BioPAX pathway converted from "Downstream TCR signaling" in the Reactome database. Downstream TCR signaling This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT 3.1.3.67 Hydrolysis of PIP3 to PI(3,4)P2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> PIP3 PI(3,4,5)P3 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate Phosphatidylinositol-3,4,5-trisphosphate Reactome DB_ID: 179838 plasma membrane GENE ONTOLOGY GO:0005886 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate(7-) [ChEBI:57836] 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate(7-) 2,3-bis(alkanoyloxy)propyl (1S,2S,3R,4S,5S,6S)-2,6-dihydroxy-3,4,5-tris(phosphonatooxy)cyclohexyl phosphate a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5-trisphosphate) ChEBI CHEBI:57836 Reactome Database ID Release 81 179838 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=179838 Reactome R-ALL-179838 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-179838.4 Reactome http://www.reactome.org COMPOUND C05981 additional information MI MI:0361 H2O water Reactome DB_ID: 29356 cytosol GENE ONTOLOGY GO:0005829 water [ChEBI:15377] water ChEBI CHEBI:15377 Reactome Database ID Release 81 29356 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29356 Reactome R-ALL-29356 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29356.5 COMPOUND C00001 Pi Orthophosphate hydrogenphosphate Phosphate Inorganic Phosphate Reactome DB_ID: 29372 hydrogenphosphate [ChEBI:43474] hydrogenphosphate hydrogen phosphate phosphate [PO3(OH)](2-) INORGANIC PHOSPHATE GROUP HYDROGENPHOSPHATE ION HPO4(2-) [P(OH)O3](2-) ChEBI CHEBI:43474 Reactome Database ID Release 81 29372 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29372 Reactome R-ALL-29372 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29372.4 COMPOUND C00009 PI(3,4)P2 1-phosphatidyl-1D-myo-inositol 3,4-bisphosphates 1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate Reactome DB_ID: 202247 1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate [ChEBI:16152] 1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate ChEBI CHEBI:16152 Reactome Database ID Release 81 202247 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202247 Reactome R-ALL-202247 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-202247.3 ACTIVATION Converted from EntitySet in Reactome Homologues of INPP5D Reactome DB_ID: 10330185 inpp5d INPP5D A0A2R8QBA3 Reactome DB_ID: 10330179 UniProt:A0A2R8QBA3 inpp5d Danio rerio NCBI Taxonomy 7955 UniProt A0A2R8QBA3 1 EQUAL 1189 EQUAL Reactome Database ID Release 81 10330179 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330179 Reactome R-DRE-197940 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-197940.1 inpp5d INPP5D E7F1C2 Reactome DB_ID: 10330183 UniProt:E7F1C2 inpp5d UniProt E7F1C2 1 EQUAL 1189 EQUAL Reactome Database ID Release 81 10330183 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330183 Reactome R-DRE-197940-2 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-197940-2.1 Reactome Database ID Release 81 10330185 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330185 Reactome R-DRE-197940-3 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-197940-3.1 GENE ONTOLOGY GO:0016314 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 81 10330186 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330186 Reactome Database ID Release 81 10330188 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330188 Reactome R-DRE-202237 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202237.1 After the generation of PIP3 by PI3K, a part of it is further dephosphorylated to generate other forms of PI which are also involved in signaling. Two major routes for the degradation of PIP3 exists: dephosphorylation by the haematopoietic-specific SH2 domain-containing inositol 5' phosphatase SHIP-1 and dephosphorylation by the 3' phosphoinositide phosphatase PTEN. <br>SHIP-1 appears to set an activation threshold on T cell signaling. SHIP-1 phosphatase activity removes the 5' phosphate of PIP3 and generate phosphatidylinositol 3,4-bisphosphate. PI(3,4)P2 along with PIP3 preferentially binds to the PH domains of PKB and PDK1. 10716940 Pubmed 2000 Structure, function, and biology of SHIP proteins Rohrschneider, LR Fuller, JF Wolf, I Liu, Y Lucas, DM Genes Dev 14:505-20 11884229 Pubmed 2002 Regulation of the immune response by SHIP March, ME Ravichandran, K Semin Immunol 14:37-47 inferred from electronic annotation EVIDENCE CODE ECO:0000203 LEFT-TO-RIGHT 3.1.3.67 PTEN dephosphorylates PIP3 PI(3,4,5)P3 is dephosphorylated to PI (4,5)P2 by PTEN at the plasma membrane This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> PIP2 PI(4,5)P2 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate Phosphatidylinositol-4,5-bisphosphate 1-phosphatidyl-1D-myo-inositol 4,5- bisphosphate Reactome DB_ID: 179856 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-) [ChEBI:58456] 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-) a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate) 2,3-bis(alkanoyloxy)propyl (1R,2R,3S,4R,5R,6S)-2,3,6-trihydroxy-4,5-bis(phosphonatooxy)cyclohexyl phosphate ChEBI CHEBI:58456 Reactome Database ID Release 81 179856 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=179856 