BioPAX pathway converted from "NOD1/2 Signaling Pathway" in the Reactome database. NOD1/2 Signaling Pathway This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT iE-DAP elicits a NOD1 response 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> iE-DAP intracellular D-gamma-Glutamyl-meso-diamino-pimelic acid gamma-D-glutamyl-meso-diaminopimelic acid Reactome DB_ID: 622271 cytosol GENE ONTOLOGY GO:0005829 gamma-D-glutamyl-meso-diaminopimelic acid [ChEBI:59271] gamma-D-glutamyl-meso-diaminopimelic acid ChEBI CHEBI:59271 Reactome Database ID Release 81 622271 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=622271 Reactome R-ALL-622271 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-622271.4 Reactome http://www.reactome.org Nod1 NOD1 D4ADT7 Reactome DB_ID: 9900781 UniProt:D4ADT7 Nod1 Rattus norvegicus NCBI Taxonomy 10116 UniProt D4ADT7 1 EQUAL 953 EQUAL Reactome Database ID Release 81 9900781 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9900781 Reactome R-RNO-168407 1 Reactome stable identifier. Use this 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-168407.1 NOD1:iE-DAP Reactome DB_ID: 9900783 1 1 Reactome Database ID Release 81 9900783 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9900783 Reactome R-RNO-168408 1 Reactome stable identifier. Use this 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-168408.1 Reactome Database ID Release 81 9900785 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9900785 Reactome R-RNO-168400 1 Reactome stable identifier. Use this 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-168400.1 Early studies suggested that NOD1 and NOD2 responded to lipopolysaccharides (LPS), but this was later shown to be due to contamination of LPS with bacterial peptidoglycans (PGNs), the true elicitor for NODs. It is generally believed that PGNs bind NOD1 though this remains to be formally demonstrated. NOD1 senses PGN moieties with a minimal dipeptide structure of D-gamma-glutamyl-meso-diaminopimelic acid (iE-DAP), which is unique to PGN structures from all Gram-negative bacteria and certain Gram-positive bacteria, including the genus Listeria and Bacillus. Attachment of acyl residues enhances NOD1 stimulation several hundred fold, possibly by facilitating PGN entry into the cell (Hasegawa et al. 2007). 17322292 Pubmed 2007 A role of lipophilic peptidoglycan-related molecules in induction of Nod1-mediated immune responses Hasegawa, M Kawasaki, A Yang, K Fujimoto, Y Masumoto, J Breukink, E Nunez, G Fukase, K Inohara, N J Biol Chem 282:11757-64 12791997 Pubmed 2003 Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan Girardin, SE Boneca, IG Carneiro, LA Antignac, A Jéhanno, M Viala, J Tedin, K Taha, MK Labigne, A Zähringer, U Coyle, AJ DiStefano, PS Bertin, J Sansonetti, PJ Philpott, DJ Science 300:1584-7 12796777 Pubmed 2003 An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid Chamaillard, M Hashimoto, M Horie, Y Masumoto, J Qiu, S Saab, L Ogura, Y Kawasaki, A Fukase, K Kusumoto, S Valvano, MA Foster, SJ Mak, TW Nunez, G Inohara, N Nat Immunol 4:702-7 inferred from electronic annotation EVIDENCE CODE ECO:0000203 LEFT-TO-RIGHT MDP elicits a NOD2 response 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> MDP muramyl dipeptide Reactome DB_ID: 708341 muramyl dipeptide [ChEBI:59414] muramyl dipeptide ChEBI CHEBI:59414 Reactome Database ID Release 81 708341 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=708341 Reactome R-ALL-708341 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-708341.4 Nod2 NOD2 A0A0G2K4Z7 Reactome DB_ID: 9900791 UniProt:A0A0G2K4Z7 Nod2 UniProt A0A0G2K4Z7 1 EQUAL 1040 EQUAL Reactome Database ID Release 81 9900791 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9900791 Reactome R-RNO-168411 1 Reactome stable identifier. Use this 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-168411.1 MDP:NOD2 Reactome DB_ID: 9900793 1 1 Reactome Database ID Release 81 9900793 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9900793 Reactome R-RNO-168414 1 Reactome stable identifier. Use this 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-168414.1 Reactome Database ID Release 81 9900807 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9900807 Reactome R-RNO-168412 1 Reactome stable identifier. Use this 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-168412.1 Muramyl dipeptide (MDP) is an essential structural component of bacterial peptidoglycan (PGN) and the minimal elicitor recognized by NOD2. As MDP is present in nearly all bacteria NOD2 is a general sensor of bacteria. NOD2 has additionally been reported to respond to ssRNA (Sabbah et al. 2009) and play a role in T cell activation (Shaw et al. 2011). 12527755 Pubmed 2003 Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection Girardin, SE Boneca, IG Viala, J Chamaillard, M Labigne, A Thomas, G Philpott, DJ Sansonetti, PJ J Biol Chem 278:8869-72 21251876 Pubmed 2011 The ever-expanding function of NOD2: autophagy, viral recognition, and T cell activation Shaw, MH Kamada, N Warner, N Kim, YG Nunez, G Trends Immunol 32:73-9 19701189 Pubmed 2009 Activation of innate immune antiviral responses by Nod2 Sabbah, A Chang, TH Harnack, R Frohlich, V Tominaga, K Dube, PH Xiang, Y Bose, S Nat Immunol 10:1073-80 12514169 Pubmed 2003 Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease Inohara, N Ogura, Y Fontalba, A Gutierrez, O Pons, F Crespo, J Fukase, K Inamura, S Kusumoto, S Hashimoto, M Foster, SJ Moran, AP Fernandez-Luna, JL Nunez, G J Biol Chem 278:5509-12 LEFT-TO-RIGHT Activated NOD1 oligomerizes This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 6 NOD1:iE-DAP oligomer Reactome DB_ID: 