineurin (CaN)Reactome DB_ID: 9879442Ppp3r1Calcineurin subunit B type 1CANB1_RATReactome DB_ID: 5339582UniProt:P63100 Ppp3r1Ppp3r1Cna2CnbFUNCTION 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:24018048). 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:24018048). Interacts with catalytic subunit PPP3CB/calcineurin A (By similarity). Interacts with CIB1 (via C-terminal region); the interaction increases upon cardiomyocyte hypertrophy. Interacts with RCAN1 (By similarity).TISSUE SPECIFICITY Isoform 2 is testis specific.MISCELLANEOUS This protein has four functional calcium-binding sites.SIMILARITY Belongs to the calcineurin regulatory subunit family.UniProtP631002EQUAL170EQUALReactome Database ID Release 755339582Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5339582ReactomeR-RNO-53395821Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5339582.11PPP3CA,B:Fe3+:Zn2+Reactome DB_ID: 9879440Fe3+iron (ferric)iron(3+)Reactome DB_ID: 111736iron(3+) [ChEBI:29034]iron(3+)ferric ironiron, ion (Fe(3+))Fe(3+)Fe(III)Fe3+FE (III) IONFerric ionChEBICHEBI:29034Reactome Database ID Release 75111736Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=111736ReactomeR-ALL-1117363Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-111736.3COMPOUNDC000231Zn2+Zn++zinc(2+)Zinc ionZn(II)Reactome DB_ID: 29426zinc(2+) [ChEBI:29105]zinc(2+)ChEBICHEBI:29105Reactome Database ID Release 7529426Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29426ReactomeR-ALL-294263Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29426.3COMPOUNDC000381Converted from EntitySet in ReactomePPP3CA,BReactome DB_ID: 9879438Ppp3cbPPP3CBP20651Reactome DB_ID: 9879435UniProt:P20651 Ppp3cbPpp3cbFUNCTION Calcium-dependent, calmodulin-stimulated protein phosphatase which plays an essential role in the transduction of intracellular Ca(2+)-mediated signals. Dephosphorylates and activates transcription factor NFATC1. Dephosphorylates and inactivates transcription factor ELK1. Dephosphorylates DARPP32.ACTIVITY REGULATION Activated by Ca(2+)-bound calmodulin following an increase in intracellular Ca(2+). At low Ca(2+) concentrations, the catalytic subunit (also known as calcineurin A) is inactive and is bound to the regulatory subunit (also known as calcineurin B) in which only two high-affinity binding sites are occupied by Ca(2+). In response to elevated calcium levels, the occupancy of the low-affinity sites on calcineurin B by Ca(2+) causes a conformational change of the C-terminal regulatory domain of calcineurin A, resulting in the exposure of the calmodulin-binding domain and in the partial activation of calcineurin A. The subsequent binding of Ca(2+)-bound calmodulin leads to the displacement of the autoinhibitory domain from the active site and possibly of the autoinhibitory segment from the substrate binding site which fully activates calcineurin A.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). 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). In response to an increase in Ca(2+) intracellular levels, forms a complex composed of PPP3CB/calcineurin A, calcineurin B and calmodulin. Interacts (via calcineurin B binding domain) with regulatory subunit PPP3R1/calcineurin B. Interacts (via calmodulin-binding domain) with calmodulin; the interaction depends on calmodulin binding to Ca(2+). Interacts with SLC12A1 (PubMed:25967121). Interacts with SORL1 (PubMed:25967121). Interacts with UNC119 (By similarity).TISSUE SPECIFICITY Expressed in kidney (at protein level).DOMAIN The poly-Pro domain may confer substrate specificity.DOMAIN The autoinhibitory domain prevents access to the catalytic site.DOMAIN The autoinhibitory segment prevents access to the substrate binding site.DOMAIN Possible isomerization of Pro-318 within the SAPNY motif triggers a conformation switch which affects the organization and thus accessibility of the active site and the substrate binding region (PxIxIF motif). The trans- to cis-transition may favor calcineurin A activation and substrate binding. The reverse cis- to trans-transition may be enhanced by peptidyl-prolyl isomerases such as PPIA.MISCELLANEOUS Unlike for protein substrates, PPP3CB activity towards synthetic phosphatase substrate p-nitrophenyl phosphate (pNPP) is increased in presence of the immunosuppressant complex FKBP12-FK506.SIMILARITY Belongs to the PPP phosphatase family. PP-2B subfamily.UniProtP206512EQUAL524EQUALReactome Database ID Release 759879435Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9879435ReactomeR-RNO-20258691Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2025869.1Ppp3caSerine/threonine protein phosphatase 2B catalytic subunit, alpha isoformP2BA_RATReactome DB_ID: 201768UniProt:P63329 Ppp3caPpp3caCalnaFUNCTION Calcium-dependent, calmodulin-stimulated protein phosphatase which plays an essential role in the transduction of intracellular Ca(2+)-mediated signals (PubMed:1322410, PubMed:24018048). Many of the substrates contain a PxIxIT motif and/or a LxVP motif (By similarity). In response to increased Ca(2+) levels, dephosphorylates and activates phosphatase SSH1 which results in cofilin dephosphorylation (By similarity). In response to increased Ca(2+) levels following mitochondrial depolarization, dephosphorylates DNM1L inducing DNM1L translocation to the mitochondrion (By similarity). Dephosphorylates heat shock protein HSPB1 (By similarity). Dephosphorylates and activates transcription factor NFATC1 (By similarity). Dephosphorylates and inactivates transcription factor ELK1 (By similarity). Dephosphorylates DARPP32 (By similarity). May dephosphorylate CRTC2 at 'Ser-171' resulting in CRTC2 dissociation from 14-3-3 proteins (By similarity).ACTIVITY REGULATION Activated by Ca(2+)-bound calmodulin following an increase in intracellular Ca(2+) (PubMed:1322410, PubMed:24018048). At low Ca(2+) concentrations, the catalytic subunit (also known as calcineurin A) is inactive and is bound to the regulatory subunit (also known as calcineurin B) in which only two high-affinity binding sites are occupied by Ca(2+) (PubMed:1322410, PubMed:24018048). In response to elevated calcium levels, the occupancy of the low-affinity sites on calcineurin B by Ca(2+) causes a conformational change of the C-terminal regulatory domain of calcineurin A, resulting in the exposure of the calmodulin-binding domain and in the partial activation of calcineurin A (PubMed:1322410, PubMed:24018048). The subsequent binding of Ca(2+)-bound calmodulin leads to the displacement of the autoinhibitory domain from the active site and possibly of the autoinhibitory segment from the substrate binding site which fully activates calcineurin A (PubMed:1322410, PubMed:24018048). Inhibited by immunosuppressant drug FK506 (tacrolimus) in complex with FKBP12 and also by immunosuppressant drug cyclosporin A (CsA) in complex with PPIA/cyclophilin A; the inhibition is Ca(2+)-dependent (By similarity).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) (By similarity). 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). In response to an increase in Ca(2+) intracellular levels, forms a complex composed of PPP3CA/calcineurin A, calcineurin B and calmodulin (By similarity). Interacts (via calcineurin B binding domain) with regulatory subunit PPP3R1/calcineurin B (By similarity). Interacts (via calmodulin-binding domain) with calmodulin; the interaction depends on calmodulin binding to Ca(2+) (By similarity). Forms a complex composed of MYOZ2 and ACTN1 (By similarity). Within the complex interacts with MYOZ2 (By similarity). Interacts with MYOZ1 (By similarity). Interacts with MYOZ3 (By similarity). Interacts with CIB1; the interaction increases upon cardiomyocyte hypertrophy (By similarity). Interacts with CHP1 and CHP2 (PubMed:10593895, PubMed:18815128). Interacts with CRTC1. Interacts with CRTC2 (By similarity). Interacts with DNM1L; the interaction dephosphorylates DNM1L and promotes its translocation to mitochondria (By similarity). Interacts with CMYA5; this interaction represses calcineurin activity in muscle (By similarity). Interacts (constitutively active form) with SYNPO2 (By similarity). Interacts with scaffold protein AKAP5 (via IAIIIT motif); the interaction recruits PPP3CA to the plasma membrane following L-type Ca(2+)-channel activation (By similarity). Interacts with NFATC2 (By similarity). Interacts with RCAN3 (By similarity). Interacts with PPIA. Interacts with RCAN1 (By similarity). Interacts with UNC119 (By similarity).TISSUE SPECIFICITY Expressed in neonatal cardiomyocytes (at protein level).DOMAIN The autoinhibitory domain prevents access to the catalytic site.DOMAIN The autoinhibitory segment prevents access to the substrate binding site.DOMAIN Possible isomerization of Pro-309 within the SAPNY motif triggers a conformation switch which affects the organization and thus accessibility of the active site and the substrate binding region (PxIxIF motif). The trans- to cis-transition may favor calcineurin A activation and substrate binding. The reverse cis- to trans-transition may be enhanced by peptidyl-prolyl isomerases such as PPIA.SIMILARITY Belongs to the PPP phosphatase family. PP-2B subfamily.UniProtP633291EQUAL521EQUALReactome Database ID Release 75201768Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=201768ReactomeR-RNO-2017681Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-201768.1Reactome Database ID Release 759879438Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9879438ReactomeR-RNO-20259551Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2025955.11Reactome Database ID Release 759879440Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9879440ReactomeR-RNO-20259491Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2025949.11Reactome Database ID Release 759879442Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9879442ReactomeR-RNO-20259771Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2025977.1Calcineurin:Calmodulin (CaN:CaM)Reactome DB_ID: 9879501PPP3CA,B:CalmodulinReactome DB_ID: 987949911Reactome Database ID Release 759879499Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9879499ReactomeR-RNO-20260031Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2026003.11Calcineurin alpha regulatory subunit:CalciumReactome DB_ID: 987949741Reactome Database ID Release 759879497Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9879497ReactomeR-RNO-20259501Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2025950.11Reactome Database ID Release 759879501Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9879501ReactomeR-RNO-20259471Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2025947.1Reactome Database ID Release 759885700Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9885700ReactomeR-RNO-27308721Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2730872.1Calcineurin (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).11015619Pubmed2000Calcineurin: form and functionRusnak, FMertz, PPhysiol. Rev. 80:1483-52118296442Pubmed2008The secondary structure of calcineurin regulatory region and conformational change induced by calcium/calmodulin bindingShen, XianrongLi, HuimingOu, YanTao, WenbingDong, AichunKong, JilieJi, CYu, ShaoningJ. Biol. Chem. 283:11407-1311123943Pubmed2000Low affinity Ca2+-binding sites of calcineurin B mediate conformational changes in calcineurin AYang, S AKlee, C BBiochemistry 39:16147-5422100452Pubmed2012Structural basis for activation of calcineurin by calmodulinRumi-Masante, JulieRusinga, Farai ILester, Terrence EDunlap, Tori BWilliams, Todd DDunker, A KeithWeis, David DCreamer, Trevor PJ. Mol. Biol. 415:307-17LEFT-TO-RIGHTCalcineurin binds and dephosphorylates NFATThis 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 Reactomep-NFATC1,2,3Reactome DB_ID: 9879495D3ZE20phospho-Nfatc1p-12S-NFATC1Reactome DB_ID: 9879458UniProt:D3ZE20Nfatc1UniProtD3ZE20175EQUALO-phospho-L-serineMODMOD:00046176EQUAL178EQUAL179EQUAL181EQUAL233EQUAL237EQUAL241EQUAL278EQUAL286EQUAL290EQUAL257EQUAL1EQUAL943EQUALReactome Database ID Release 759879458Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9879458ReactomeR-RNO-20259531Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2025953.1A0A0G2JTY4phospho-Nfatc3p-13S-NFATC3Reactome DB_ID: 9879475UniProt:A0A0G2JTY4Nfatc3UniProtA0A0G2JTY4168EQUAL169EQUAL171EQUAL172EQUAL174EQUAL236EQUAL240EQUAL244EQUAL288EQUAL296EQUAL300EQUAL344EQUAL265EQUAL2EQUAL1075EQUALReactome Database ID Release 759879475Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9879475ReactomeR-RNO-20259201Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2025920.1D4A0I8phospho-Nfatc2p-14S-NFATC2Reactome DB_ID: 9879493UniProt:D4A0I8Nfatc2UniProtD4A0I8171EQUAL172EQUAL174EQUAL175EQUAL177EQUAL213EQUAL217EQUAL221EQUAL268EQUAL274EQUAL276EQUAL280EQUAL326EQUAL243EQUAL1EQUAL925EQUALReactome Database ID Release 