Reactome R-ALL-179856 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-179856.4 COMPOUND C04637 ACTIVATION PTEN ptena E7FC59 Reactome DB_ID: 10329216 UniProt:E7FC59 ptena UniProt E7FC59 2 EQUAL 403 EQUAL Reactome Database ID Release 81 10329216 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10329216 Reactome R-DRE-199420 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-199420.1 Reactome Database ID Release 81 10329217 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10329217 Reactome Database ID Release 81 10329219 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10329219 Reactome R-DRE-199456 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-199456.1 GENE ONTOLOGY GO:0051898 gene ontology term for cellular process MI MI:0359 At the plasma membrane, phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase aka phosphatase and tensin homolog (PTEN) dephosphorylates phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) (Maehama & Dixon 1998, Myers et al. 1998, Das et al. 2003). The PI3K network is negatively regulated by phospholipid phosphatases that dephosphorylate PIP3, thus hampering AKT activation (Myers et al. 1998). The tumour suppressor PTEN is the primary phospholipid phosphatase.<br>Early studies indicated that magnesium ion, Mg2+, was needed for the catalytic activity of PTEN isolated from bovine thymus (Kabuyama et al. 1996). Subsequent studies have shown that PTEN was catalytically active in buffers free of magnesium and magnesium was not detected as part of the PTEN crystal (Lee et al. 1999). 8681945 Pubmed 1996 Purification and characterization of the phosphatidylinositol-3,4,5-trisphosphate phosphatase in bovine thymus Kabuyama, Y Nakatsu, N Homma, Y Fukui, Y Eur. J. Biochem. 238:350-6 10555148 Pubmed 1999 Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association Lee, Jie-Oh Yang, Haijuan Georgescu, Maria-Magdalena Di Cristofano, Antonio Maehama, Tomohiko Shi, Y Dixon, Jack Pandolfi, Pier Pavletich, Nikola Cell 99:323-34 9811831 Pubmed 1998 The lipid phosphatase activity of PTEN is critical for its tumor supressor function Myers, MP Pass, I Batty, IH van der Kaay, J Stolarov, JP Hemmings, BA Downes, CP Tonks, NK Wigler, Michael H Proc Natl Acad Sci U S A 95:13513-8 12808147 Pubmed 2003 Membrane-binding and activation mechanism of PTEN Das, S Dixon, JE Cho, W Proc Natl Acad Sci U S A 100:7491-6 9593664 Pubmed 1998 The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate Maehama, T Dixon, JE J Biol Chem 273:13375-8 LEFT-TO-RIGHT Translocation of PDK1 to Plasma membrane This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> PDPK1 pdpk1b Q6NZV1 Reactome DB_ID: 10330154 UniProt:Q6NZV1 pdpk1b UniProt Q6NZV1 1 EQUAL 556 EQUAL Reactome Database ID Release 81 10330154 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330154 Reactome R-DRE-202210 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202210.1 Converted from EntitySet in Reactome PIP3, PI(3,4)P2 Reactome DB_ID: 202277 Reactome Database ID Release 81 202277 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202277 Reactome R-ALL-202277 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-202277.1 PDK1:PIP2,PIP3 Reactome DB_ID: 10330156 1 PDPK1 pdpk1b Q6NZV1 Reactome DB_ID: 10317738 1 EQUAL 556 EQUAL Reactome Database ID Release 81 10317738 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10317738 Reactome R-DRE-61459 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-61459.1 1 Reactome Database ID Release 81 10330156 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330156 Reactome R-DRE-202311 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202311.1 Reactome Database ID Release 81 10330158 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330158 Reactome R-DRE-202164 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202164.1 PI3K activation results in recruitment of the serine/threonine kinase PDK1, (3-phosphoinositide-dependent kinase 1) to the plasma membrane where PDK1 subsequently phosphorylates and activates AKT. PDK1 with its PH domain binds to either PIP3 or PIP2 and is translocated to the plasma membrane. PDK1 seems to exist in an active, phosphorylated configuration under basal conditions (Vanhaesebroeck & Alessi 2000). 10698680 Pubmed 2000 The PI3K-PDK1 connection: more than just a road to PKB Vanhaesebroeck, B Alessi, DR Biochem J 346:561-76 LEFT-TO-RIGHT Translocation of PKC theta to plasma membrane This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> DAG DAGs diacylglycerols diglyceride Reactome DB_ID: 112275 diglyceride [ChEBI:18035] diglyceride ChEBI CHEBI:18035 Reactome Database ID Release 81 112275 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=112275 Reactome R-ALL-112275 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-112275.3 COMPOUND C00165 prkcq PRKCQ F1R506 Reactome DB_ID: 10329764 UniProt:F1R506 prkcq UniProt F1R506 1 EQUAL 706 EQUAL Reactome Database ID Release 81 10329764 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10329764 Reactome R-DRE-58216 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-58216.1 PKC-theta (open): DAG Reactome DB_ID: 10330242 1 prkcq PRKCQ F1R506 Reactome DB_ID: 10330240 1 EQUAL 706 EQUAL Reactome Database ID Release 81 10330240 