9900787 6 Reactome Database ID Release 81 9900787 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9900787 Reactome R-RNO-622306 1 Reactome stable identifier. Use this 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-622306.1 Reactome Database ID Release 81 9923390 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9923390 Reactome R-RNO-622310 1 Reactome stable identifier. Use this 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-622310.1 NOD1 is activated by iE-DAP in a LRR domain dependent manner. The LRR domain has a negative influence on NOD1 self-association (Inohara et al. 2000); binding of iE-DAP likely causes conformational changes that free the NACHT domain, allowing oligomerization and subsequent association of other proteins. Coimmunoprecipitation experiments demonstrate that NOD1 can interact with itself (Inohara et al. 1999) via the NACHT domain (Inohara et al. 2000). NACHT domains are part of the AAA+ domain family. Members of this family form hexamers or heptamers. Based on this observation, NOD1 and NOD2 are believed to form oligomers of this size (Martinon & Tschopp, 2005). 10880512 Pubmed 2000 An induced proximity model for NF-kappa B activation in the Nod1/RICK and RIP signaling pathways Inohara, N Koseki, T Lin, J del Peso, L Lucas, PC Chen, FF Ogura, Y Nunez, G J Biol Chem 275:27823-31 10329646 Pubmed 1999 Nod1, an Apaf-1-like activator of caspase-9 and nuclear factor-kappaB Inohara, N Koseki, T del Peso, L Hu, Y Yee, C Chen, S Carrio, R Merino, J Liu, D Ni, J Nunez, G J Biol Chem 274:14560-7 15967716 Pubmed 2005 NLRs join TLRs as innate sensors of pathogens Martinon, F Tschopp, Jürg Trends Immunol 26:447-54 LEFT-TO-RIGHT Activated NOD2 oligomerizes This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 6 MDP:NOD2 oligomer Reactome DB_ID: 9900795 6 Reactome Database ID Release 81 9900795 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9900795 Reactome R-RNO-708350 1 Reactome stable identifier. Use this 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-708350.1 Reactome Database ID Release 81 9923542 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9923542 Reactome R-RNO-708349 1 Reactome stable identifier. Use this 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-708349.1 NOD2 is activated by MDP in a LRR domain dependent manner. Based on studies of NOD1 activation and structural data from the NLR-related scaffold Apaf-1, the LRR domain is believed to have a negative influence on NOD2 self-association (Inohara et al. 2000, Riedl & Salvesen 2007); binding of MDP is believed to cause conformational changes that free the NACHT domain, allowing oligomerization and subsequent association of other proteins. Coimmunoprecipitation experiments demonstrate that NOD1 can interact with itself (Inohara et al. 1999) via the NACHT domain (Inohara et al. 2000). NACHT domains are part of the AAA+ domain family. Members of this family form hexamers or heptamers. Based on these observations, NOD2 is generally believed to form hexamers or heptamers (Martinon & Tschopp, 2005). NOD2 oliogomerization has been observed in NOD2-transfected HEK293T cells (Zhao et al. 2007). 17303577 Pubmed 2007 Differential modulation of Nods signaling pathways by fatty acids in human colonic epithelial HCT116 cells Zhao, L Kwon, MJ Huang, S Lee, JY Fukase, K Inohara, N Hwang, DH J Biol Chem 282:11618-28 17377525 Pubmed 2007 The apoptosome: signalling platform of cell death Riedl, SJ Salvesen, Guy S. Nat Rev Mol Cell Biol 8:405-13 LEFT-TO-RIGHT Activated NOD oligomer recruites RIP2 (RICK) 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> Ripk2 RIPK2 G3V783 Reactome DB_ID: 9900801 UniProt:G3V783 Ripk2 UniProt G3V783 1 EQUAL 540 EQUAL Reactome Database ID Release 81 9900801 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9900801 Reactome R-RNO-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-RNO-168402.1 6 Converted from EntitySet in Reactome PAMP:NOD oligomer Reactome DB_ID: 9900797 Reactome Database ID Release 81 9900797 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9900797 Reactome R-RNO-708346 1 Reactome stable identifier. Use this 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-708346.1 PAMP:NOD oligomer:RIP2 Reactome DB_ID: 9900803 6 1 Reactome Database ID Release 81 9900803 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9900803 Reactome R-RNO-168409 1 Reactome stable identifier. Use this 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-168409.1 Reactome Database ID Release 81 9900805 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9900805 Reactome R-RNO-168405 1 Reactome stable identifier. Use this 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-168405.1 NOD1 and NOD2 (NOD) interact with the inflammatory kinase RIP2 (RICK) via a homophilic association between CARD domains (Inohara et al. 1999, Ogura et al. 2001). This has the effect of bringing several RIP2 molecules into close proximity, enhancing RIP2-RIP2 interactions (Inohara et al. 2000), a key step in what is termed the 'Induced Proximity Model' for NOD activation of NFkappaB. Note that though the interaction of every NOD with RIP2 is implied here this may not be required for RIP2 activation. RIP2 recruitment leads to subsequent activation of NFkappaB. The kinase activity of RIP2 was initially described as not required (Inohara et al. 2000) but subsequently suggested to be involved in determining signal strength (Windheim et al. 2007) and recently found to be essential for maintaining RIP2 stability and it's role in mediating NOD signaling (Nembrini et al. 2009). 