759879493Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9879493ReactomeR-RNO-20258481Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2025848.1Reactome Database ID Release 759879495Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9879495ReactomeR-RNO-20259241Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2025924.1NFAT:CaN:CaMReactome DB_ID: 9885593Converted from EntitySet in ReactomeDephosphorylated NFATReactome DB_ID: 9885591D4A0I8phospho-Nfatc2p-S243-NFATC2Reactome DB_ID: 98855851EQUAL925EQUALReactome Database ID Release 759885585Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9885585ReactomeR-RNO-26856261Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2685626.1D3ZE20phospho-Nfatc1p-S257-NFATC1Reactome DB_ID: 98855871EQUAL943EQUALReactome Database ID Release 759885587Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9885587ReactomeR-RNO-26856181Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2685618.1A0A0G2JTY4phospho-Nfatc3p-S265-NFATC3Reactome DB_ID: 98855892EQUAL1075EQUALReactome Database ID Release 759885589Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9885589ReactomeR-RNO-26856141Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2685614.1Reactome Database ID Release 759885591Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9885591ReactomeR-RNO-26856541Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2685654.111Reactome Database ID Release 759885593Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9885593ReactomeR-RNO-26857051Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2685705.1PiOrthophosphatehydrogenphosphatePhosphateInorganic PhosphateReactome DB_ID: 29372hydrogenphosphate [ChEBI:43474]hydrogenphosphatehydrogen phosphatephosphate[PO3(OH)](2-)INORGANIC PHOSPHATE GROUPHYDROGENPHOSPHATE IONHPO4(2-)[P(OH)O3](2-)ChEBICHEBI:43474Reactome Database ID Release 7529372Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29372ReactomeR-ALL-293724Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29372.4COMPOUNDC0000913ACTIVATIONGENE ONTOLOGYGO:0033192Reactome Database ID Release 759885594Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9885594Reactome Database ID Release 759885596Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9885596ReactomeR-RNO-27308491Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2730849.1Nuclear 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). 8799126Pubmed1996Interaction of calcineurin with a domain of the transcription factor NFAT1 that controls nuclear importLuo, CShaw, KTRaghavan, AAramburu, JGarcia-Cozar, FPerrino, BAHogan, PGRao, AProc Natl Acad Sci U S A 93:8907-1210860980Pubmed2000A second calcineurin binding site on the NFAT regulatory domainPark, SUesugi, MVerdine, GLProc Natl Acad Sci U S A 97:7130-511030334Pubmed2000Concerted dephosphorylation of the transcription factor NFAT1 induces a conformational switch that regulates transcriptional activityOkamura, HAramburu, JGarcía-Rodríguez, CViola, JPRaghavan, ATahiliani, MZhang, XQin, JHogan, PGRao, AMol Cell 6:539-5012975316Pubmed2003Transcriptional regulation by calcium, calcineurin, and NFATHogan, Patrick GChen, LNardone, JRao, AnjanaGenes Dev. 17:2205-3217502104Pubmed2007Structure of the calcineurin-NFAT complex: defining a T cell activation switch using solution NMR and crystal coordinatesTakeuchi, KohRoehrl, Michael H ASun, Zhen-Yu JWagner, GerhardStructure 15:587-978631904Pubmed1996Calcineurin binds the transcription factor NFAT1 and reversibly regulates its activityLoh, CShaw, KTCarew, JViola, JPLuo, CPerrino, BARao, AJ Biol Chem 271:10884-91LEFT-TO-RIGHTTranslocation of CaN:CaM:NFAT to nucleusThis 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>NFAT:CaN:CaMReactome DB_ID: 9885686nucleoplasmGENE ONTOLOGYGO:0005654Converted from EntitySet in ReactomeDephosphorylated NFATC1,2,3Reactome DB_ID: 9885684D4A0I8phospho-Nfatc2p-S243-NFATC2Reactome DB_ID: 98856781EQUAL925EQUALReactome Database ID Release 759885678Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9885678ReactomeR-RNO-20258941Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2025894.1D3ZE20phospho-Nfatc1p-S257-NFATC1Reactome DB_ID: 98856801EQUAL943EQUALReactome Database ID Release 759885680Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9885680ReactomeR-RNO-20259351Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2025935.1A0A0G2JTY4phospho-Nfatc3p-S265-NFATC3Reactome DB_ID: 98856822EQUAL1075EQUALReactome Database ID Release 759885682Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9885682ReactomeR-RNO-20259881Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2025988.1Reactome Database ID Release 759885684Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9885684ReactomeR-RNO-20258521Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2025852.11CaN:CaM:Ca2+Reactome DB_ID: 9885676CaN catalytic alpha/beta:Zn++:Fe3+:CaM:Ca2+Reactome DB_ID: 9885674CaN catalytic alpha/beta:Zn++:Fe3+Reactome DB_ID: 9885672Fe3+iron (ferric)iron(3+)Reactome DB_ID: 2685584Reactome Database ID Release 752685584Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2685584ReactomeR-ALL-26855843Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2685584.3COMPOUNDC000231Converted from EntitySet in ReactomeCaN-catalytic alpha/beta chainsReactome DB_ID: 9885670Ppp3caPPP3CAP63329Reactome DB_ID: 98856661EQUAL521EQUALReactome Database ID Release 759885666Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9885666ReactomeR-RNO-26855991Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2685599.1Ppp3cbPPP3CBP20651Reactome DB_ID: 98856682EQUAL524EQUALReactome Database ID Release 759885668Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9885668ReactomeR-RNO-26856241Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2685624.1Reactome Database ID Release 759885670Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9885670ReactomeR-RNO-26856491Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2685649.11Zn2+Zn++zinc(2+)Zinc ionZn(II)Reactome DB_ID: 200493Reactome Database ID Release 75200493Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=200493ReactomeR-ALL-2004933Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-200493.3COMPOUNDC000381Reactome Database ID Release 759885672Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9885672ReactomeR-RNO-26857141Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2685714.11CALM1:4xCa2+Reactome DB_ID: 9829277Calm3CALM1P0DP31Reactome DB_ID: 98292752EQUAL149EQUALReactome Database ID Release 759829275Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9829275ReactomeR-RNO-90168711Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-9016871.11Ca2+Calciumcalcium(2+)Reactome DB_ID: 29496Reactome Database ID Release 7529496Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29496ReactomeR-ALL-294963Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29496.3COMPOUNDC000764Reactome Database ID Release 759829277Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9829277ReactomeR-RNO-6296581Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-629658.11Reactome Database ID Release 759885674Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9885674ReactomeR-RNO-26857161Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2685716.11CaN alpha regulatory:Ca2+Reactome DB_ID: 98856644Ppp3r1PPP3R1P63100Reactome DB_ID: 98856622EQUAL170EQUALReactome Database ID Release 759885662Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9885662ReactomeR-RNO-26856311Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2685631.11Reactome Database ID Release 759885664Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9885664ReactomeR-RNO-26857041Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2685704.11Reactome Database ID Release 759885676Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9885676ReactomeR-RNO-26856981Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2685698.11Reactome Database ID Release 759885686Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9885686ReactomeR-RNO-26856901Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2685690.1Reactome Database ID Release 759885688Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9885688ReactomeR-RNO-27308671Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2730867.1Dephosphorylated NFAT-calcineurin (CaN) complex translocates to nucleus, where it activates transcription of several cytokine genes (e.g..IL2).Reactome Database ID Release 759929956Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9929956ReactomeR-RNO-56077631Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607763.1CLEC7A (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).17312158Pubmed2007Dectin-1 stimulation by Candida albicans yeast or zymosan triggers NFAT activation in macrophages and dendritic cellsGoodridge, Helen SSimmons, Randi MUnderhill, David MJ. Immunol. 178:3107-1521728173Pubmed2011CLEC-2 signaling via Syk in myeloid cells can regulate inflammatory responsesMourão-Sá, DiegoRobinson, Matthew JZelenay, SantiagoSancho, DavidChakravarty, ProbirLarsen, RasmusPlantinga, MaudVan Rooijen, NicoSoares, Miguel PLambrecht, BartReis e Sousa, CEur. J. Immunol. 41:3040-5322611159Pubmed2012NFAT control of innate immunityFric, JanZelante, TeresaWong, Alicia Y WMertes, AlexandraYu, Hong-BingRicciardi-Castagnoli, PaolaBlood 120:1380-923570314Pubmed2013C-type lectin-like receptors of the dectin-1 cluster: ligands and signaling pathwaysPlato, AnthonyWillment, Janet ABrown, Gordon DInt. Rev. Immunol. 32:134-56LEFT-TO-RIGHTPKC-delta translocates to plasma membraneThis 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>P09215phospho-Prkcdp-T507,S645,S664-PRKCDReactome DB_ID: 9892371UniProt:P09215PrkcdUniProtP09215507EQUALO-phospho-L-threonineMODMOD:00047645EQUAL664EQUAL1EQUAL676EQUALReactome Database ID Release 759892371Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9892371ReactomeR-RNO-52187341Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5218734.1DAGs:p-T507,S645,S664-PRKCDReactome DB_ID: 989501311Reactome Database ID Release 759895013Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895013ReactomeR-RNO-56077001Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607700.1Reactome Database ID Release 759895015Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895015ReactomeR-RNO-56077341Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607734.1Protein 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).7499357Pubmed1995Protein kinase C: structure, function, and regulationNewton, A CJ. Biol. Chem. 270:28495-812473183Pubmed2002Protein kinase C delta (PKC delta): activation mechanisms and functionsKikkawa, UshioMatsuzaki, HidenoriYamamoto, ToshiyoshiJ. Biochem. 132:831-98749392Pubmed1995Protein kinase C is regulated in vivo by three functionally distinct phosphorylationsKeranen, Lisa MDutil, Erica MNewton, Alexandra CCurr. Biol. 5:1394-140322265677Pubmed2012Syk kinase-coupled C-type lectin receptors engage protein kinase C-? to elicit Card9 adaptor-mediated innate immunityStrasser, DominikusNeumann, KonstantinBergmann, HannaMarakalala, Mohlopheni JGuler, RetoRojowska, AnnaHopfner, KPBrombacher, FrankUrlaub, HenningBaier, GottfriedBrown, Gordon DLeitges, MichaelRuland, JürgenImmunity 36:32-4215105418Pubmed2004Mechanism of diacylglycerol-induced membrane targeting and activation of protein kinase CdeltaStahelin, Robert VDigman, Michelle AMedkova, MartinaAnanthanarayanan, BharathRafter, John DMelowic, Heather RCho, WonhwaJ. Biol. Chem. 279:29501-129305920Pubmed1997Identification of serine 643 of protein kinase C-delta as an important autophosphorylation site for its enzymatic activityLi, WZhang, JBottaro, D PPierce, J HJ. Biol. Chem. 272:24550-59889098Pubmed1998Regulation of conventional protein kinase C isozymes by phosphoinositide-dependent kinase 1 (PDK-1)Dutil, Erica MToker, AlexNewton, Alexandra CCurr. Biol. 8:1366-7519934406Pubmed2010Protein kinase C: poised to signalNewton, Alexandra CAm. J. Physiol. Endocrinol. Metab. 