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330240 Reactome R-DRE-202346 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202346.1 1 Reactome Database ID Release 81 10330242 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330242 Reactome R-DRE-202187 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202187.1 Reactome Database ID Release 81 10330244 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330244 Reactome R-DRE-202328 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202328.1 DAG along with intracellular calcium signals cooperatively to activate PKCs, which then trigger other pathways such as the NF-kB pathway, ultimately leading to mast cell (MC) degranulation and cytokine production (Wu 2011). PKC theta is a member of the Ca++ independent and DAG dependent, novel PKC subfamily expressed mainly in T cells. It contains, N-term C2 like domain, a pseudosubstrate (PS), DAG binding (C1) domain and a C-term kinase domain. The PS sequence resembles an ideal substrate with the exception that it contains an alanine residue instead of a substrate serine residue, is bound to the kinase domain in the resting state. As a result, PKC theta is maintained in a closed inactive state, which is inaccessible to cellular substrates.<br>MCs express several Protein kinase C (PKC) isozymes and these kinases are involved in both the activation and termination of the degranulation process. PKC-delta is a negative regulator of FCERI mediated mast cell degranulation, whereas PKC-theta facilitates in degranulation (Leitges et al. 2002, Liu et al. 2001). In response to FCERI activation PKC-theta translocates to membrane by binding to DAG with its C1 domain. PKC-theta exists in two conformations closed/inactive and open/active state. In resting state, PKC-theta is autoinhibited where the pseudosubstrate sequence in the N-terminal regulatory region of PKC-theta forms intramolecular interaction with the substrate-binding region in the catalytic domain. This prevents the catalytic domain gaining access to substrates. The allosteric change of PKC-theta from closed to open state involves two important mechanisms: DAG binding to the C1 domains and autophosphorylation of T538 on the activation loop. Interaction with DAG induces conformational change resulting in the exposure of the activation loop of PKC-theta (Wang et al. 2012, Melowic et al. 2007). 11358993 Pubmed 2001 Protein kinase C theta is expressed in mast cells and is functionally involved in Fcepsilon receptor I signaling Liu, Y Graham, C Parravicini, V Brown, M J Rivera, J Shaw, S J. Leukoc. Biol. 69:831-40 16978534 Pubmed 2006 Selective function of PKC-theta in T cells Manicassamy, S Gupta, S Sun, Z Cell Mol Immunol 3:263-70 17548359 Pubmed 2007 Mechanism of diacylglycerol-induced membrane targeting and activation of protein kinase Ctheta Melowic, Heather R Stahelin, Robert V Blatner, Nichole R Tian, Wen Hayashi, Keitaro Altman, Amnon Cho, Wonhwa J. Biol. Chem. 282:21467-76 12473184 Pubmed 2002 Protein kinase C-theta (PKC theta): a key enzyme in T cell life and death Altman, A Villalba, M J Biochem (Tokyo) 132:841-6 LEFT-TO-RIGHT 2.7.11.1 Phosphorylation of PKC theta This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> p-Y90-PKC-theta:DAG Reactome DB_ID: 10330165 1 F1R506 phospho-prkcq p-Y90-PRKCQ Reactome DB_ID: 10330163 90 EQUAL O4'-phospho-L-tyrosine MOD MOD:00048 1 EQUAL 706 EQUAL Reactome Database ID Release 81 10330163 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330163 Reactome R-DRE-202395 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202395.1 1 Reactome Database ID Release 81 10330165 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330165 Reactome R-DRE-202300 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202300.1 ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 113592 ATP(4-) [ChEBI:30616] ATP(4-) ATP atp Adenosine 5'-triphosphate ChEBI CHEBI:30616 Reactome Database ID Release 81 113592 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113592 Reactome R-ALL-113592 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113592.5 COMPOUND C00002 3 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 29370 ADP(3-) [ChEBI:456216] ADP(3-) ADP 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP trianion ChEBI CHEBI:456216 Reactome Database ID Release 81 29370 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29370 Reactome R-ALL-29370 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29370.5 COMPOUND C00008 3 Active PKC theta bound to DAG Reactome DB_ID: 10330172 F1R506 phospho-prkcq p-Y90,T538,S676,S695-PRKCQ Reactome DB_ID: 10330170 538 EQUAL O-phospho-L-threonine MOD MOD:00047 676 EQUAL O-phospho-L-serine MOD MOD:00046 695 EQUAL 1 EQUAL 706 EQUAL Reactome Database ID Release 81 10330170 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330170 Reactome R-DRE-202152 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202152.1 1 1 Reactome Database ID Release 81 10330172 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330172 Reactome R-DRE-202442 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202442.1 ACTIVATION GENE ONTOLOGY GO:0004674 Reactome Database ID Release 81 10330173 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330173 