11087742 Pubmed 2001 Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB Ogura, Y Inohara, N Benito, A Chen, FF Yamaoka, S Nunez, G J Biol Chem 276:4812-8 17348859 Pubmed 2007 Molecular mechanisms involved in the regulation of cytokine production by muramyl dipeptide Windheim, M Lang, C Peggie, M Plater, LA Cohen, P Biochem J 404:179-90 10224040 Pubmed 1999 Human CARD4 protein is a novel CED-4/Apaf-1 cell death family member that activates NF-kappaB Bertin, J Nir, WJ Fischer, CM Tayber, OV Errada, PR Grant, JR Keilty, JJ Gosselin, ML Robison, KE Wong, GH Glucksmann, MA DiStefano, PS J Biol Chem 274:12955-8 19473975 Pubmed 2009 The kinase activity of Rip2 determines its stability and consequently Nod1- and Nod2-mediated immune responses Nembrini, C Kisielow, J Shamshiev, AT Tortola, L Coyle, AJ Kopf, M Marsland, BJ J Biol Chem 284:19183-8 LEFT-TO-RIGHT RIP2 binds NEMO 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> Ikbkg IKBKG Q6TMG5 Reactome DB_ID: 9900670 UniProt:Q6TMG5 Ikbkg UniProt Q6TMG5 1 EQUAL 419 EQUAL Reactome Database ID Release 81 9900670 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9900670 Reactome R-RNO-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-RNO-168108.1 PAMP:NOD oligomer:RIP2:NEMO Reactome DB_ID: 9923476 1 1 Reactome Database ID Release 81 9923476 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9923476 Reactome R-RNO-688994 1 Reactome stable identifier. Use this 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-688994.1 Reactome Database ID Release 81 9923478 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9923478 Reactome R-RNO-622415 1 Reactome stable identifier. Use this 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-622415.1 An intermediate region located between the CARD and kinase domains mediates the interaction of RIP2 with the IKK complex regulatory subunit NEMO. This interaction is presumed to link NOD1:RIP2 to the IKK complex, ultimately leading to the phosphorylation of IkappaB-alpha and the activation of NF-kappaB (Inohara et al. 2000). Although every NOD molecule in the oligomeric complex is represented as binding RIP2, binding to every member of the complex may not be required for subsequent signaling events. 18079694 Pubmed 2008 A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-kappaB activation Hasegawa, M Fujimoto, Y Lucas, PC Nakano, H Fukase, K Nunez, G Inohara, N EMBO J 27:373-83 LEFT-TO-RIGHT 6.3.2.19 RIP2 induces K63-linked ubiquitination of NEMO 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: 9900861 Reactome Database ID Release 81 9900861 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9900861 Reactome R-RNO-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-RNO-450152.1 PAMP:NOD oligomer:RIP2:K63-Ub-K285-NEMO Reactome DB_ID: 9923589 Ikbkg Ub-285-IKBKG Q6TMG5 Reactome DB_ID: 9923587 285 EQUAL ubiquitinylated lysine MOD MOD:01148 1 EQUAL 419 EQUAL Reactome Database ID Release 81 9923587 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9923587 Reactome R-RNO-741397 1 Reactome stable identifier. Use this 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-741397.1 1 1 Reactome Database ID Release 81 9923589 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9923589 Reactome R-RNO-741389 1 Reactome stable identifier. Use this 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-741389.1 ACTIVATION TRAF6 E3/E2 ubiquitin ligase complex Reactome DB_ID: 9923519 Traf6 TRAF6 B5DF45 Reactome DB_ID: 9900542 UniProt:B5DF45 Traf6 UniProt B5DF45 1 EQUAL 522 EQUAL Reactome Database ID Release 81 9900542 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9900542 Reactome R-RNO-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-RNO-166366.1 1 UBE2N:UBE2V1 Reactome DB_ID: 9907833 Ube2n UBE2N Q9EQX9 Reactome DB_ID: 9907827 UniProt:Q9EQX9 Ube2n UniProt Q9EQX9 1 EQUAL 152 EQUAL Reactome Database ID Release 81 9907827 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9907827 Reactome R-RNO-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-RNO-206072.1 1 UBE2V1 LOC100912618 D3ZFY8 Reactome DB_ID: 9907831 UniProt:D3ZFY8 LOC100912618 UniProt D3ZFY8 2 EQUAL 147 EQUAL Reactome Database ID Release 81 9907831 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9907831 Reactome R-RNO-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-RNO-205753.1 1 Reactome Database ID Release 81 9907833 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9907833 Reactome R-RNO-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-RNO-202463.1 1 Reactome Database ID Release 81 9923519 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9923519 Reactome R-RNO-1248657 1 Reactome stable identifier. Use this 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-1248657.1 GENE ONTOLOGY GO:0004842 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 81 9923590 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9923590 Reactome Database ID Release 81 9923592 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9923592 Reactome R-RNO-741386 1 Reactome stable identifier. Use this 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-741386.1 RIP2 induces the K63-linked ubiquitination of NEMO at K285 and K399, positively modulating subsequent NF-kappaB activation (Abbot et al. 2007). TRAF6 E3 ligase is capable of performing this ubiquitination step when overexpressed in HEK239 cells, and this effect is blocked if RIP2 siRNA is co-transfected, but small interfering RNA (siRNA) experiments indicate that there are additional E3 ligases that can substitute for TRAF6 in NEMO ubiquitination. In addition to TRAF6, the K63-specific E2 ligase Ubc13 is required for NEMO ubiquitination suggesting a common mechanism for NEMO ubiquitination in NOD and TLR signaling. 