298:E395-402LEFT-TO-RIGHTPKC-delta is activatedThis 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>DAGs:active p-T507,S645,S664-PRKCDReactome DB_ID: 9895030P09215phospho-Prkcdp-T507,S645,S664-PRKCD(1-676)Reactome DB_ID: 98397831EQUAL676EQUALReactome Database ID Release 759839783Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9839783ReactomeR-RNO-1982941Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-198294.111Reactome Database ID Release 759895030Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895030ReactomeR-RNO-56076891Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607689.1Reactome Database ID Release 759895046Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895046ReactomeR-RNO-56077461Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607746.1Membrane-bound PKC adopts an open conformation, in which the pseudosubstrate is released from the kinase domain, allowing downstream signaling (Newton 2010).LEFT-TO-RIGHTPKC-delta phosphorylates CARD9This 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>Card9CARD9Q9EPY0Reactome DB_ID: 9895028UniProt:Q9EPY0Card9UniProtQ9EPY01EQUAL536EQUALReactome Database ID Release 759895028Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895028ReactomeR-RNO-56076621Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607662.1Q9EPY0phospho-Card9p-T231-CARD9Reactome DB_ID: 9894984231EQUAL1EQUAL536EQUALReactome Database ID Release 759894984Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894984ReactomeR-RNO-56076231Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607623.1ACTIVATIONGENE ONTOLOGYGO:0004699Reactome Database ID Release 759895031Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895031Reactome Database ID Release 759895033Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895033ReactomeR-RNO-56077401Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607740.1Activation 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).20538615Pubmed2010CARD9 mediates dectin-2-induced IkappaBalpha kinase ubiquitination leading to activation of NF-kappaB in response to stimulation by the hyphal form of Candida albicansBi, LiangkuanGojestani, SaraWu, WeihuiHsu, Yen-Michael SZhu, JiayuanAriizumi, KiyoshiLin, XinJ. Biol. Chem. 285:25969-7719864672Pubmed2009A homozygous CARD9 mutation in a family with susceptibility to fungal infectionsGlocker, Erik-OliverHennigs, AndreNabavi, MohammadSchäffer, Alejandro AWoellner, CristinaSalzer, UlrichPfeifer, DietmarVeelken, HendrikWarnatz, KlausTahami, FaribaJamal, SarahManguiat, AnnabelleRezaei, NimaAmirzargar, Ali AkbarPlebani, AlessandroHannesschläger, NicoleGross, OlafRuland, JürgenGrimbacher, BodoN. Engl. J. Med. 361:1727-3519359218Pubmed2009CARD9 versus CARMA1 in innate and adaptive immunityHara, HiromitsuSaito, TakashiTrends Immunol. 30:234-4216862125Pubmed2006Card9 controls a non-TLR signalling pathway for innate anti-fungal immunityGross, OGewies, AFinger, KSchäfer, MSparwasser, TPeschel, CFörster, IRuland, JNature 442:651-6LEFT-TO-RIGHTCARD9 oligomerizesThis 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>Card9CARD9Q9EPY0Reactome DB_ID: 98950691EQUAL536EQUALReactome Database ID Release 759895069Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895069ReactomeR-RNO-5611941Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-561194.12p-T231-CARD9 oligomerReactome DB_ID: 9894986Reactome Database ID Release 759894986Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894986ReactomeR-RNO-56076221Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607622.1Reactome Database ID Release 759895071Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895071ReactomeR-RNO-56077531Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607753.1Activated 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).11053425Pubmed2000CARD9 is a novel caspase recruitment domain-containing protein that interacts with BCL10/CLAP and activates NF-kappa BBertin, JGuo, YWang, LSrinivasula, S MJacobson, M DPoyet, J LMerriam, SDu, M QDyer, M JRobison, K EDiStefano, P SAlnemri, E SJ. Biol. Chem. 275:41082-6LEFT-TO-RIGHTBCL10 binds CARD9This 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>Bcl10BCL10Q9QYN5Reactome DB_ID: 9885625UniProt:Q9QYN5Bcl10UniProtQ9QYN51EQUAL233EQUALReactome Database ID Release 759885625Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9885625ReactomeR-RNO-2024471Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-202447.1p-T231-CARD9 oligomer:BCL10Reactome DB_ID: 989500911Reactome Database ID Release 759895009Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895009ReactomeR-RNO-56076781Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607678.1Reactome Database ID Release 759895011Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895011ReactomeR-RNO-56077331Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607733.1B-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).LEFT-TO-RIGHTBCL10 oligomerizesThis 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>2p-T231-CARD9:BCL10 oligomersReactome DB_ID: 9894988BCL10 oligomerReactome DB_ID: 9885627Reactome Database ID Release 759885627Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9885627ReactomeR-RNO-26857021Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2685702.111Reactome Database ID Release 759894988Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894988ReactomeR-RNO-56076761Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607676.1Reactome Database ID Release 759895026Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895026ReactomeR-RNO-56077371Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607737.1CARD interactions between CARD9 and BCL10 induce BCL10 oligomerization (through its CARD domain), required for oligomerization and activation of MALT1.10187770Pubmed1999CIPER, a novel NF kappaB-activating protein containing a caspase recruitment domain with homology to Herpesvirus-2 protein E10Koseki, TInohara, NChen, SCarrio, RMerino, JHottiger, M ONabel, G JNunez, GJ. Biol. Chem. 274:9955-61LEFT-TO-RIGHTMALT1 binds BCL10This 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>Malt1MALT1D4A980Reactome DB_ID: 9842139UniProt:D4A980Malt1UniProtD4A9801EQUAL824EQUALReactome Database ID Release 759842139Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9842139ReactomeR-RNO-2024611Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-202461.1p-T231-CARD9:BCL10 oligomers:MALT1Reactome DB_ID: 989502211Reactome Database ID Release 759895022Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895022ReactomeR-RNO-56076821Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607682.1Reactome Database ID Release 759895044Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895044ReactomeR-RNO-56077441Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607744.1Mucosa-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).11262391Pubmed2001Bcl10 and MALT1, independent targets of chromosomal translocation in malt lymphoma, cooperate in a novel NF-kappa B signaling pathwayLucas, P CYonezumi, MInohara, NMcAllister-Lucas, L MAbazeed, M EChen, F FYamaoka, SSeto, MNunez, GJ. Biol. Chem. 276:19012-911090634Pubmed2000Identification of paracaspases and metacaspases: two ancient families of caspase-like proteins, one of which plays a key role in MALT lymphomaUren, A GO'Rourke, KAravind, L APisabarro, MTSeshagiri, SKoonin, EVDixit, V MMol. Cell 6:961-7LEFT-TO-RIGHTMALT1 oligomerizesThis 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>2p-T231-CARD9:BCL10:MALT1 oligomersReactome DB_ID: 98949901MALT1 oligomerReactome DB_ID: 9885629Reactome Database ID Release 759885629Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9885629ReactomeR-RNO-26856731Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2685673.11Reactome Database ID Release 759894990Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894990ReactomeR-RNO-56076961Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607696.1Reactome Database ID Release 759895024Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895024ReactomeR-RNO-56077361Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607736.1After 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).24074955Pubmed2013Structural architecture of the CARMA1/Bcl10/MALT1 signalosome: nucleation-induced filamentous assemblyQiao, QiYang, ChenghuaZheng, ChaoFontán, LorenaDavid, LironYu, XiongBracken, ClayRosen, MonicaMelnick, AriEgelman, Edward HWu, HMol. Cell 51:766-7921966355Pubmed2011Oligomeric structure of the MALT1 tandem Ig-like domainsQiu, LiyanDhe-Paganon, SiranoPLoS ONE 6:e2322018285772Pubmed2008Finally, MALT1 is a protease!McAllister-Lucas, Linda MLucas, Peter CNat. Immunol. 9:231-3LEFT-TO-RIGHTTRAF6 binds MALT1 oligomersThis 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>Traf6TRAF6B5DF45Reactome DB_ID: 9834094UniProt:B5DF45Traf6UniProtB5DF451EQUAL522EQUALReactome Database ID Release 759834094Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834094ReactomeR-RNO-1663661Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-166366.1p-T231-CARD9:BCL10:MALT1 oligomers:TRAF6Reactome DB_ID: 989504811Reactome Database ID Release 759895048Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895048ReactomeR-RNO-56077011Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607701.1Reactome Database ID Release 759895050Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895050ReactomeR-RNO-56077471Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607747.1TRAF6 (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).23148225Pubmed2012Tumor 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 infectionGorjestani, SaraDarnay, BGLin, XinJ. Biol. Chem. 287:44143-5015125833Pubmed2004The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytesSun, LDeng, LEa, CKXia, ZPChen, ZJMol Cell 14:289-301LEFT-TO-RIGHTTRAF6 oligomerizesThis 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>2p-T231-CARD9:BCL10:MALT1:TRAF6 oligomersReactome DB_ID: 98950651TRAF6 oligomerReactome DB_ID: 9885734Reactome Database ID Release 759885734Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9885734ReactomeR-RNO-26857081Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2685708.11Reactome Database ID Release 759895065Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895065ReactomeR-RNO-56076741Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607674.1Reactome Database ID Release 759895067Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895067ReactomeR-RNO-56077511Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607751.1The MALT1 oligomers bound to TRAF6 induce TRAF6 oligomerization and activate TRAF6 E3 ubiquitin ligase activity (Sun et al. 2004).LEFT-TO-RIGHT6.3.2.19TRAF6 oligomer autoubiquitinatesThis 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>K63polyUbReactome DB_ID: 9834431Reactome Database ID Release 759834431Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834431ReactomeR-RNO-4501521Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-450152.1UBE2N:UBE2V1Reactome DB_ID: 9834360Ube2nUBE2NQ9EQX9Reactome DB_ID: 9834354UniProt:Q9EQX9Ube2nUniProtQ9EQX91EQUAL152EQUALReactome Database ID Release 759834354Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834354ReactomeR-RNO-2060721Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-206072.11UBE2V1LOC100912618D3ZFY8Reactome DB_ID: 9834358UniProt:D3ZFY8LOC100912618UniProtD3ZFY82EQUAL147EQUALReactome Database ID Release 759834358Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834358ReactomeR-RNO-2057531Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-205753.11Reactome Database ID Release 759834360Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834360ReactomeR-RNO-2024631Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-202463.1PPipyrophosphatediphosphoric acidpyrophosphoric aciddiphosphateReactome DB_ID: 111294diphosphoric acid [ChEBI:29888]diphosphoric acidChEBICHEBI:29888Reactome Database ID Release 75111294Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=111294ReactomeR-ALL-1112943Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-111294.3COMPOUNDC00013p-T231-CARD9:BCL10:MALT1:K63polyUb-TRAF6 oligomersReactome DB_ID: 98949941K63polyUb-TRAF6 oligomerReactome DB_ID: 9894992Reactome Database ID Release 759894992Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894992ReactomeR-RNO-56076251Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607625.11Reactome Database ID Release 759894994Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894994ReactomeR-RNO-56076751Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607675.1AMPadenosine 5'-monophosphateAdenylic acidAdenylate5'-AMP5'-Adenylic acid5'-Adenosine monophosphateAdenosine 5'-phosphateReactome DB_ID: 76577adenosine 5'-monophosphate [ChEBI:16027]adenosine 5'-monophosphateChEBICHEBI:16027Reactome Database ID Release 7576577Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=76577ReactomeR-ALL-765774Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-76577.4COMPOUNDC00020ACTIVATIONactiveUnit: #Protein35GENE ONTOLOGYGO:0004842Reactome Database ID Release 759895076Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895076Reactome Database ID Release 759895078Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895078ReactomeR-RNO-56077561Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607756.1TRAF6 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.11057907Pubmed2000Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chainDeng, LWang, CSpencer, EYang, LBraun, AYou, JSlaughter, CPickart, CChen, ZJCell 103:351-6117135271Pubmed2007Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activationLamothe, BBesse, ACampos, ADWebster, WKWu, HDarnay, BGJ Biol Chem 282:4102-12LEFT-TO-RIGHTTRIKA2 binds K63polyUb-TRAF6 oligomerThis 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>TAK1 complexReactome DB_ID: 