Reactome Database ID Release 81 10330175 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330175 Reactome R-DRE-202222 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202222.1 Raft localized PKC theta is further phosphorylated and activated by PDK1. The threonine residue (T538) in the kinase domain is the potential target of PDK1. Phosphorylation of this site is critical for the PKC theta kinase activity, and its ability to activate NF-kB pathway. PKC theta is later trans-autophopshorylated on putative phosphorylation sites (S676, S695) for the fine-tuning of its kinase activity. LEFT-TO-RIGHT Translocation of CARMA1 to Plasma membrane This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> card11 CARD11 X1WGE1 Reactome DB_ID: 10330259 UniProt:X1WGE1 card11 UniProt X1WGE1 1 EQUAL 1154 EQUAL Reactome Database ID Release 81 10330259 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330259 Reactome R-DRE-202161 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202161.1 CARMA1 bound to PDK1 Reactome DB_ID: 10330261 1 1 Reactome Database ID Release 81 10330261 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330261 Reactome R-DRE-202349 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202349.1 Reactome Database ID Release 81 10330263 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330263 Reactome R-DRE-202394 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202394.1 CARMA1 and Bcl10 are the possible link between PKC theta and IKK activation. PDK1 is also required for PKC theta mediated activation of IKK. CARMA1 has a N-terminal CARD motif, a coiled coiled region, a linker region, and a MAGUK-typical PDZ, SH3 and a GUK domains. The linker region is proposed to contain a hinge region and a CARD binding domain. CARMA1 exists in an inactive conformation in which the linker region binds to and blocks the accessibility of the CARD motif. CARMA1 is recruited to the plasma membrane by binding to the 'PxxP' motif of membrane bound PDK1 with its SH3 domain. 15122200 Pubmed 2004 CARMA1, BCL-10 and MALT1 in lymphocyte development and activation Thome, M Nat Rev Immunol 4:348-59 17468049 Pubmed 2007 Post-translational modifications regulate distinct functions of CARMA1 and BCL10 Thome, M Weil, R Trends Immunol 28:281-8 15541657 Pubmed 2004 The roles of CARMA1, Bcl10, and MALT1 in antigen receptor signaling Lin, X Wang, D Semin Immunol 16:429-35 LEFT-TO-RIGHT 2.7.11.1 Phosphorylation of CARMA1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Activated CARMA1 Reactome DB_ID: 10330271 1 X1WGE1 phospho-card11 p-S552-CARD11 Reactome DB_ID: 10330269 552 EQUAL 1 EQUAL 1154 EQUAL Reactome Database ID Release 81 10330269 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330269 Reactome R-DRE-202438 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202438.1 1 Reactome Database ID Release 81 10330271 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330271 Reactome R-DRE-202440 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202440.1 ACTIVATION Reactome Database ID Release 81 10330272 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330272 Reactome Database ID Release 81 10330274 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330274 Reactome R-DRE-202437 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202437.1 Antigen receptor triggered PKC theta dependent linker phosphorylation of S552 residue is required to release this inhibition and expose the CARD motif for downstream Bcl10 recruitment. PDK1 and maybe other unknown adapter proteins bring PKC theta and CARMA1 into close proximity, facilitating PKC theta mediated CARMA1 phosphorylation and consequent activation. 16356853 Pubmed 2005 Phosphorylation of CARMA1: the link(er) to NF-kappaB activation Rueda, D Thome, M Immunity 23:551-3 LEFT-TO-RIGHT Oligomerization of CARMA1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2 CARMA1 trimer Reactome DB_ID: 10330276 1 3 Reactome Database ID Release 81 10330276 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330276 Reactome R-DRE-202445 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202445.1 Reactome Database ID Release 81 10330278 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330278 Reactome R-DRE-202443 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202443.1 After the phosphorylation and activation CARMA1 undergoes oligomerization, likely through its CC domain. CARMA1 is thought to oligomerize first as a trimer which triggers downstream oligomerization cascade that is ultimately necessary for the subsequent activation of the IKK complex. LEFT-TO-RIGHT Interaction of Bcl10 to CARMA1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> bcl10 BCL10 E7F8A6 Reactome DB_ID: 10330319 UniProt:E7F8A6 bcl10 UniProt E7F8A6 1 EQUAL 233 EQUAL Reactome Database ID Release 81 10330319 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330319 Reactome R-DRE-202447 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202447.1 Bcl10 bound to CARMA1 Reactome DB_ID: 10330321 1 1 Reactome Database ID Release 81 10330321 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330321 Reactome R-DRE-202454 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202454.1 Reactome Database ID Release 81 10330328 