17562858 Pubmed 2007 Coordinated regulation of Toll-like receptor and NOD2 signaling by K63-linked polyubiquitin chains Abbott, Derek W Yang, Y Hutti, JE Madhavarapu, S Kelliher, MA Cantley, Lewis C Mol Cell Biol 27:6012-25 LEFT-TO-RIGHT CYLD deubiquitinates NEMO This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> ACTIVATION Cyld CYLD Q66H62 Reactome DB_ID: 9897186 UniProt:Q66H62 Cyld UniProt Q66H62 1 EQUAL 956 EQUAL Reactome Database ID Release 81 9897186 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9897186 Reactome R-RNO-741420 1 Reactome stable identifier. Use this 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-741420.1 GENE ONTOLOGY GO:0061578 Reactome Database ID Release 81 9923593 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9923593 Reactome Database ID Release 81 9923595 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9923595 Reactome R-RNO-741411 1 Reactome stable identifier. Use this 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-741411.1 RIP2-induced ubiquitination of NEMO and consequent NFkappaB activation can be reversed in a dose-responsive manner by the deubiquitinase CYLD, suggesting that CYLD negatively regulates RIP2-induced NEMO ubiquitinylation. 15620648 Pubmed 2004 The Crohn's disease protein, NOD2, requires RIP2 in order to induce ubiquitinylation of a novel site on NEMO Abbott, Derek W Wilkins, A Asara, JM Cantley, Lewis C Curr Biol 14:2217-27 12917691 Pubmed 2003 The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination Kovalenko, A Chable-Bessia, C Cantarella, G Israel, A Wallach, D Courtois, G Nature 424:801-5 LEFT-TO-RIGHT RIP2 is K63 polyubiquitinated 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> 6 PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO Reactome DB_ID: 9921638 1 PAMP:NOD oligomer:K63-Ub-RIP2 Reactome DB_ID: 9921636 1 Ripk2 Ub-209-RIPK2 G3V783 Reactome DB_ID: 9921634 209 EQUAL 1 EQUAL 540 EQUAL Reactome Database ID Release 81 9921634 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9921634 Reactome R-RNO-706483 1 Reactome stable identifier. Use this 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-706483.1 6 Reactome Database ID Release 81 9921636 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9921636 Reactome R-RNO-706482 1 Reactome stable identifier. Use this 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-706482.1 1 Reactome Database ID Release 81 9921638 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9921638 Reactome R-RNO-706480 1 Reactome stable identifier. Use this 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-706480.1 ACTIVATION Converted from EntitySet in Reactome RIP2 ubiquitin ligases Reactome DB_ID: 9923525 Itch ITCH A0A0G2K9T1 Reactome DB_ID: 9923517 UniProt:A0A0G2K9T1 Itch UniProt A0A0G2K9T1 1 EQUAL 903 EQUAL Reactome Database ID Release 81 9923517 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9923517 Reactome R-RNO-975995 1 Reactome stable identifier. Use this 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-975995.1 Birc3 BIRC3 F7FLN8 Reactome DB_ID: 9923523 UniProt:F7FLN8 Birc3 UniProt F7FLN8 1 EQUAL 604 EQUAL Reactome Database ID Release 81 9923523 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9923523 Reactome R-RNO-50845 1 Reactome stable identifier. Use this 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-50845.1 Birc2 BIRC2 Q6P6S1 Reactome DB_ID: 9908106 UniProt:Q6P6S1 Birc2 UniProt Q6P6S1 1 EQUAL 618 EQUAL Reactome Database ID Release 81 9908106 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9908106 Reactome R-RNO-50847 1 Reactome stable identifier. Use this 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-50847.1 Reactome Database ID Release 81 9923525 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9923525 Reactome R-RNO-1248659 1 Reactome stable identifier. Use this 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-1248659.1 GENE ONTOLOGY GO:0019787 Reactome Database ID Release 81 9923526 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9923526 Reactome Database ID Release 81 9923528 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9923528 Reactome R-RNO-688137 1 Reactome stable identifier. Use this 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-688137.1 The close physical proximity of RIP2 proteins that results from NOD oligomerization triggers the conjugation of lysine (K)-63 linked polyubiquitin chains onto RIP2. Ubiquitination at K209 within the kinase domain was required for subsequent NFkappaB signaling (Hasegawa et al. 2008). The identity of the ubiquitin ligase responsible is an open question, with several candidates capable of RIP2 ubiquitination. TRAF6 has been reported as the ubiquitin ligase responsible (Yang et al. 2007) but subsequent reports suggest it is not responsible (see Tao et al. 2009 and Bertrand et al. 2009). Other candidates include the HECT-domain containing E3 ubiquitin ligase ITCH, which is able to K63 ubiquitinate RIP2 (at an undetermined site that is not K209) and is required for optimal NOD2:RIP2-induced p38 and JNK activation, while inhibiting NOD2:RIP2-induced NFkappaB activation (Tao et al. 2009). The Baculoviral IAP repeat-containing proteins (Birc/cIAP) 2 and 3 have also been shown capable of RIP2 ubiquitination and required for NOD2 signaling (Bertrand et al. 2009). It has been suggested that ITCH and a K209 E3 ligase compete for ubiquitination of RIP2, so that a subset of RIP2 becomes ubiquitinated on K209 to stimulate NEMO ubiquitination and subsequent NFkappaB activation while a second subset of RIP2 is polyubiquitinated by ITCH to activate JNK and p38 signaling (Tao et al. 2009). 