9834383Converted from EntitySet in ReactomeTAB2,TAB3Reactome DB_ID: 9834381Tab2TAB2Q5U303Reactome DB_ID: 9834375UniProt:Q5U303Tab2UniProtQ5U3031EQUAL693EQUALReactome Database ID Release 759834375Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834375ReactomeR-RNO-1681171Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-168117.1Tab3TAB3F1M1D2Reactome DB_ID: 9834379UniProt:F1M1D2Tab3UniProtF1M1D22EQUAL712EQUALReactome Database ID Release 759834379Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834379ReactomeR-RNO-4502641Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-450264.1Reactome Database ID Release 759834381Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834381ReactomeR-RNO-4468741Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-446874.11Map3k7MAP3K7P0C8E4Reactome DB_ID: 9834367UniProt:P0C8E4Map3k7UniProtP0C8E41EQUAL606EQUALReactome Database ID Release 759834367Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834367ReactomeR-RNO-1681561Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-168156.11Tab1TAB1A0A0U1RRU5Reactome DB_ID: 9834371UniProt:A0A0U1RRU5Tab1UniProtA0A0U1RRU51EQUAL504EQUALReactome Database ID Release 759834371Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834371ReactomeR-RNO-1679231Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-167923.11Reactome Database ID Release 759834383Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834383ReactomeR-RNO-4468781Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-446878.1p-T231-CARD9:BCL10:MALT1:K63polyUb-TRAF6 oligomers:TRIKA2Reactome DB_ID: 989508011Reactome Database ID Release 759895080Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895080ReactomeR-RNO-56076721Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607672.1Reactome Database ID Release 759895085Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895085ReactomeR-RNO-56077591Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607759.1K-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).17496917Pubmed2007Ubiquitin-mediated activation of TAK1 and IKKAdhikari, AXu, MChen, ZJOncogene 26:3214-2615327770Pubmed2004TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chainsKanayama, ASeth, RBSun, LEa, CKHong, MShaito, AChiu, YHDeng, LChen, ZJMol Cell 15:535-4817158449Pubmed2007TAK1-dependent signaling requires functional interaction with TAB2/TAB3Besse, ALamothe, BCampos, ADWebster, WKMaddineni, ULin, SCWu, HDarnay, BGJ Biol Chem 282:3918-2819955178Pubmed2010Transforming 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 pathwayBroglie, PeterMatsumoto, KunihiroAkira, ShizuoBrautigan, David LNinomiya-Tsuji, JunJ. Biol. Chem. 285:2333-914633987Pubmed2003Role of the TAB2-related protein TAB3 in IL-1 and TNF signalingIshitani, TTakaesu, GNinomiya-Tsuji, JShibuya, HGaynor, RBMatsumoto, KEMBO J 22:6277-8810882101Pubmed2000TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathwayTakaesu, GKishida, SHiyama, AYamaguchi, KShibuya, HIrie, KNinomiya-Tsuji, JMatsumoto, KMol Cell 5:649-58LEFT-TO-RIGHT6.3.2.19K63polyUb-TRAF6 ubiquitinates TAK1This 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>p-T231-CARD9:BCL10:MALT1:K63polyUb-TRAF6 oligomers:TAB1:TAB2/TAB3:K63polyUb-34,158-TAK1Reactome DB_ID: 9894996TAB1:TAB2/TAB3:K63polyUb-34,158-TAK1Reactome DB_ID: 989497911Map3k7K63polyUb-34,158-TAK1P0C8E4Reactome DB_ID: 989497734EQUALubiquitinylated lysineMODMOD:01148158EQUAL1EQUAL606EQUALReactome Database ID Release 759894977Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894977ReactomeR-RNO-56076431Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607643.11Reactome Database ID Release 759894979Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894979ReactomeR-RNO-56076911Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607691.111Reactome Database ID Release 759894996Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894996ReactomeR-RNO-56076951Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607695.1ACTIVATIONactiveUnit: #Protein35Reactome Database ID Release 759895081Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895081Reactome Database ID Release 759895083Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895083ReactomeR-RNO-56077571Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607757.1TAK1-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).20038579Pubmed2010Lysine 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 activationFan, YihuiYu, YangShi, YiSun, WenjingXie, MinGe, NinglingMao, RenfangChang, AlexXu, GufengSchneider, Michael DZhang, HFu, SongbinQin, JYang, JianhuaJ. Biol. Chem. 285:5347-6022069318Pubmed2012Polyubiquitination of transforming growth factor ? (TGF?)-associated kinase 1 mediates nuclear factor-?B activation in response to different inflammatory stimuliHamidi, Anahitavon Bulow, VerenaHamidi, RositaWinssinger, NicolasBarluenga, SofiaHeldin, Carl-HenrikLandström, MareneJ. Biol. Chem. 287:123-33LEFT-TO-RIGHT2.7.11K63polyUb-TAK1 autophosphorylatesThis 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>44p-T231-CARD9:BCL10:MALT1:K63polyUb-TRAF6 oligomers:TAB1:TAB2/TAB3:K63polyUb-34,158-p3Y,1S-TAK1Reactome DB_ID: 9895004TAB1:TAB2,TAB3:K63polyUb-34,158-p-T178,184,187,S192-TAK1Reactome DB_ID: 98950021P0C8E4phospho-Map3k7K63polyUb-34,158-p-T178,184,187,S192-TAK1Reactome DB_ID: 9895000178EQUAL184EQUAL187EQUAL192EQUAL1EQUAL606EQUALReactome Database ID Release 759895000Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895000ReactomeR-RNO-56076491Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607649.111Reactome Database ID Release 759895002Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895002ReactomeR-RNO-56076831Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607683.111Reactome Database ID Release 759895004Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895004ReactomeR-RNO-56076731Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607673.1ACTIVATIONactiveUnit: #Protein43GENE ONTOLOGYGO:0004674Reactome Database ID Release 759895005Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895005Reactome Database ID Release 759895007Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895007ReactomeR-RNO-56077321Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607732.1TAK1-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).20538596Pubmed2010Autoactivation of transforming growth factor beta-activated kinase 1 is a sequential bimolecular processScholz, RolandSidler, Corinne LThali, Ramon FWinssinger, NicolasCheung, Peter C FNeumann, DJ. Biol. Chem. 285:25753-66LEFT-TO-RIGHT2.7.11K63polyUb-p-3T,1S-TAK1 phosphorylates IKK-betaThis 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>CHUK:IKBKB:IKBKGReactome DB_ID: 9834338IkbkbIKBKBQ9QY78Reactome DB_ID: 9834336UniProt:Q9QY78IkbkbUniProtQ9QY781EQUAL756EQUALReactome Database ID Release 759834336Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834336ReactomeR-RNO-1681141Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-168114.11ChukCHUKG3V926Reactome DB_ID: 9834334UniProt:G3V926ChukUniProtG3V9261EQUAL745EQUALReactome Database ID Release 759834334Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834334ReactomeR-RNO-1681041Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-168104.11IkbkgIKBKGQ6TMG5Reactome DB_ID: 9834230UniProt:Q6TMG5IkbkgUniProtQ6TMG51EQUAL419EQUALReactome Database ID Release 759834230Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834230ReactomeR-RNO-1681081Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-168108.11Reactome Database ID Release 759834338Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834338ReactomeR-RNO-1681131Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-168113.12p-S177,S181-IKKB:IKKA:NEMOReactome DB_ID: 98421541Q9QY78phospho-Ikbkbp-S177,S181-IKBKBReactome DB_ID: 9834242177EQUAL181EQUAL1EQUAL756EQUALReactome Database ID Release 759834242Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834242ReactomeR-RNO-2025061Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-202506.111Reactome Database ID Release 759842154Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9842154ReactomeR-RNO-2025131Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-202513.12ACTIVATIONactiveUnit: #Protein44Reactome Database ID Release 759895040Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895040Reactome Database ID Release 759895042Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895042ReactomeR-RNO-56077421Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607742.1In 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.20300203Pubmed2010The IKK complex, a central regulator of NF-kappaB activationIsrael, ACold Spring Harb Perspect Biol 2:a00015811460167Pubmed2001TAK1 is a ubiquitin-dependent kinase of MKK and IKKWang, CDeng, LHong, MAkkaraju, GRInoue, JChen, ZJNature 412:346-5111325957Pubmed2001Persistent activation of NF-kappa B by the tax transforming protein involves chronic phosphorylation of IkappaB kinase subunits IKKbeta and IKKgammaCarter, R SGeyer, B CXie, MAcevedo-Suárez, C ABallard, D WJ. Biol. Chem. 276:24445-814514672Pubmed2003Signal-induced ubiquitination of I kappaB Kinase-betaCarter, Robert SPennington, Kevin NUngurait, Bradley JArrate, PiaBallard, Dean WJ. Biol. Chem. 278:48903-617047224Pubmed2006Regulation and function of IKK and IKK-related kinasesHacker, HKarin, MSci STKE 2006:re13LEFT-TO-RIGHT6.3.2.19Ubiquitination of NEMO by TRAF6This 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>p-S177,S181-IKKB:IKKA:pUb-NEMOReactome DB_ID: 9842179IkbkgK63polyUb-NEMOQ6TMG5Reactome DB_ID: 9842177321EQUAL325EQUAL326EQUAL1EQUAL419EQUALReactome Database ID Release 759842177Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9842177ReactomeR-RNO-2025301Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-202530.1111Reactome Database ID Release 759842179Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9842179ReactomeR-RNO-2025621Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-202562.1ACTIVATIONactiveUnit: #Protein50Ub-TRAF6 trimer bound to CBM complexReactome DB_ID: 9842147Traf6K63polyUb-TRAF6B5DF45Reactome DB_ID: 9834350124EQUAL1EQUAL522EQUALReactome Database ID Release 759834350Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834350ReactomeR-RNO-26856811Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2685681.13MALT1 trimer bound to Bcl10 and CARMA1 trimerReactome DB_ID: 9842143Bcl10 trimer bound to CARMA1 trimerReactome DB_ID: 9842135Q9QYN5phospho-Bcl10p-BCL10Reactome DB_ID: 9842133phosphorylated residueMODMOD:006961EQUAL233EQUALReactome Database ID Release 759842133Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9842133ReactomeR-RNO-2024881Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-202488.13CARMA1 trimerReactome DB_ID: 9842128Ghost homologue of p-S552-CARD11Reactome DB_ID: 9842126Reactome Database ID Release 759842126Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9842126ReactomeR-RNO-2024381Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-202438.13PDK1:PIP2,PIP3Reactome DB_ID: 9841850Converted from EntitySet in ReactomePIP3, PI(3,4)P2Reactome DB_ID: 202277PIP3PI(3,4,5)P31-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphatePhosphatidylinositol-3,4,5-trisphosphateReactome DB_ID: 1798381-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate [ChEBI:16618]1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphatePIP3ChEBICHEBI:16618Reactome Database ID Release 75179838Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=179838ReactomeR-ALL-1798383Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-179838.3COMPOUNDC05981PI(3,4)P21-phosphatidyl-1D-myo-inositol 3,4-bisphosphates1-phosphatidyl-1D-myo-inositol 3,4-bisphosphateReactome DB_ID: 2022471-phosphatidyl-1D-myo-inositol 3,4-bisphosphate [ChEBI:16152]1-phosphatidyl-1D-myo-inositol 3,4-bisphosphateChEBICHEBI:16152Reactome Database ID Release 75202247Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202247ReactomeR-ALL-2022473Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-202247.3Reactome Database ID Release 75202277Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202277ReactomeR-ALL-2022771Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-202277.11Pdpk1PDPK1O55173Reactome DB_ID: 9828577UniProt:O55173 Pdpk1Pdpk1Pdk1FUNCTION Serine/threonine kinase which acts as a master kinase, phosphorylating and activating a subgroup of the AGC family of protein kinases. Its targets include: protein kinase B (PKB/AKT1, PKB/AKT2, PKB/AKT3), p70 ribosomal protein S6 kinase (RPS6KB1), p90 ribosomal protein S6 kinase (RPS6KA1, RPS6KA2 and RPS6KA3), cyclic AMP-dependent protein kinase (PRKACA), protein kinase C (PRKCD and PRKCZ), serum and glucocorticoid-inducible kinase (SGK1, SGK2 and SGK3), p21-activated kinase-1 (PAK1), protein kinase PKN (PKN1 and PKN2). Plays a central role in the transduction of signals from insulin by providing the activating phosphorylation to