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330328 Reactome R-DRE-202466 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202466.1 Bcl10 is recruited to activated, oligomeric CARMA1 through a CARD-CARD interaction. Bcl10 is characterized by an N-terminal CARD motif and a C-terminal extension of ~130 amino acids rich in serine and threonine residues that serve as targets for multiple phosphorylation events. LEFT-TO-RIGHT 2.7.11.1 Phosphorylation of Bcl10 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Phosphorylated Bcl10 bound to CARMA1 and RIP2 Reactome DB_ID: 10330323 1 E7F8A6 phospho-bcl10 p-BCL10 Reactome DB_ID: 10330283 phosphorylated residue MOD MOD:00696 1 EQUAL 233 EQUAL Reactome Database ID Release 81 10330283 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330283 Reactome R-DRE-202488 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202488.1 1 Reactome Database ID Release 81 10330323 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330323 Reactome R-DRE-202480 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202480.1 ACTIVATION ripk2 RIPK2 A0A0R4IKJ5 Reactome DB_ID: 10323536 UniProt:A0A0R4IKJ5 ripk2 UniProt A0A0R4IKJ5 1 EQUAL 540 EQUAL Reactome Database ID Release 81 10323536 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10323536 Reactome R-DRE-168402 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-168402.1 Reactome Database ID Release 81 10330324 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330324 Reactome Database ID Release 81 10330326 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330326 Reactome R-DRE-202459 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202459.1 Upon interaction with CARMA1, Bcl10 undergoes phosphorylation and oligomerization. The oligomerized Bcl10 acts as a adaptor for the incoming MALT1 and TRAF6. Phosphorylation events of Bcl10 can both positively and negatively regulate the NF-kB pathway. Phosphorylation of Bcl10 that depends on the Ser/Thr kinase RIP2 and correlated with the physical association of Bcl10 with RIP2 has a activation effect on the NF-kB pathway. The target sites of RIP2-mediated phosphorylation has not yet been identified. LEFT-TO-RIGHT Oligomerization of Bcl10 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2 Bcl10 trimer bound to CARMA1 trimer Reactome DB_ID: 10330285 1 3 Reactome Database ID Release 81 10330285 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330285 Reactome R-DRE-202475 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202475.1 Reactome Database ID Release 81 10330334 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330334 Reactome R-DRE-202489 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202489.1 Association with RIP2 and its phosphorylation allows subsequent trimerization of Bcl10. LEFT-TO-RIGHT Interaction and oligomerization of MALT1 to Bcl10 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> MALT1 trimer Reactome DB_ID: 10330291 malt1 MALT1 E7EZZ7 Reactome DB_ID: 10330289 UniProt:E7EZZ7 malt1 UniProt E7EZZ7 1 EQUAL 824 EQUAL Reactome Database ID Release 81 10330289 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330289 Reactome R-DRE-202461 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202461.1 3 Reactome Database ID Release 81 10330291 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330291 Reactome R-DRE-202487 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202487.1 MALT1 trimer bound to Bcl10 and CARMA1 trimer Reactome DB_ID: 10330293 1 1 Reactome Database ID Release 81 10330293 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330293 Reactome R-DRE-202468 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202468.1 Reactome Database ID Release 81 10330332 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330332 Reactome R-DRE-202478 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202478.1 Oligomerized Bcl10 facilitates the association with MALT1 to form the CBM signalosome. MALT1 possesses one death domain (DD) and 2 immunoglobulin-like domains (Ig-like) in its N-terminal region and a caspase like domain (CLD) in its C-terminal region. The region between amino acids 107 and 119 of Bcl10 bind to the two Ig-like domains of MALT1. After binding to CARMA1 and Bcl10 complex, MALT1 also undergoes oligomerization. Only the oligomerized forms of Bcl10 and MALT1 are capable of activating IKK. 15125833 Pubmed 2004 The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes Sun, L Deng, L Ea, CK Xia, ZP Chen, ZJ Mol Cell 14:289-301 LEFT-TO-RIGHT Translocation of TRAF6 to CBM complex This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> traf6 TRAF6 Q6IWL4 Reactome DB_ID: 10323268 UniProt:Q6IWL4 traf6 UniProt Q6IWL4 1 EQUAL 522 EQUAL Reactome Database ID Release 81 10323268 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10323268 Reactome R-DRE-166366 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-166366.1 3 TRAF6 trimer bound to CBM complex Reactome DB_ID: 10330295 3 1 Reactome Database ID Release 81 10330295 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330295 Reactome R-DRE-202471 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202471.1 Reactome Database ID Release 81 10330330 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330330 