19464198 Pubmed 2009 Cellular inhibitors of apoptosis cIAP1 and cIAP2 are required for innate immunity signaling by the pattern recognition receptors NOD1 and NOD2 Bertrand, MJ Doiron, K Labbé, K Korneluk, RG Barker, PA Saleh, M Immunity 30:789-801 19592251 Pubmed 2009 ITCH K63-ubiquitinates the NOD2 binding protein, RIP2, to influence inflammatory signaling pathways Tao, M Scacheri, PC Marinis, JM Harhaj, EW Matesic, LE Abbott, Derek W Curr Biol 19:1255-63 17947236 Pubmed 2007 NOD2 pathway activation by MDP or Mycobacterium tuberculosis infection involves the stable polyubiquitination of Rip2 Yang, Y Yin, C Pandey, A Abbott, Derek W Sassetti, C Kelliher, MA J Biol Chem 282:36223-9 LEFT-TO-RIGHT TNFAIP3 (A20) deubiquitinates RIP2 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> 6 ACTIVATION M0R7V5 Tnfaip3 TNFAIP3 Reactome DB_ID: 9897190 UniProt:M0R7V5 Tnfaip3 UniProt M0R7V5 1 EQUAL 790 EQUAL Reactome Database ID Release 81 9897190 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9897190 Reactome R-RNO-688989 1 Reactome stable identifier. Use this 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-688989.1 Reactome Database ID Release 81 9923511 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9923511 Reactome Database ID Release 81 9923513 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9923513 Reactome R-RNO-688136 1 Reactome stable identifier. Use this 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-688136.1 The deubiquitinase A20 is a negative feedback regulator of inflammatory responses, induced by NFkappaB activation (Krikos et al. 1992) and NOD stimulation (Masumoto et al. 2006). A20 can deubiquitinate RIP2 and restricts NOD2 induced signals (Hitosumatsu et al. 2008). 16418393 Pubmed 2006 Nod1 acts as an intracellular receptor to stimulate chemokine production and neutrophil recruitment in vivo Masumoto, J Yang, K Varambally, S Hasegawa, M Tomlins, SA Qiu, S Fujimoto, Y Kawasaki, A Foster, SJ Horie, Y Mak, TW Nunez, G Chinnaiyan, AM Fukase, K Inohara, N J Exp Med 203:203-13 18342009 Pubmed 2008 The ubiquitin-editing enzyme A20 restricts nucleotide-binding oligomerization domain containing 2-triggered signals Hitotsumatsu, O Ahmad, RC Tavares, R Wang, M Philpott, D Turer, EE Lee, BL Shiffin, N Advincula, R Malynn, BA Werts, C Ma, A Immunity 28:381-90 1381359 Pubmed 1992 Transcriptional activation of the tumor necrosis factor alpha-inducible zinc finger protein, A20, is mediated by kappa B elements Krikos, A Laherty, CD Dixit, VM J Biol Chem 267:17971-6 LEFT-TO-RIGHT K63 polyubiquitinated RIP2 associates with the TAK1 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> TAK1 complex Reactome DB_ID: 9923534 plasma membrane GENE ONTOLOGY GO:0005886 Map3k7 MAP3K7 P0C8E4 Reactome DB_ID: 9921050 UniProt:P0C8E4 Map3k7 UniProt P0C8E4 1 EQUAL 606 EQUAL Reactome Database ID Release 81 9921050 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9921050 Reactome R-RNO-168156 1 Reactome stable identifier. Use this 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-168156.1 1 Tab1 TAB1 A0A0U1RRU5 Reactome DB_ID: 9921054 UniProt:A0A0U1RRU5 Tab1 UniProt A0A0U1RRU5 1 EQUAL 504 EQUAL Reactome Database ID Release 81 9921054 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9921054 Reactome R-RNO-167923 1 Reactome stable identifier. Use this 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-167923.1 1 Converted from EntitySet in Reactome TAB2,TAB3 Reactome DB_ID: 9923532 Tab2 TAB2 Q5U303 Reactome DB_ID: 9907851 UniProt:Q5U303 Tab2 UniProt Q5U303 1 EQUAL 693 EQUAL Reactome Database ID Release 81 9907851 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9907851 Reactome R-RNO-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-RNO-168116.1 Tab3 TAB3 F1M1D2 Reactome DB_ID: 9923530 UniProt:F1M1D2 Tab3 UniProt F1M1D2 2 EQUAL 712 EQUAL Reactome Database ID Release 81 9923530 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9923530 Reactome R-RNO-446879 1 Reactome stable identifier. Use this 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-446879.1 Reactome Database ID Release 81 9923532 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9923532 Reactome R-RNO-8947969 1 Reactome stable identifier. Use this 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-8947969.1 1 Reactome Database ID Release 81 9923534 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9923534 Reactome R-RNO-8947970 1 Reactome stable identifier. Use this 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-8947970.1 PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO:TAK1 complex Reactome DB_ID: 9923536 1 1 Reactome Database ID Release 81 9923536 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9923536 Reactome R-RNO-706478 1 Reactome stable identifier. Use this 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-706478.1 Reactome Database ID Release 81 9923538 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9923538 Reactome R-RNO-688985 1 Reactome stable identifier. Use this 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-688985.1 K63-polyubiquitinated RIP2 is able to recruit the components of the TAK1 complex, which consists of TAK1, TAB1 and TAB2. LEFT-TO-RIGHT TAK1 is activated This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO:activated TAK1 complex Reactome DB_ID: 9921640 TAK1 complex Reactome DB_ID: 9921064 1 Converted from EntitySet in Reactome TAB2,TAB3 Reactome DB_ID: 9921062 Tab2 TAB2 Q5U303 Reactome DB_ID: 9921056 1 EQUAL 693 EQUAL Reactome Database ID Release 81 9921056 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9921056 Reactome R-RNO-168117 1 Reactome stable identifier. Use this 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-168117.1 