PKB/AKT1, thus propagating the signal to downstream targets controlling cell proliferation and survival, as well as glucose and amino acid uptake and storage. Negatively regulates the TGF-beta-induced signaling by: modulating the association of SMAD3 and SMAD7 with TGF-beta receptor, phosphorylating SMAD2, SMAD3, SMAD4 and SMAD7, preventing the nuclear translocation of SMAD3 and SMAD4 and the translocation of SMAD7 from the nucleus to the cytoplasm in response to TGF-beta. Activates PPARG transcriptional activity and promotes adipocyte differentiation. Activates the NF-kappa-B pathway via phosphorylation of IKKB. The tyrosine phosphorylated form is crucial for the regulation of focal adhesions by angiotensin II. Controls proliferation, survival, and growth of developing pancreatic cells. Participates in the regulation of Ca(2+) entry and Ca(2+)-activated K(+) channels of mast cells. Essential for the motility of vascular endothelial cells (ECs) and is involved in the regulation of their chemotaxis. Plays a critical role in cardiac homeostasis by serving as a dual effector for cell survival and beta-adrenergic response. Plays an important role during thymocyte development by regulating the expression of key nutrient receptors on the surface of pre-T cells and mediating Notch-induced cell growth and proliferative responses. Provides negative feedback inhibition to toll-like receptor-mediated NF-kappa-B activation in macrophages (By similarity).ACTIVITY REGULATION Homodimerization regulates its activity by maintaining the kinase in an autoinhibitory conformation. NPRL2 down-regulates its activity by interfering with tyrosine phosphorylation at the Tyr-9, Tyr-376 and Tyr-379 residues. The 14-3-3 protein YWHAQ acts as a negative regulator by association with the residues surrounding the Ser-244 residue. STRAP positively regulates its activity by enhancing its autophosphorylation and by stimulating its dissociation from YWHAQ. SMAD2, SMAD3, SMAD4 and SMAD7 also positively regulate its activity by stimulating its dissociation from YWHAQ. Activated by phosphorylation on Tyr-9, Tyr-376 and Tyr-379 by INSR in response to insulin (By similarity).SUBUNIT Homodimer in its autoinhibited state. Active as monomer. Interacts with NPRL2, PPARG, PAK1, PTK2B, GRB14, PKN1 (via C-terminus), STRAP and IKKB. The Tyr-9 phosphorylated form interacts with SRC, RASA1 and CRK (via their SH2 domains). Interacts with SGK3 in a phosphorylation-dependent manner. The tyrosine-phosphorylated form interacts with PTPN6. The Ser-244 phosphorylated form interacts with YWHAH and YWHAQ. Binds INSR in response to insulin. Interacts (via PH domain) with SMAD3, SMAD4 and SMAD7 (By similarity). Interacts with PKN2; the interaction stimulates PDPK1 autophosphorylation, its PI(3,4,5)P3-dependent kinase activity toward 'Ser-473' of AKT1 but also activates its kinase activity toward PRKCD and PRKCZ.DOMAIN The PH domain plays a pivotal role in the localization and nuclear import of PDPK1 and is also essential for its homodimerization.DOMAIN The PIF-pocket is a small lobe in the catalytic domain required by the enzyme for the binding to the hydrophobic motif of its substrates. It is an allosteric regulatory site that can accommodate small compounds acting as allosteric inhibitors.PTM Phosphorylation on Ser-244 in the activation loop is required for full activity. PDPK1 itself can autophosphorylate Ser-244, leading to its own activation. Autophosphorylation is inhibited by the apoptotic C-terminus cleavage product of PKN2. Tyr-9 phosphorylation is critical for stabilization of both PDPK1 and the PDPK1/SRC complex via HSP90-mediated protection of PDPK1 degradation. Angiotensin II stimulates the tyrosine phosphorylation of PDPK1 in vascular smooth muscle in a calcium- and SRC-dependent manner. Phosphorylated on Tyr-9, Tyr-376 and Tyr-379 by INSR in response to insulin. Palmitate negatively regulates autophosphorylation at Ser-244 and palmitate-induced phosphorylation at Ser-532 and Ser-504 by PKC/PRKCQ negatively regulates its ability to phosphorylate PKB/AKT1. Phosphorylation at Thr-357 by MELK partially inhibits kinase activity, the inhibition is cooperatively enhanced by phosphorylation at Ser-397 and Ser-401 by MAP3K5 (By similarity).PTM Monoubiquitinated in the kinase domain, deubiquitinated by USP4.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. PDPK1 subfamily.UniProtO551731EQUAL556EQUALReactome Database ID Release 759828577Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9828577ReactomeR-RNO-614591Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-61459.11Reactome Database ID Release 759841850Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9841850ReactomeR-RNO-2023111Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-202311.11Reactome Database ID Release 759842128Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9842128ReactomeR-RNO-2024451Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-202445.11Reactome Database ID Release 759842135Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9842135ReactomeR-RNO-2024751Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-202475.11MALT1 trimerReactome DB_ID: 98421413Reactome Database ID Release 759842141Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9842141ReactomeR-RNO-2024871Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-202487.11Reactome Database ID Release 759842143Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9842143ReactomeR-RNO-2024681Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-202468.11Reactome Database ID Release 759842147Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9842147ReactomeR-RNO-2024561Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-202456.1Reactome Database ID Release 759842180Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9842180Reactome Database ID Release 759842182Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9842182ReactomeR-RNO-2025341Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-202534.1During 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). 19136968Pubmed2009Involvement of linear polyubiquitylation of NEMO in NF-kappaB activationTokunaga, FuminoriSakata, Shin-ichiSaeki, YasushiSatomi, YoshinoriKirisako, TakayoshiKamei, KiyokoNakagawa, TomokoKato, MichikoMurata, ShigeoYamaoka, ShojiYamamoto, MAkira, ShizuoTakao, ToshifumiTanaka, KeijiIwai, KazuhiroNat. Cell Biol. 11:123-3217728323Pubmed2007Identification of TRAF6-dependent NEMO polyubiquitination sites through analysis of a new NEMO mutation causing incontinentia pigmentiSebban-Benin, HPescatore, AFusco, FPascuale, VGautheron, JYamaoka, SMoncla, AUrsini, MVCourtois, GHum Mol Genet 127:LEFT-TO-RIGHT2.7.11p-S177,S181-IKKB:IKKA:pUb-NEMO phosphorylates IkB-alpha:NF-kBThis 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>IkB(alpha):NF-kB complexReactome DB_ID: 9838630NfkbiaNFKBIAQ63746Reactome DB_ID: 9834208UniProt:Q63746NfkbiaUniProtQ637461EQUAL317EQUALReactome Database ID Release 759834208Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834208ReactomeR-RNO-1681511Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-168151.11NFKB1(1-433):RELAReactome DB_ID: 9838571Nfkb1NFKB1(1-433)F1LQH2Reactome DB_ID: 9834196UniProt:F1LQH2Nfkb1UniProtF1LQH21EQUAL433EQUALReactome Database ID Release 759834196Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834196ReactomeR-RNO-1681681Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-168168.11RelaRELAQ7TQN4Reactome DB_ID: 9834192UniProt:Q7TQN4RelaUniProtQ7TQN41EQUAL551EQUALReactome Database ID Release 759834192Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834192ReactomeR-RNO-1681721Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-168172.11Reactome Database ID Release 759838571Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9838571ReactomeR-RNO-1940431Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-194043.11Reactome Database ID Release 759838630Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9838630ReactomeR-RNO-1939381Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-193938.12p-S32,36-IkB-alpha:NF-kB complexReactome DB_ID: 98421841Q63746phospho-Nfkbiap-S32,S36-NFKBIAReactome DB_ID: 983422032EQUAL36EQUAL1EQUAL317EQUALReactome Database ID Release 759834220Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834220ReactomeR-RNO-1776771Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-177677.11Reactome Database ID Release 759842184Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9842184ReactomeR-RNO-56076711Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607671.12ACTIVATIONactiveUnit: #Protein48Reactome Database ID Release 759842185Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9842185Reactome Database ID Release 759842187Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9842187ReactomeR-RNO-2025411Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-202541.1NF-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)9252186Pubmed1997A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaBDiDonato, JAHayakawa, MRothwarf, DMZandi, EKarin, MNature 388:548-5415145317Pubmed2004The two NF-kappaB activation pathways and their role in innate and adaptive immunityBonizzi, GKarin, MTrends Immunol 25:280-815371334Pubmed2004Signaling to NF-kappaBHayden, MSGhosh, SGenes Dev 18:2195-22410837071Pubmed2000Phosphorylation meets ubiquitination: the control of NF-[kappa]B activityKarin, MBen-Neriah, YAnnu. Rev. Immunol. 18:621-638601309Pubmed1996Site-specific phosphorylation of IkappaBalpha by a novel ubiquitination-dependent protein kinase activityChen, Z JParent, LManiatis, TCell 84:853-6217363905Pubmed2007Phosphorylation and ubiquitination of the IkappaB kinase complex by two distinct signaling pathwaysShambharkar, PBBlonska, MPappu, BPLi, HYou, YSakurai, HDarnay, BGHara, HPenninger, JLin, XEMBO J 26:1794-805LEFT-TO-RIGHT6.3.2.19beta-TRCP ubiquitinates IkB-alpha in p-S32,33-IkB-alpha:NF-kB complexThis 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>CUL1:FBXW11:SKP1Reactome DB_ID: 9867579Cul1CUL1B1WBY1Reactome DB_ID: 9835484UniProt:B1WBY1Cul1UniProtB1WBY11EQUAL776EQUALReactome Database ID Release 759835484Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9835484ReactomeR-RNO-1742301Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-174230.11Skp1SKP1Q6PEC4Reactome DB_ID: 9835482UniProt:Q6PEC4Skp1UniProtQ6PEC42EQUAL163EQUALReactome Database ID Release 759835482Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9835482ReactomeR-RNO-1741501Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-174150.11Fbxw11FBXW11A0A0G2JVE0Reactome DB_ID: 9864908UniProt:A0A0G2JVE0Fbxw11UniProtA0A0G2JVE01EQUAL542EQUALReactome Database ID Release 759864908Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9864908ReactomeR-RNO-9760351Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-976035.11Reactome Database ID Release 759867579Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9867579ReactomeR-RNO-11685921Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-1168592.1Converted from EntitySet in ReactomeUBE2D2,UBE2D1,(CDC34)Reactome DB_ID: 9894966UBE2D2D3ZL88Reactome DB_ID: 9865445UniProt:D3ZL88UniProtD3ZL881EQUAL147EQUALReactome Database ID Release 759865445Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9865445ReactomeR-RNO-9346281Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-934628.1Ube2d1UBE2D1D3ZDK2Reactome DB_ID: 9821796UniProt:D3ZDK2Ube2d1UniProtD3ZDK21EQUAL147EQUALReactome Database ID Release 759821796Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821796ReactomeR-RNO-1742361Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-174236.1Cdc34CDC34D4A453Reactome DB_ID: 9865511UniProt:D4A453Cdc34UniProtD4A4531EQUAL236EQUALReactome Database ID Release 759865511Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9865511ReactomeR-RNO-9476211Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-947621.1Reactome Database ID Release 759894966Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894966ReactomeR-RNO-56076691Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607669.1Converted from EntitySet in ReactomeK48-UbK48-ubiquitinReactome DB_ID: 9860870Rps27aUb-48-RPS27A(1-76)P62982Reactome DB_ID: 9860829UniProt:P62982Rps27aUniProtP6298248EQUAL1EQUAL76EQUALReactome Database ID Release 759860829Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9860829ReactomeR-RNO-9392021Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-939202.1Uba52Ub-48-UBA52(1-76)P62986Reactome DB_ID: 9860832UniProt:P62986Uba52UniProtP6298648EQUAL1EQUAL76EQUALReactome Database ID Release 759860832Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9860832ReactomeR-RNO-9392501Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-939250.1UbbUb-48-UBB(1-76)P0CG51Reactome DB_ID: 9860835UniProt:P0CG51UbbUniProtP0CG5148EQUAL1EQUAL76EQUALReactome Database ID Release 