Reactome R-DRE-202472 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202472.1 TRAF6, which plays central role in innate immune responses, is implicated as proximal downstream effector of MALT1. TRAF6 is a member of the TRAF proteins. It contains an N-term RING domain, followed by several Zn finger domains and C-term MATH domain. The MALT1 oligomers bind to TRAF6, induce TRAF6 oligomerization and thereby activate the ubiquitin ligase activity of TRAF6 to polyubiquitinate itself and NEMO. LEFT-TO-RIGHT 6.3.2.19 Auto-ubiquitination of TRAF6 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> K63polyUb Reactome DB_ID: 10323599 Reactome Database ID Release 81 10323599 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10323599 Reactome R-DRE-450152 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-450152.1 3 UBE2N:UBE2V1 Reactome DB_ID: 10330309 Converted from EntitySet in Reactome Homologues of UBE2N Reactome DB_ID: 10330303 UBE2N A0A2R8QIN6 Reactome DB_ID: 10330297 UniProt:A0A2R8QIN6 UniProt A0A2R8QIN6 1 EQUAL 152 EQUAL Reactome Database ID Release 81 10330297 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330297 Reactome R-DRE-206072 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-206072.1 UBE2N ube2nb Q7T3F3 Reactome DB_ID: 10330299 UniProt:Q7T3F3 ube2nb UniProt Q7T3F3 1 EQUAL 152 EQUAL Reactome Database ID Release 81 10330299 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330299 Reactome R-DRE-206072-2 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-206072-2.1 UBE2N ube2na Q803J2 Reactome DB_ID: 10330301 UniProt:Q803J2 ube2na UniProt Q803J2 1 EQUAL 152 EQUAL Reactome Database ID Release 81 10330301 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330301 Reactome R-DRE-206072-3 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-206072-3.1 Reactome Database ID Release 81 10330303 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330303 Reactome R-DRE-206072-4 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-206072-4.1 1 ube2v1 UBE2V1 F1R1E9 Reactome DB_ID: 10330307 UniProt:F1R1E9 ube2v1 UniProt F1R1E9 2 EQUAL 147 EQUAL Reactome Database ID Release 81 10330307 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330307 Reactome R-DRE-205753 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-205753.1 1 Reactome Database ID Release 81 10330309 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330309 Reactome R-DRE-202463 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202463.1 3 Ub-TRAF6 trimer bound to CBM complex Reactome DB_ID: 10330314 traf6 K63polyUb-TRAF6 Q6IWL4 Reactome DB_ID: 10330312 124 EQUAL ubiquitinylated lysine MOD MOD:01148 1 EQUAL 522 EQUAL Reactome Database ID Release 81 10330312 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330312 Reactome R-DRE-2685681 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-2685681.1 3 1 Reactome Database ID Release 81 10330314 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330314 Reactome R-DRE-202456 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202456.1 3 ACTIVATION activeUnit: #Protein17 GENE ONTOLOGY GO:0004842 Reactome Database ID Release 81 10330315 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330315 Reactome Database ID Release 81 10330317 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330317 Reactome R-DRE-202453 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202453.1 TRAF6 possesses ubiquitin ligase activity and undergoes K-63-linked auto-ubiquitination after its oligomerization. In the first step, ubiquitin is activated by an E1 ubiquitin activating enzyme. The activated ubiquitin is transferred to a E2 conjugating enzyme (a heterodimer of proteins Ubc13 and Uev1A) forming the E2-Ub thioester. Finally, in the presence of ubiquitin-protein ligase E3 (TRAF6, a RING-domain E3), ubiquitin is attached to the target protein (TRAF6 on residue Lysine 124) through an isopeptide bond between the C-terminus of ubiquitin and the epsilon-amino group of a lysine residue in the target protein. In contrast to K-48-linked ubiquitination that leads to the proteosomal degradation of the target protein, K-63-linked polyubiquitin chains act as a scaffold to assemble protein kinase complexes and mediate their activation through proteosome-independent mechanisms. This K63 polyubiquitinated TRAF6 activates the TAK1 kinase complex. 17135271 Pubmed 2007 Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation Lamothe, B Besse, A Campos, AD Webster, WK Wu, H Darnay, BG J Biol Chem 282:4102-12 LEFT-TO-RIGHT 2.7.11.1 Activation of TAK1-TAB2 complex This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> TAB2/TAK1 complex Reactome DB_ID: 10330360 tab2 TAB2 Q5RFW2 Reactome DB_ID: 10330342 UniProt:Q5RFW2 tab2 UniProt Q5RFW2 1 EQUAL 693 EQUAL Reactome Database ID Release 81 10330342 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330342 Reactome R-DRE-168116 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-168116.1 1 p-MAP3K7 phospho-map3k7 A0A0R4IVJ5 Reactome DB_ID: 10330358 UniProt:A0A0R4IVJ5 map3k7 UniProt A0A0R4IVJ5 1 EQUAL 606 EQUAL Reactome Database ID Release 81 10330358 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330358 Reactome R-DRE-168163 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-168163.1 