Tab3 TAB3 F1M1D2 Reactome DB_ID: 9921060 2 EQUAL 712 EQUAL Reactome Database ID Release 81 9921060 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9921060 Reactome R-RNO-450264 1 Reactome stable identifier. Use this 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-450264.1 Reactome Database ID Release 81 9921062 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9921062 Reactome R-RNO-446874 1 Reactome stable identifier. Use this 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-446874.1 1 1 Reactome Database ID Release 81 9921064 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9921064 Reactome R-RNO-446878 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-446878.1 1 1 Reactome Database ID Release 81 9921640 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9921640 Reactome R-RNO-706477 1 Reactome stable identifier. Use this 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-706477.1 Reactome Database ID Release 81 9923540 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9923540 Reactome R-RNO-706479 1 Reactome stable identifier. Use this 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-706479.1 The TAK1 complex consists of Transforming growth factor-beta (TGFB)-activated kinase (TAK1) and TAK1-binding protein 1 (TAB1), TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Shibuya et al. 1996, Sakurai et al. 2000). TAB1 promotes TAK1 autophosphorylation at the kinase activation lobe, probably through an allosteric mechanism (Brown et al. 2005, Ono et al. 2001). The TAK1 complex is regulated by polyubiquitination. Binding of TAB2 and TAB3 to Lys63-linked polyubiquitin chains leads to the activation of TAK1 by an uncertain mechanism. Binding of multiple TAK1 complexes to the same polyubiquitin chain may promote oligomerization of TAK1, facilitating TAK1 autophosphorylation and subsequent activation of its kinase activity (Kishimoto et al. 2000). The binding of TAB2/3 to polyubiquitinated TRAF6 may facilitate polyubiquitination of TAB2/3 by TRAF6 (Ishitani et al. 2003), which might result in conformational changes within the TAK1 complex that lead to TAK1 activation. Another possibility is that TAB2/3 may recruit the IKK complex by binding to ubiquitinated NEMO; polyubiquitin chains may function as a scaffold for higher order signaling complexes that allow interaction between TAK1 and IKK (Kanayama et al. 2004). 15327770 Pubmed 2004 TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains Kanayama, A Seth, RB Sun, L Ea, CK Hong, M Shaito, A Chiu, YH Deng, L Chen, ZJ Mol Cell 15:535-48 14633987 Pubmed 2003 Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling Ishitani, T Takaesu, G Ninomiya-Tsuji, J Shibuya, H Gaynor, RB Matsumoto, K EMBO J 22:6277-88 10702308 Pubmed 2000 TAK1 mitogen-activated protein kinase kinase kinase is activated by autophosphorylation within its activation loop Kishimoto, K Matsumoto, K Ninomiya-Tsuji, J J Biol Chem 275:7359-64 LEFT-TO-RIGHT 2.7.11.25 TAK1 phosphorylates MKK6 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> Map2k6 MAP2K6 Q925D6 Reactome DB_ID: 9921655 UniProt:Q925D6 Map2k6 UniProt Q925D6 1 EQUAL 334 EQUAL Reactome Database ID Release 81 9921655 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9921655 Reactome R-RNO-167998 1 Reactome stable identifier. Use this 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-167998.1 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 additional information MI MI:0361 2 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 2 Q925D6 phospho-Map2k6 p-S207,T211-MAP2K6 Reactome DB_ID: 9921602 207 EQUAL O-phospho-L-serine MOD MOD:00046 211 EQUAL O-phospho-L-threonine MOD MOD:00047 1 EQUAL 334 EQUAL Reactome Database ID Release 81 9921602 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9921602 Reactome R-RNO-206255 1 Reactome stable identifier. Use this 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-206255.1 ACTIVATION activeUnit: #Protein15 GENE ONTOLOGY GO:0004709 Reactome Database ID Release 81 9923575 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9923575 Reactome Database ID Release 81 9923577 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9923577 Reactome R-RNO-727819 1 Reactome stable identifier. Use this 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-727819.1 Within the TAK1 complex (TAK1 plus TAB1 and TAB2/3) activated TAK1 phosphorylates IKKB, MAPK kinase 6 (MKK6) and other MAPKs to activate the NFkappaB and MAPK signaling pathways. TAB2 within the TAK1 complex can be linked to polyubiquitinated TRAF6; current models of IL-1 signaling suggest that the TAK1 complex is linked to TRAF6, itself complexed with polyubiquitinated IRAK1 which is linked via NEMO to the IKK complex. The TAK1 complex is also essential for NOD signaling; NOD receptors bind RIP2 which recruits the TAK1 complex (Hasegawa et al. 2008). 