759860835Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9860835ReactomeR-RNO-9392491Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-939249.1UbcUb-48-UBC(1-76)Q63429Reactome DB_ID: 9860844UniProt:Q63429UbcUniProtQ6342948EQUAL1EQUAL76EQUALReactome Database ID Release 759860844Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9860844ReactomeR-RNO-9392191Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-939219.1Reactome Database ID Release 759860870Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9860870ReactomeR-RNO-9127221Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-912722.14K48PolyUb-K21,22-p-S32,36-IkBA:NF-kB complexReactome DB_ID: 98949511Q63746phospho-NfkbiaK48PolyUb-K21,22-p-S32,S36-IkBAReactome DB_ID: 989494921EQUAL22EQUAL1EQUAL317EQUALReactome Database ID Release 759894949Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894949ReactomeR-RNO-56076591Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607659.11Reactome Database ID Release 759894951Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894951ReactomeR-RNO-56076971Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607697.1ACTIVATIONReactome Database ID Release 759894967Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894967Reactome Database ID Release 759894969Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894969ReactomeR-RNO-56077281Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607728.1Two 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).10918611Pubmed2000SCF(beta-TRCP) and phosphorylation dependent ubiquitinationof I kappa B alpha catalyzed by Ubc3 and Ubc4Strack, PCaligiuri, MPelletier, MBoisclair, MTheodoras, ABeer-Romero, PGlass, SParsons, TCopeland, R AAuger, K RBenfield, PBrizuela, LRolfe, MOncogene 19:3529-367479848Pubmed1995Stimulation-dependent I kappa B alpha phosphorylation marks the NF-kappa B inhibitor for degradation via the ubiquitin-proteasome pathwayAlkalay, IYaron, AHatzubai, AOrian, ACiechanover, ABen-Neriah, YProc Natl Acad Sci U S A 92:10599-60320347421Pubmed2010Priming and extending: a UbcH5/Cdc34 E2 handoff mechanism for polyubiquitination on a SCF substrateWu, KKovacev, JPan, ZQMol Cell 37:784-967479976Pubmed1995Signal-induced degradation of I kappa B alpha requires site-specific ubiquitinationScherer, DCBrockman, JAChen, ZManiatis, TBallard, DWProc Natl Acad Sci U S A 92:11259-639990853Pubmed1999Signal-induced ubiquitination of IkappaBalpha by the F-box protein Slimb/beta-TrCPSpencer, EJiang, JChen, ZJGenes Dev 13:284-948649784Pubmed1996Identification of lysine residues required for signal-induced ubiquitination and degradation of I kappa B-alpha in vivoRodriguez, M SWright, JThompson, JThomas, DBaleux, FVirelizier, J LHay, R TArenzana-Seisdedos, FOncogene 12:2425-358550590Pubmed1996Critical role for lysines 21 and 22 in signal-induced, ubiquitin-mediated proteolysis of I kappa B-alphaBaldi, LBrown, KFranzoso, GSiebenlist, UJ. Biol. Chem. 271:376-9LEFT-TO-RIGHT26S proteasome processes K48PolyUb-K21,22-p-S32,36-IkBA:NF-kB complex to form NF-kB complexThis 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>ACTIVATION26S proteasomeReactome DB_ID: 9821468Psma5PSMA5P34064Reactome DB_ID: 9821306UniProt:P34064Psma5UniProtP340641EQUAL241EQUALReactome Database ID Release 759821306Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821306ReactomeR-RNO-687321Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68732.11Psmc4PSMC4Q63570Reactome DB_ID: 9821376UniProt:Q63570Psmc4UniProtQ635701EQUAL418EQUALReactome Database ID Release 759821376Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821376ReactomeR-RNO-687771Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68777.11Psme2PSME2Q63798Reactome DB_ID: 9821444UniProt:Q63798Psme2UniProtQ637982EQUAL239EQUALReactome Database ID Release 759821444Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821444ReactomeR-RNO-688141Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68814.11Ghost homologue of SHFM1Reactome DB_ID: 9821466Reactome Database ID Release 759821466Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821466ReactomeR-RNO-88666741Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-8866674.11Psmd4PSMD4O88321Reactome DB_ID: 9821416UniProt:O88321Psmd4UniProtO883211EQUAL377EQUALReactome Database ID Release 759821416Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821416ReactomeR-RNO-688001Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68800.11Psmb7PSMB7Q9JHW0Reactome DB_ID: 9821352UniProt:Q9JHW0Psmb7UniProtQ9JHW044EQUAL277EQUALReactome Database ID Release 759821352Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821352ReactomeR-RNO-687591Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68759.11Psme4PSME4A0A0G2KAX0Reactome DB_ID: 9821456UniProt:A0A0G2KAX0Psme4UniProtA0A0G2KAX01EQUAL1843EQUALReactome Database ID Release 759821456Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821456ReactomeR-RNO-9476061Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-947606.11Psma1PSMA1P18420Reactome DB_ID: 9821290UniProt:P18420Psma1UniProtP184201EQUAL263EQUALReactome Database ID Release 759821290Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821290ReactomeR-RNO-687241Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68724.11Psmd14PSMD14Q4V8E2Reactome DB_ID: 9821286UniProt:Q4V8E2Psmd14UniProtQ4V8E21EQUAL310EQUALReactome Database ID Release 759821286Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821286ReactomeR-RNO-687221Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68722.11Psmd3PSMD3Q5U2S7Reactome DB_ID: 9821412UniProt:Q5U2S7Psmd3UniProtQ5U2S71EQUAL534EQUALReactome Database ID Release 759821412Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821412ReactomeR-RNO-687981Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68798.11Psmc5PSMC5P62198Reactome DB_ID: 9821380UniProt:P62198Psmc5UniProtP621982EQUAL406EQUALReactome Database ID Release 759821380Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821380ReactomeR-RNO-687801Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68780.11Psma2PSMA2P17220Reactome DB_ID: 9821294UniProt:P17220Psma2UniProtP172202EQUAL234EQUALReactome Database ID Release 759821294Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821294ReactomeR-RNO-687261Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68726.11Psmb5PSMB5P28075Reactome DB_ID: 9821338UniProt:P28075Psmb5UniProtP2807560EQUAL263EQUALReactome Database ID Release 759821338Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821338ReactomeR-RNO-687531Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68753.11Psmd10PSMD10Q9Z2X3Reactome DB_ID: 9821392UniProt:Q9Z2X3Psmd10UniProtQ9Z2X31EQUAL226EQUALReactome Database ID Release 759821392Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821392ReactomeR-RNO-687881Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68788.11Psmb3PSMB3P40112Reactome DB_ID: 9821330UniProt:P40112Psmb3UniProtP401122EQUAL205EQUALReactome Database ID Release 759821330Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821330ReactomeR-RNO-687471Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68747.11Psma3PSMA3P18422Reactome DB_ID: 9821298UniProt:P18422Psma3UniProtP184222EQUAL255EQUALReactome Database ID Release 759821298Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821298ReactomeR-RNO-687281Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68728.11Psmd1PSMD1O88761Reactome DB_ID: 9821388UniProt:O88761Psmd1UniProtO887611EQUAL953EQUALReactome Database ID Release 759821388Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821388ReactomeR-RNO-687861Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68786.11Psmb8PSMB8P28064Reactome DB_ID: 9821356UniProt:P28064Psmb8UniProtP2806473EQUAL276EQUALReactome Database ID Release 759821356Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821356ReactomeR-RNO-687621Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68762.11Psmc1PSMC1P62193Reactome DB_ID: 9821364UniProt:P62193Psmc1UniProtP621932EQUAL440EQUALReactome Database ID Release 759821364Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821364ReactomeR-RNO-687681Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68768.11Psmc3PSMC3Q63569Reactome DB_ID: 9821372UniProt:Q63569Psmc3UniProtQ635691EQUAL439EQUALReactome Database ID Release 759821372Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821372ReactomeR-RNO-687741Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68774.11Psma6PSMA6P60901Reactome DB_ID: 9821310UniProt:P60901Psma6UniProtP609011EQUAL246EQUALReactome Database ID Release 759821310Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821310ReactomeR-RNO-687341Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68734.11Psmd12PSMD12Q5XIC6Reactome DB_ID: 9821400UniProt:Q5XIC6Psmd12UniProtQ5XIC62EQUAL456EQUALReactome Database ID Release 759821400Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821400ReactomeR-RNO-687921Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68792.11Psma8PSMA8F1M6I7Reactome DB_ID: 9821460UniProt:F1M6I7Psma8UniProtF1M6I71EQUAL256EQUALReactome Database ID Release 759821460Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821460ReactomeR-RNO-9476101Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-947610.11Psmd7PSMD7D4AEH3Reactome DB_ID: 9821428UniProt:D4AEH3Psmd7UniProtD4AEH31EQUAL324EQUALReactome Database ID Release 759821428Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821428ReactomeR-RNO-688061Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68806.11Psmf1PSMF1Q5XIU5Reactome DB_ID: 9821452UniProt:Q5XIU5Psmf1UniProtQ5XIU51EQUAL271EQUALReactome Database ID Release 759821452Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821452ReactomeR-RNO-688181Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68818.11Converted from EntitySet in ReactomeHomologues of PSMB6Reactome DB_ID: 9821348PSMB6LOC100360846A0A0G2JSL0Reactome DB_ID: 9821342UniProt:A0A0G2JSL0LOC100360846UniProtA0A0G2JSL035EQUAL239EQUALReactome Database ID Release 759821342Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821342ReactomeR-RNO-687561Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68756.1Psmb6PSMB6P28073Reactome DB_ID: 9821346UniProt:P28073Psmb6UniProtP2807335EQUAL239EQUALReactome Database ID Release 759821346Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821346ReactomeR-RNO-68756-21Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68756-2.1Reactome Database ID Release 759821348Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821348ReactomeR-RNO-68756-31Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68756-3.11Psme1PSME1Q63797Reactome DB_ID: 9821440UniProt:Q63797Psme1UniProtQ637971EQUAL249EQUALReactome Database ID Release 759821440Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821440ReactomeR-RNO-688121Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68812.11Psmb11PSMB11M0R7C4Reactome DB_ID: 9821464UniProt:M0R7C4Psmb11UniProtM0R7C450EQUAL300EQUALReactome Database ID Release 759821464Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821464ReactomeR-RNO-9476071Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-947607.11Psmb1PSMB1P18421Reactome DB_ID: 9821318UniProt:P18421Psmb1UniProtP1842129EQUAL241EQUALReactome Database ID Release 759821318Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821318ReactomeR-RNO-687381Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68738.11Psme3PSME3Q5FVM2Reactome DB_ID: 9821448UniProt:Q5FVM2Psme3UniProtQ5FVM22EQUAL254EQUALReactome Database ID Release 759821448Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821448ReactomeR-RNO-688161Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68816.11Psmb4PSMB4P34067Reactome DB_ID: 9821334UniProt:P34067Psmb4UniProtP3406746EQUAL264EQUALReactome Database ID Release 759821334Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821334ReactomeR-RNO-687501Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68750.11Psmd5PSMD5G3V8G2Reactome DB_ID: 9821420UniProt:G3V8G2Psmd5UniProtG3V8G22EQUAL504EQUALReactome Database ID Release 759821420Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821420ReactomeR-RNO-688021Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68802.11Psmb2PSMB2P40307Reactome DB_ID: 9821326UniProt:P40307Psmb2UniProtP403071EQUAL201EQUALReactome Database ID Release 759821326Database identifier. 