1 Reactome Database ID Release 81 10330360 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330360 Reactome R-DRE-202504 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202504.1 2 2 TAK1/TAB2 complex bound to TRAF6/CBM complex Reactome DB_ID: 10330352 1 phosphorylated TAK1 bound to TAB2 Reactome DB_ID: 10330350 A0A0R4IVJ5 phospho-map3k7 p-T184,T187-MAP3K7 Reactome DB_ID: 10330348 184 EQUAL 187 EQUAL 1 EQUAL 606 EQUAL Reactome Database ID Release 81 10330348 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330348 Reactome R-DRE-202527 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202527.1 1 1 Reactome Database ID Release 81 10330350 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330350 Reactome R-DRE-202516 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202516.1 1 Reactome Database ID Release 81 10330352 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330352 Reactome R-DRE-202507 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202507.1 ACTIVATION activeUnit: #Protein25 Reactome Database ID Release 81 10330361 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330361 Reactome Database ID Release 81 10330363 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330363 Reactome R-DRE-202510 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202510.1 Ubiquitinated TRAF6 recruits TAB2 and activates the TAB2-associated TAK1 kianse by promoting the autophosphorylation of TAK1. TAB2 contains an N-term pseudophosphatase domain, which is indispensable for TAK1 activation, and a C-term domain that binds to and activates TAK1. The activation of TAK1/TAB2 complex requires a ubiquitination reaction catalysed by E1, Ubc13/Uev1A (E2) and TRAF6 (E3). TAK1 undergoes autophosphorylation on residues T184 and T187 and gets activated. Activated TAK1 then phosphorylates and activates IKK beta. 16056267 Pubmed 2005 Ubiquitin signalling in the NF-kappaB pathway Chen, ZJ Nat Cell Biol 7:758-65 17496917 Pubmed 2007 Ubiquitin-mediated activation of TAK1 and IKK Adhikari, A Xu, M Chen, ZJ Oncogene 26:3214-26 LEFT-TO-RIGHT 2.7.11.1 Activation of IKK complex This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> CHUK:IKBKB:IKBKG Reactome DB_ID: 10330336 ikbkb IKBKB B0R199 Reactome DB_ID: 10327255 UniProt:B0R199 ikbkb UniProt B0R199 1 EQUAL 756 EQUAL Reactome Database ID Release 81 10327255 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10327255 Reactome R-DRE-168114 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-168114.1 1 chuk CHUK Q4G3H4 Reactome DB_ID: 10328110 UniProt:Q4G3H4 chuk UniProt Q4G3H4 1 EQUAL 745 EQUAL Reactome Database ID Release 81 10328110 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10328110 Reactome R-DRE-168104 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-168104.1 1 ikbkg IKBKG F1QHG7 Reactome DB_ID: 10323414 UniProt:F1QHG7 ikbkg UniProt F1QHG7 1 EQUAL 419 EQUAL Reactome Database ID Release 81 10323414 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10323414 Reactome R-DRE-168108 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-168108.1 1 Reactome Database ID Release 81 10330336 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330336 Reactome R-DRE-168113 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-168113.1 2 2 p-S177,S181-IKKB:IKKA:NEMO Reactome DB_ID: 10330338 1 1 B0R199 phospho-ikbkb p-S177,S181-IKBKB Reactome DB_ID: 10323426 177 EQUAL 181 EQUAL 1 EQUAL 756 EQUAL Reactome Database ID Release 81 10323426 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10323426 Reactome R-DRE-202506 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202506.1 1 Reactome Database ID Release 81 10330338 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330338 Reactome R-DRE-202513 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202513.1 ACTIVATION activeUnit: #Protein26 Reactome Database ID Release 81 10330353 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330353 Reactome Database ID Release 81 10330355 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330355 Reactome R-DRE-202500 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202500.1 The IkB kinase (IKK) complex serves as the master regulator for the activation of NF-kB by various stimuli. It contains two catalytic subunits, IKK alpha and IKK beta, and a regulatory subunit, IKKgamma/NEMO. The activation of IKK complex is dependent on the phosphorylation of IKK alpha/beta at its activation loop and the K63-linked ubiquitination of NEMO. This basic trimolecular complex is referred to as the IKK complex. <br>IKK subunits have a N-term kinase domain a leucine zipper (LZ) motifs, a helix-loop-helix (HLH) and a C-ter NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs. IKK beta is the major IKK catalytic subunit for NF-kB activation. Activated TAK1 phosphorylate IKK beta on serine residues (S177 and S181) in the activation loop and thus activate the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation. 