11460167 Pubmed 2001 TAK1 is a ubiquitin-dependent kinase of MKK and IKK Wang, C Deng, L Hong, M Akkaraju, GR Inoue, J Chen, ZJ Nature 412:346-51 LEFT-TO-RIGHT NOD1 induced apoptosis is mediated by RIP2 and CARD8 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Long prodomain caspases Reactome DB_ID: 9923484 Casp8 CASP8(1-479) Q9JHX4 Reactome DB_ID: 9892391 UniProt:Q9JHX4 Casp8 UniProt Q9JHX4 1 EQUAL 479 EQUAL Reactome Database ID Release 81 9892391 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9892391 Reactome R-RNO-57031 1 Reactome stable identifier. Use this 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-57031.1 Casp1 CASP1(1-404) P43527 Reactome DB_ID: 9921250 UniProt:P43527 Casp1 UniProt P43527 1 EQUAL 404 EQUAL Reactome Database ID Release 81 9921250 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9921250 Reactome R-RNO-448692 1 Reactome stable identifier. Use this 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-448692.1 Casp9 CASP9(1-416) Q9JHK1 Reactome DB_ID: 9896267 UniProt:Q9JHK1 Casp9 UniProt Q9JHK1 1 EQUAL 416 EQUAL Reactome Database ID Release 81 9896267 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9896267 Reactome R-RNO-57033 1 Reactome stable identifier. Use this 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-57033.1 Casp2 CASP2(2-452) P55215 Reactome DB_ID: 9909132 UniProt:P55215 Casp2 UniProt P55215 2 EQUAL 452 EQUAL Reactome Database ID Release 81 9909132 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9909132 Reactome R-RNO-622412 1 Reactome stable identifier. Use this 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-622412.1 Casp4 CASP4(?-377) E9PSM0 Reactome DB_ID: 9923482 UniProt:E9PSM0 Casp4 UniProt E9PSM0 -1 EQUAL 377 EQUAL Reactome Database ID Release 81 9923482 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9923482 Reactome R-RNO-622418 1 Reactome stable identifier. Use this 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-622418.1 Reactome Database ID Release 81 9923484 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9923484 Reactome R-RNO-622416 1 Reactome stable identifier. Use this 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-622416.1 NOD1:iE-DAP:Long prodomain caspases Reactome DB_ID: 9923486 1 1 Reactome Database ID Release 81 9923486 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9923486 Reactome R-RNO-622417 1 Reactome stable identifier. Use this 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-622417.1 Reactome Database ID Release 81 9923488 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9923488 Reactome R-RNO-622420 1 Reactome stable identifier. Use this 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-622420.1 NOD1 was found to coimmunoprecipitate with several procaspases containing long prodomains with CARDs or DEDs, including caspase-1, caspase-2, caspase-4, caspase-8, and caspase-9, but not those with short prodomains like caspase-3 or caspase-7. Deletions of caspase-9 determined that the CARD domain was required for this interaction (Inohara et al. 1999). More recently, NOD1 activation of apoptosis was shown to require the RIP2-dependent activation of caspase-8, this effect being inhibited by CASP8 and FADD-like apoptosis regulator, also called FLICE-inhibitory protein, FLIP or CLARP (da Silva Correia et al. 2007), which is a specific inhibitor of caspase-8 (Irmler et al. 1997). 9217161 Pubmed 1997 Inhibition of death receptor signals by cellular FLIP Irmler, M Thome, M Hahne, M Schneider, P Hofmann, K Steiner, V Bodmer, JL Schröter, M Burns, K Mattmann, C Rimoldi, D French, LE Tschopp, Jürg Nature 388:190-5 17186025 Pubmed 2007 Regulation of Nod1-mediated signaling pathways da Silva Correia, J Miranda, Y Leonard, N Hsu, J Ulevitch, RJ Cell Death Differ 14:830-9 LEFT-TO-RIGHT 2.7.12.2 Activation of p38 MAPK This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome p38 MAPK Reactome DB_ID: 9931946 Mapk14 MAPK14 P70618 Reactome DB_ID: 9919079 UniProt:P70618 Mapk14 Mapk14 Csbp1 Csbp2 FUNCTION Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK14 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases which are activated through phosphorylation and further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1. RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery. On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2. MAPK14 interacts also with casein kinase II, leading to its activation through autophosphorylation and further phosphorylation of TP53/p53. In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF-induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. In a similar way, MAPK14 phosphorylates the ubiquitin ligase SIAH2, regulating its activity towards EGLN3. MAPK14 may also inhibit the lysosomal degradation pathway of autophagy by interfering with the intracellular trafficking of the transmembrane protein ATG9. Another function of MAPK14 is to regulate the endocytosis of membrane receptors by different mechanisms that impinge on the small GTPase RAB5A. In addition, clathrin-mediated EGFR internalization induced by inflammatory cytokines and UV irradiation depends on MAPK14-mediated phosphorylation of EGFR itself as well as of RAB5A effectors. Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane-associated metalloprotease ADAM17. Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Another p38 MAPK substrate is FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A. The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers. The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF-kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment. Phosphorylates CDC25B and CDC25C which is required for binding to 14-3-3 proteins and leads to initiation of a G2 delay after ultraviolet radiation. Phosphorylates TIAR following DNA damage, releasing TIAR from GADD45A mRNA and preventing mRNA degradation. The p38 MAPKs may also have kinase-independent roles, which are thought to be due to the binding to targets in the absence of phosphorylation. Protein O-Glc-N-acylation catalyzed by the OGT is regulated by MAPK14, and, although OGT does not seem to be phosphorylated by MAPK14, their interaction increases upon MAPK14 activation induced by glucose deprivation. This interaction may regulate OGT activity by recruiting it to specific targets such as neurofilament H, stimulating its O-Glc-N-acylation. Required in mid-fetal development for the growth of embryo-derived blood