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Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821368ReactomeR-RNO-687711Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68771.11Psmd13PSMD13B0BN93Reactome DB_ID: 9821404UniProt:B0BN93Psmd13UniProtB0BN931EQUAL376EQUALReactome Database ID Release 759821404Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821404ReactomeR-RNO-687941Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68794.11Psmd2PSMD2Q4FZT9Reactome DB_ID: 9821408UniProt:Q4FZT9Psmd2UniProtQ4FZT91EQUAL908EQUALReactome Database ID Release 759821408Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821408ReactomeR-RNO-687961Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68796.11Psmd9PSMD9Q9WTV5Reactome DB_ID: 9821436UniProt:Q9WTV5Psmd9UniProtQ9WTV51EQUAL223EQUALReactome Database ID Release 759821436Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821436ReactomeR-RNO-688101Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68810.11Psmd6PSMD6Q6PCT9Reactome DB_ID: 9821424UniProt:Q6PCT9Psmd6UniProtQ6PCT91EQUAL389EQUALReactome Database ID Release 759821424Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821424ReactomeR-RNO-688041Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68804.11Psma7PSMA7P48004Reactome DB_ID: 9821314UniProt:P48004Psma7UniProtP480041EQUAL248EQUALReactome Database ID Release 759821314Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821314ReactomeR-RNO-687361Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68736.11Psmd11PSMD11F1LMZ8Reactome DB_ID: 9821396UniProt:F1LMZ8Psmd11UniProtF1LMZ82EQUAL422EQUALReactome Database ID Release 759821396Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821396ReactomeR-RNO-687901Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68790.11Psmb10PSMB10Q4KM35Reactome DB_ID: 9821322UniProt:Q4KM35Psmb10UniProtQ4KM3540EQUAL273EQUALReactome Database ID Release 759821322Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821322ReactomeR-RNO-687411Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68741.11Psma4PSMA4P21670Reactome DB_ID: 9821302UniProt:P21670Psma4UniProtP216701EQUAL261EQUALReactome Database ID Release 759821302Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821302ReactomeR-RNO-687301Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68730.11Psmc6PSMC6G3V6W6Reactome DB_ID: 9821384UniProt:G3V6W6Psmc6UniProtG3V6W61EQUAL389EQUALReactome Database ID Release 759821384Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821384ReactomeR-RNO-687831Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68783.11Psmd8PSMD8F1LMQ3Reactome DB_ID: 9821432UniProt:F1LMQ3Psmd8UniProtF1LMQ31EQUAL350EQUALReactome Database ID Release 759821432Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821432ReactomeR-RNO-688081Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68808.11Reactome Database ID Release 759821468Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821468ReactomeR-RNO-688191Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-68819.1GENE ONTOLOGYGO:0004175Reactome Database ID Release 759821469Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821469Reactome Database ID Release 759894953Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894953ReactomeR-RNO-56077241Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607724.1Following ubiquitination Ikappa B-alpha (IKBA) is rapidly degraded by 26S-proteasome, allowing NF-kB to translocate into the nucleus where it activates gene transcription (Spencer et al. 1999).9362451Pubmed1997The carboxy-terminus of I kappaB alpha determines susceptibility to degradation by the catalytic core of the proteasomeKroll, MConconi, MDesterro, M JMarin, AThomas, DFriguet, BHay, R TVirelizier, J LArenzana-Seisdedos, FRodriguez, M SOncogene 15:1841-50LEFT-TO-RIGHTReleased NF-kB complex is transported to the nucleusNFKB1:RELA translocates from the cytosol to the nucleusThis 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>NFKB1(1-433):RELAReactome DB_ID: 9838573Nfkb1NFKB1(1-433)F1LQH2Reactome DB_ID: 98342911EQUAL433EQUALReactome Database ID Release 759834291Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834291ReactomeR-RNO-1776551Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-177655.11RelaRELAQ7TQN4Reactome DB_ID: 98342971EQUAL551EQUALReactome Database ID Release 759834297Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834297ReactomeR-RNO-1776761Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-177676.11Reactome Database ID Release 759838573Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9838573ReactomeR-RNO-1940471Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-194047.1Reactome Database ID Release 759885720Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9885720ReactomeR-RNO-27308941Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2730894.1The 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.17072321Pubmed2006Introduction to NF-kappaB: players, pathways, perspectivesGilmore, T DOncogene 25:6680-4Dectin-1 mediated noncanonical NF-kB signalingThis 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>LEFT-TO-RIGHTActivation of NIKThis 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>D3ZTD1Map3k14MAP3K14Reactome DB_ID: 9852670UniProt:D3ZTD1Map3k14UniProtD3ZTD11EQUAL947EQUALReactome Database ID Release 759852670Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852670ReactomeR-RNO-1681891Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-168189.1Reactome Database ID Release 759894923Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894923ReactomeR-RNO-56077211Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607721.1The 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).20501935Pubmed2010Controlling the fate of NIK: a central stage in noncanonical NF-kappaB signalingSun, Shao-CongSci Signal 3:pe1822718757Pubmed2012Structure of the nuclear factor ?B-inducing kinase (NIK) kinase domain reveals a constitutively active conformationLiu, JinsongSudom, AthenaMin, XiaoshanCao, ZGao, XiongAyres, MerrillLee, FeiCao, PingJohnstone, ShereePlotnikova, OlgaWalker, NigelChen, GuoqingWang, ZhulunJ. Biol. Chem. 287:27326-3420501937Pubmed2010Negative feedback in noncanonical NF-kappaB signaling modulates NIK stability through IKKalpha-mediated phosphorylationRazani, BahramZarnegar, BrianYtterberg, AJShiba, TravisDempsey, Paul WWare, Carl FLoo, Joseph ACheng, GenhongSci Signal 3:ra419020361Pubmed1997MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1Malinin, N LBoldin, M PKovalenko, A VWallach, DNature 385:540-4LEFT-TO-RIGHT2.7.11Active NIK phosphorylates IKKA dimerThis 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>IKKA dimerReactome DB_ID: 98949252Reactome Database ID Release 759894925Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894925ReactomeR-RNO-56077051Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607705.144Active NIK:p-S176,180-IKKA dimerReactome DB_ID: 9894911p-S176,S180-IKKA dimerReactome DB_ID: 9894909G3V926phospho-Chukp-S176,S180-CHUKReactome DB_ID: 9834236176EQUAL180EQUAL1EQUAL745EQUALReactome Database ID Release 759834236Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834236ReactomeR-RNO-1776671Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-177667.12Reactome Database ID Release 759894909Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894909ReactomeR-RNO-56077021Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607702.111Reactome Database ID Release 759894911Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894911ReactomeR-RNO-56076811Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607681.1ACTIVATIONReactome Database ID Release 759894926Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894926Reactome Database ID Release 759894928Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894928ReactomeR-RNO-56077221Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607722.1Accumulated 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).9520446Pubmed1998NF-kappaB-inducing kinase activates IKK-alpha by phosphorylation of Ser-176Ling, LCao, ZGoeddel, DVProc Natl Acad Sci U S A 95:3792-715140882Pubmed2004Induction of p100 processing by NF-kappaB-inducing kinase involves docking IkappaB kinase alpha (IKKalpha) to p100 and IKKalpha-mediated phosphorylationXiao, GutianFong, AbrahamSun, Shao-CongJ. Biol. Chem. 279:30099-10511520989Pubmed2001Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathwaySenftleben, UCao, YXiao, GGreten, F RKrähn, GBonizzi, GChen, YHu, YFong, ASun, S CKarin, MScience 293:1495-9LEFT-TO-RIGHTp100:RELB binds active NIK:p-IKKA dimerThis 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>p100:RELBReactome DB_ID: 9894917RelbRELBD4A8H1Reactome DB_ID: 9894915UniProt:D4A8H1RelbUniProtD4A8H11EQUAL579EQUALReactome Database ID Release 759894915Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894915ReactomeR-RNO-56076521Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607652.11Nfkb2NFKB2(1-900)Q5U2Z4Reactome DB_ID: 9891410UniProt:Q5U2Z4Nfkb2UniProtQ5U2Z41EQUAL900EQUALReactome Database ID Release 759891410Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9891410ReactomeR-RNO-26779311Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2677931.11Reactome Database ID Release 759894917Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894917ReactomeR-RNO-56077031Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607703.1Active NIK:p-S176,180-IKKA dimer:p100:RELBReactome DB_ID: 989491911Reactome Database ID Release 759894919Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894919ReactomeR-RNO-56076901Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607690.1Reactome Database ID Release 759894921Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894921ReactomeR-RNO-56077201Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607720.1NFKB2 (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).11239468Pubmed2001NF-kappaB-inducing kinase regulates the processing of NF-kappaB2 p100Xiao, GHarhaj, E WSun, S CMol. Cell 7:401-9LEFT-TO-RIGHT2.7.11Active NIK:p-S176,180-IKKA dimer phosphorylates p100:RELBThis 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>7Active NIK:p-S176,180-IKKA dimer:p-7S-p100:RELBReactome DB_ID: 9894941p-7S-p100:RELBReactome DB_ID: 98949391Q5U2Z4phospho-Nfkb2p-7S-p100Reactome DB_ID: 989493799EQUAL108EQUAL115EQUAL123EQUAL866EQUAL870EQUAL872EQUAL1EQUAL900EQUALReactome Database ID Release 759894937Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894937ReactomeR-RNO-56076291Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607629.11Reactome Database ID Release 759894939Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894939ReactomeR-RNO-56076861Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607686.111Reactome Database ID Release 759894941Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894941ReactomeR-RNO-56076981Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607698.17ACTIVATIONactiveUnit: #Complex50Reactome Database ID Release 759894962Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894962Reactome Database ID Release 759894964Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894964ReactomeR-RNO-56077261Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607726.1After 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).16303288Pubmed2006beta-TrCP binding and processing of NF-kappaB2/p100 involve its phosphorylation at serines 866 and 870Liang, ChunyangZhang, MinyingSun, Shao-CongCell. Signal. 18:1309-17LEFT-TO-RIGHTSCF-beta-TRCP binds p-7S-p100 in active NIK:p-S176,180-IKKA dimer:p-7S-p100:RELBThis 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>Active NIK:p-176,S180-IKKA dimer:p-7S-p100:SCF-beta-TRCPReactome DB_ID: 989494311Reactome Database ID Release 759894943Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894943ReactomeR-RNO-56076931Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607693.1Reactome Database ID Release 759894945Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894945ReactomeR-RNO-56077231Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607723.1Phosphorylated 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).15340381Pubmed2004The SCF ubiquitin ligase: insights into a molecular machineCardozo, TimothyPagano, MicheleNat. Rev. Mol. Cell Biol. 5:739-519346238Pubmed1997F-box proteins are receptors that recruit phosphorylated substrates to the SCF ubiquitin-ligase complexSkowyra, DCraig, K LTyers, MElledge, S JHarper, JWCell 91:209-1923680451Pubmed2013New insights on the function of SCF ubiquitin E3 ligases in the lungWeathington, Nathaniel MMallampalli, Rama KCell. Signal. 