17047224 Pubmed 2006 Regulation and function of IKK and IKK-related kinases Hacker, H Karin, M Sci STKE 2006:re13 LEFT-TO-RIGHT 6.3.2.19 Ubiquitination of NEMO by TRAF6 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> p-S177,S181-IKKB:IKKA:pUb-NEMO Reactome DB_ID: 10330371 1 1 ikbkg K63polyUb-NEMO F1QHG7 Reactome DB_ID: 10330369 321 EQUAL 325 EQUAL 326 EQUAL 1 EQUAL 419 EQUAL Reactome Database ID Release 81 10330369 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330369 Reactome R-DRE-202530 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202530.1 1 Reactome Database ID Release 81 10330371 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330371 Reactome R-DRE-202562 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202562.1 ACTIVATION activeUnit: #Protein23 Reactome Database ID Release 81 10330372 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330372 Reactome Database ID Release 81 10330374 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330374 Reactome R-DRE-202534 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202534.1 During the phosphorylation of the IKK beta, the regulatory subunit NEMO undergoes K-63-linked polyubiquitination. Ubiquitinated TRAF6 trimer, acts as a E3 ligase and induces this ubiquitination. The ubiquitin target sites in NEMO are not yet clearly identified. Studies of different NF-kB signaling pathways revealed several potential ubiquitination sites on NEMO (e.g., K285, K277, K309 and K399) (Fuminori et al. 2009). 17728323 Pubmed 2007 Identification of TRAF6-dependent NEMO polyubiquitination sites through analysis of a new NEMO mutation causing incontinentia pigmenti Sebban-Benin, H Pescatore, A Fusco, F Pascuale, V Gautheron, J Yamaoka, S Moncla, A Ursini, MV Courtois, G Hum Mol Genet 127: 19136968 Pubmed 2009 Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation Tokunaga, Fuminori Sakata, Shin-ichi Saeki, Yasushi Satomi, Yoshinori Kirisako, Takayoshi Kamei, Kiyoko Nakagawa, Tomoko Kato, Michiko Murata, Shigeo Yamaoka, Shoji Yamamoto, M Akira, Shizuo Takao, Toshifumi Tanaka, Keiji Iwai, Kazuhiro Nat. Cell Biol. 11:123-32 Reactome Database ID Release 81 10425715 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10425715 Reactome R-DRE-202424 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DRE-202424.1 Changes in gene expression are required for the T cell to gain full proliferative competence and to produce effector cytokines. Three transcription factors in particular have been found to play a key role in TCR-stimulated changes in gene expression, namely NFkappaB, NFAT and AP-1. A key step in NFkappaB activation is the stimulation and translocation of PRKCQ. The critical element that effects PRKCQ activation is PI3K. PI3K translocates to the plasma membrane by interacting with phospho-tyrosines on CD28 via its two SH2 domains located in p85 subunit (step 24). The p110 subunit of PI3K phosphorylates the inositol ring of PIP2 to generate PIP3 (steps 25). The reverse dephosphorylation process from PIP3 to PIP2 is catalysed by PTEN (step 27). PIP3 may also be dephosphorylated by the phosphatase SHIP to generate PI-3,4-P2 (step 26). PIP3 and PI-3,4-P2 acts as binding sites to the PH domain of PDK1 (step 28) and AKT (step 29). PKB is activated in response to PI3K stimulation by PDK1 (step 30). PDK1 has an essential role in regulating the activation of PRKCQ and recruitment of CBM complex to the immune synapse. PRKCQ is a member of novel class (DAG dependent, Ca++ independent) of PKC and the only member known to translocate to this synapse. Prior to TCR stimulation PRKCQ exists in an inactive closed conformation. TCR signals stimulate PRKCQ (step 31) and release DAG molecules. Subsequently, DAG binds to PRKCQ via the C1 domain and undergoes phosphorylation on tyrosine 90 by LCK to attain an open conformation (step 32). PRKCQ is further phosphorylated by PDK1 on threonine 538 (step 33). This step is critical for PKC activity. CARMA1 translocates to the plasma membrane following the interaction of its SH3 domain with the 'PxxP' motif on PDK1 (step 34). CARMA1 is phosphorylated by PKC-theta on residue S552 (step 35), leading to the oligomerization of CARMA1. This complex acts as a scaffold, recruiting BCL10 to the synapse by interacting with their CARD domains (step 36). BCL10 undergoes phosphorylation mediated by the enzyme RIP2 (step 37). Activated BCL10 then mediates the ubiquitination of IKBKG by recruiting MALT1 and TRAF6. MALT1 binds to BCL10 with its Ig-like domains and undergoes oligomerization (step 38). TRAF6 binds to the oligomerized MALT1 and also undergoes oligomerization (step 39). Oligomerized TRAF6 acts as a ubiquitin-protein ligase, catalyzing auto-K63-linked polyubiquitination (step 40). This K-63 ubiquitinated TRAF6 activates MAP3K7 kinase bound to TAB2 (step 41) and also ubiquitinates IKBKG in the IKK complex (step 44). MAP3K7 undergoes autophosphorylation on residues T184 and T187 and gets activated (step 42). Activated MAP3K7 kinase phosphorylates IKBKB on residues S177 and S181 in the activation loop and activates the IKK kinase activity (step 43). IKBKB phosphorylates the NFKBIA bound to the NFkappaB heterodimer, on residues S19 and S23 (step 45) and directs NFKBIA to 26S proteasome degradation (step 47). The NFkappaB heterodimer with a free NTS sequence finally migrates to the nucleus to regulate gene transcription (step 46). 15084594 Pubmed 2004 T cell receptor signaling: beyond complex complexes Huang, Y Wange, RL J Biol Chem 279:28827-30