25:1792-88706131Pubmed1996SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-boxBai, CSen, PHofmann, KMa, LGoebl, MHarper, JWElledge, S JCell 86:263-749499404Pubmed1998Cdc53 is a scaffold protein for multiple Cdc34/Skp1/F-box proteincomplexes that regulate cell division and methionine biosynthesis in yeastPatton, E EWillems, A RSa, DKuras, LThomas, DCraig, K LTyers, MGenes Dev. 12:692-705LEFT-TO-RIGHT6.3.2.19SCF-beta-TRCP ubiquitinates p-7S-p100:RELB in active NIK:p-176,S180-IKKA dimer:p-7S-p100:SCF-beta-TRCPThis 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>Ube2mG76-NEDD8-C111-AcM-UBE2MD3ZNQ6Reactome DB_ID: 9890321UniProt:D3ZNQ6Ube2mUniProtD3ZNQ6111EQUALS-(glycyl)-L-cysteine (Cys-Gly)MODMOD:002111EQUALN-acetyl-L-methionineMODMOD:000581EQUAL183EQUALReactome Database ID Release 759890321Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9890321ReactomeR-RNO-44198941Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-4419894.1Uba3UBA3Q99MI7Reactome DB_ID: 9865606UniProt:Q99MI7Uba3UniProtQ99MI71EQUAL463EQUALReactome Database ID Release 759865606Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9865606ReactomeR-RNO-9476321Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-947632.14K48-polyUb-p-7S-p100:RELBReactome DB_ID: 98949581Q5U2Z4phospho-Nfkb2K48-polyUb-p-7S-p100Reactome DB_ID: 9894956855EQUAL1EQUAL900EQUALReactome Database ID Release 759894956Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894956ReactomeR-RNO-56076361Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607636.11Reactome Database ID Release 759894958Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894958ReactomeR-RNO-56076941Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607694.1ACTIVATIONactiveUnit: #Complex44Reactome Database ID Release 759894959Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894959Reactome Database ID Release 759894961Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894961ReactomeR-RNO-56077251Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607725.1Ubiquitination 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).10713156Pubmed2000Nedd8 modification of cul-1 activates SCF(beta(TrCP))-dependent ubiquitination of IkappaBalphaRead, M ABrownell, J EGladysheva, T BHottelet, MParent, L ACoggins, M BPierce, J WPodust, VNLuo, R SChau, VPalombella, V JMol. Cell. Biol. 20:2326-3314990998Pubmed2004Proteasomes and their kin: proteases in the machine agePickart, Cecile MCohen, Robert ENat. Rev. Mol. Cell Biol. 5:177-8711483504Pubmed2001NEDD8 recruits E2-ubiquitin to SCF E3 ligaseKawakami, TChiba, TSuzuki, TIwai, KYamanaka, KMinato, NSuzuki, HShimbara, NHidaka, YOsaka, FOmata, MTanaka, KEMBO J. 20:4003-1214676825Pubmed2004Mechanism 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 ligaseAmir, Ruthie EHaecker, HansKarin, MCiechanover, AaronOncogene 23:2540-710772955Pubmed2000Modification of cullin-1 by ubiquitin-like protein Nedd8 enhances the activity of SCF(skp2) toward p27(kip1)Morimoto, MNishida, THonda, RYasuda, HBiochem. Biophys. Res. Commun. 270:1093-6LEFT-TO-RIGHT26S proteasome processes p-7S-p100:RELB to form p52:RELBThis 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 ReactomeUbubiquitinReactome DB_ID: 9821278Rps27aRPS27A(1-76)P62982Reactome DB_ID: 98212441EQUAL76EQUALReactome Database ID Release 759821244Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821244ReactomeR-RNO-9392051Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-939205.1Uba52UBA52(1-76)P62986Reactome DB_ID: 98212481EQUAL76EQUALReactome Database ID Release 759821248Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821248ReactomeR-RNO-9392031Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-939203.1UbbUBB(1-76)P0CG51Reactome DB_ID: 98212521EQUAL76EQUALReactome Database ID Release 759821252Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821252ReactomeR-RNO-9392141Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-939214.1UbcUBC(1-76)Q63429Reactome DB_ID: 98212601EQUAL76EQUALReactome Database ID Release 759821260Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821260ReactomeR-RNO-9391881Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-939188.1Reactome Database ID Release 759821278Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9821278ReactomeR-RNO-1135951Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-113595.14p52:RELBReactome DB_ID: 98949711Nfkb2NFKB2(1-454)Q5U2Z4Reactome DB_ID: 98342001EQUAL454EQUALReactome Database ID Release 759834200Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834200ReactomeR-RNO-1681441Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-168144.11Reactome Database ID Release 759894971Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894971ReactomeR-RNO-56076991Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607699.1ACTIVATIONReactome Database ID Release 759894973Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894973ReactomeR-RNO-56077311Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607731.1Once 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).LEFT-TO-RIGHTp52:RELB translocates from cytosol to nucleusThis 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>p52:RELBReactome DB_ID: 9895037RelbRELBD4A8H1Reactome DB_ID: 98950351EQUAL579EQUALReactome Database ID Release 759895035Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895035ReactomeR-RNO-56076561Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607656.11Nfkb2NFKB2(1-454)Q5U2Z4Reactome DB_ID: 98342931EQUAL454EQUALReactome Database ID Release 759834293Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834293ReactomeR-RNO-1776741Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-177674.11Reactome Database ID Release 759895037Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895037ReactomeR-RNO-56076791Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607679.1Reactome Database ID Release 759895039Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9895039ReactomeR-RNO-56077411Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607741.1Following 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). 12654254Pubmed2003NF-kappaB in cancer: a marked targetLin, AnningKarin, MSemin. Cancer Biol. 13:107-148921937Pubmed1996Differential nuclear localization of p50, p52, and RelB proteins in human accessory cells of the immune response in situFeuillard, JKörner, MIsraël, AVassy, JRaphael, MEur. J. Immunol. 26:2547-5119122653Pubmed2009Dectin-1 directs T helper cell differentiation by controlling noncanonical NF-kappaB activation through Raf-1 and SykGringhuis, Sonja Iden Dunnen, JeroenLitjens, Manjavan der Vlist, MichielWevers, BrigitteBruijns, Sven C MGeijtenbeek, Teunis B HNat. Immunol. 10:203-13Reactome Database ID Release 759930148Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9930148ReactomeR-RNO-56077611Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607761.1In 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). 19521399Pubmed2009Signalling through C-type lectin receptors: shaping immune responsesGeijtenbeek, Teunis B HGringhuis, Sonja INat. Rev. Immunol. 9:465-7919302050Pubmed2009Regulation and function of NF-kappaB transcription factors in the immune systemVallabhapurapu, SivakumarKarin, MAnnu. Rev. Immunol. 27:693-733CLEC7A/inflammasome pathwayThis 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>LEFT-TO-RIGHTCaspase-8 binds MALTThis 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>active caspase-8 Reactome DB_ID: 9830500Caspase-8 dimerReactome DB_ID: 9830498Casp8CASP8(217-374)Q9JHX4Reactome DB_ID: 9830494UniProt:Q9JHX4Casp8UniProtQ9JHX4217EQUAL374EQUALReactome Database ID Release 759830494Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9830494ReactomeR-RNO-759751Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-75975.11Casp8CASP8(385-479)Q9JHX4Reactome DB_ID: 9830496385EQUAL479EQUALReactome Database ID Release 759830496Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9830496ReactomeR-RNO-761581Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-76158.11Reactome Database ID Release 759830498Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9830498ReactomeR-RNO-1399501Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-139950.12Reactome Database ID Release 759830500Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9830500ReactomeR-RNO-25625501Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2562550.1MALT1:active caspase-8Reactome DB_ID: 989807311Reactome Database ID Release 759898073Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9898073ReactomeR-RNO-56606541Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5660654.1Reactome Database ID Release 759898082Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9898082ReactomeR-RNO-56606651Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5660665.1After 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).22267217Pubmed2012Dectin-1 is an extracellular pathogen sensor for the induction and processing of IL-1? via a noncanonical caspase-8 inflammasomeGringhuis, Sonja IKaptein, Tanja MWevers, Brigitte ATheelen, Bartvan der Vlist, MichielBoekhout, TeunGeijtenbeek, Teunis B HNat. Immunol. 13:246-5418691973Pubmed2008The paracaspase MALT1 controls caspase-8 activation during lymphocyte proliferationKawadler, HolliGantz, Mary ARiley, James LYang, XMol. Cell 31:415-21LEFT-TO-RIGHTASC binds Caspase-8 complexThis 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>PycardPYCARDG3V8L1Reactome DB_ID: 9860236UniProt:G3V8L1PycardUniProtG3V8L11EQUAL195EQUALReactome Database ID Release 759860236Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9860236ReactomeR-RNO-5611911Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-561191.1MALT1 oligomers:active caspase-8:ASCReactome DB_ID: 989807511Reactome Database ID Release 759898075Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9898075ReactomeR-RNO-56606531Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5660653.1Reactome Database ID Release 759898077Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9898077ReactomeR-RNO-56606621Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5660662.1ASC (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).12646168Pubmed2003ASC is an activating adaptor for NF-kappa B and caspase-8-dependent apoptosisMasumoto, JunyaDowds, Theresa ASchaner, PhilipChen, Felicia FOgura, YasunoriLi, MuZhu, LiKatsuyama, TsutomuSagara, JunjiTaniguchi, Shun'ichiroGumucio, Deborah LNúñez, GabrielInohara, NaohiroBiochem. Biophys. Res. Commun. 303:69-73LEFT-TO-RIGHT3.4.22Caspase-8 cleaves IL1B precursorThis 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>Il1bIL1B(1-269)Q63264Reactome DB_ID: 9857550UniProt:Q63264Il1bUniProtQ632641EQUAL269EQUALReactome Database ID Release 759857550Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9857550ReactomeR-RNO-4486891Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-448689.1Il1bIL1B(117-269)Q63264Reactome DB_ID: 9857556117EQUAL269EQUALReactome Database ID Release 759857556Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9857556ReactomeR-RNO-4490461Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-449046.1Il1bIL1B(1-116)Q63264Reactome DB_ID: 98575621EQUAL116EQUALReactome Database ID Release 759857562Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9857562ReactomeR-RNO-4490301Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-449030.1ACTIVATIONactiveUnit: #Complex59GENE ONTOLOGYGO:0004197Reactome Database ID Release 759898078Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9898078Reactome Database ID Release 759898080Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9898080ReactomeR-RNO-56606631Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5660663.1Interleukin-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.1574116Pubmed1992A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytesThornberry, NABull, HGCalaycay, JRChapman, KTHoward, ADKostura, MJMiller, Douglas KMolineaux, SMWeidner, JRAunins, JNature 356:768-74Reactome Database ID Release 759930232Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9930232ReactomeR-RNO-56606681Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5660668.1Antifungal 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).21531876Pubmed2011The dectin-1/inflammasome pathway is responsible for the induction of protective T-helper 17 responses that discriminate between yeasts and hyphae of Candida albicansCheng, Shih-Chinvan de Veerdonk, Frank LLenardon, MeganStoffels, MoniquePlantinga, TheoSmeekens, SanneRizzetto, LisaMukaremera, LilianePreechasuth, KanyaCavalieri, DuccioKanneganti, Thirumala Devivan der Meer, Jos W MKullberg, Bart JanJoosten, Leo A BGow, Neil A RNetea, Mihai GJ. Leukoc. Biol. 90:357-66Reactome Database ID Release 759928852Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9928852ReactomeR-RNO-56077641Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5607764.1CLEC7A (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).15956283Pubmed2005Dectin-1 activates Syk tyrosine kinase in a dynamic subset of macrophages for reactive oxygen productionUnderhill, David MRossnagle, EddieLowell, Clifford ASimmons, Randi MBlood 106:2543-5019223162Pubmed2009Pattern recognition: recent insights from Dectin-1Reid, Delyth MGow, Neil A RBrown, Gordon DCurr. Opin. Immunol. 21:30-712719479Pubmed2003Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2Gantner, Benjamin NSimmons, Randi MCanavera, Scott JAkira, ShizuoUnderhill, David MJ. Exp. Med. 197:1107-1712719478Pubmed2003Dectin-1 mediates the biological effects of beta-glucansBrown, Gordon DHerre, JurgenWilliams, David LWillment, Janet AMarshall, Andrew S JGordon, SiamonJ. Exp. Med. 197:1119-2414698225Pubmed2004Dectin-1 and its role in the recognition of beta-glucans by macrophagesHerre, JürgenGordon, SiamonBrown, Gordon DMol. Immunol. 40:869-76