vessels in the labyrinth layer of the placenta. Also plays an essential role in developmental and stress-induced erythropoiesis, through regulation of EPO gene expression. Phosphorylates S100A9 at 'Thr-113' (By similarity).ACTIVITY REGULATION Activated by cell stresses such as DNA damage, heat shock, osmotic shock, anisomycin and sodium arsenite, as well as pro-inflammatory stimuli such as bacterial lipopolysaccharide (LPS) and interleukin-1. Activation occurs through dual phosphorylation of Thr-180 and Tyr-182 by either of two dual specificity kinases, MAP2K3/MKK3 or MAP2K6/MKK6, and potentially also MAP2K4/MKK4, as well as by TAB1-mediated autophosphorylation. MAPK14 phosphorylated on both Thr-180 and Tyr-182 is 10-20-fold more active than MAPK14 phosphorylated only on Thr-180, whereas MAPK14 phosphorylated on Tyr-182 alone is inactive. whereas Thr-180 is necessary for catalysis, Tyr-182 may be required for auto-activation and substrate recognition. Phosphorylated at Tyr-323 by ZAP70 in an alternative activation pathway in response to TCR signaling in T-cells. This alternative pathway is inhibited by GADD45A. Inhibited by dual specificity phosphatases, such as DUSP1, DUSP10, and DUSP16. Specifically inhibited by the binding of pyridinyl-imidazole compounds, which are cytokine-suppressive anti-inflammatory drugs (CSAID). SB203580 is an inhibitor of MAPK14 (By similarity).SUBUNIT Component of a signaling complex containing at least AKAP13, PKN1, MAPK14, ZAK and MAP2K3. Within this complex, AKAP13 interacts directly with PKN1, which in turn recruits MAPK14, MAP2K3 and ZAK (By similarity). Binds to a kinase interaction motif within the protein tyrosine phosphatase, PTPRR (By similarity). This interaction retains MAPK14 in the cytoplasm and prevents nuclear accumulation (By similarity). Interacts with SPAG9 and GADD45A (By similarity). Interacts with CDC25B, CDC25C, DUSP1, DUSP10, DUSP16, NP60, SUPT20H and TAB1. Interacts with casein kinase II subunits CSNK2A1 and CSNK2B. Interacts with PPM1D. Interacts with CDK5RAP3; recruits PPM1D to MAPK14 and may regulate its dephosphorylation (By similarity).DOMAIN The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.PTM Dually phosphorylated on Thr-180 and Tyr-182 by the MAP2Ks MAP2K3/MKK3, MAP2K4/MKK4 and MAP2K6/MKK6 in response to inflammatory cytokines, environmental stress or growth factors, which activates the enzyme. Dual phosphorylation can also be mediated by TAB1-mediated autophosphorylation. TCR engagement in T-cells also leads to Tyr-323 phosphorylation by ZAP70. Dephosphorylated and inactivated by DUPS1, DUSP10 and DUSP16 (By similarity). PPM1D also mediates dephosphorylation and inactivation of MAPK14 (By similarity).PTM Acetylated at Lys-53 and Lys-152 by KAT2B and EP300. Acetylation at Lys-53 increases the affinity for ATP and enhances kinase activity. Lys-53 and Lys-152 are deacetylated by HDAC3 (By similarity).PTM Ubiquitinated. Ubiquitination leads to degradation by the proteasome pathway (By similarity).SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily. UniProt P70618 2 EQUAL 360 EQUAL Reactome Database ID Release 81 9919079 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9919079 Reactome R-RNO-428933 1 Reactome stable identifier. Use this 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-428933.1 Mapk11 MAPK11 D4A3U7 Reactome DB_ID: 9922038 UniProt:D4A3U7 Mapk11 UniProt D4A3U7 1 EQUAL 364 EQUAL Reactome Database ID Release 81 9922038 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9922038 Reactome R-RNO-170989 1 Reactome stable identifier. Use this 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-170989.1 Mapk13 MAPK13 Q9WTY9 Reactome DB_ID: 9922042 UniProt:Q9WTY9 Mapk13 UniProt Q9WTY9 1 EQUAL 365 EQUAL Reactome Database ID Release 81 9922042 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9922042 Reactome R-RNO-171012 1 Reactome stable identifier. Use this 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-171012.1 Mapk12 MAPK12 Q63538 Reactome DB_ID: 9922044 UniProt:Q63538 Mapk12 UniProt Q63538 1 EQUAL 367 EQUAL Reactome Database ID Release 81 9922044 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9922044 Reactome R-RNO-171025 1 Reactome stable identifier. Use this 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-171025.1 Reactome Database ID Release 81 9931946 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9931946 Reactome R-RNO-1250102 1 Reactome stable identifier. Use this 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-1250102.1 8 8 Converted from EntitySet in Reactome Phospho-p38 MAPK Reactome DB_ID: 9931952 P70618 phospho-Mapk14 p-T180,Y182-MAPK14 Reactome DB_ID: 9903376 180 EQUAL 182 EQUAL O4'-phospho-L-tyrosine MOD MOD:00048 2 EQUAL 360 EQUAL Reactome Database ID Release 81 9903376 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9903376 Reactome R-RNO-428935 1 Reactome stable identifier. Use this 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-428935.1 D4A3U7 phospho-Mapk11 p-T180,Y182-MAPK11 Reactome DB_ID: 9903374 180 EQUAL 182 EQUAL 1 EQUAL 364 EQUAL Reactome Database ID Release 81 9903374 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9903374 Reactome R-RNO-171009 1 Reactome stable identifier. Use this 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-171009.1 Q9WTY9 phospho-Mapk13 p-T180,Y182-MAPK13 Reactome DB_ID: 9931950 180 EQUAL 182 EQUAL 1 EQUAL 365 EQUAL Reactome Database ID Release 81 9931950 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9931950 Reactome R-RNO-171022 1 Reactome stable identifier. Use this 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-171022.1 Q63538 phospho-Mapk12 p-T183,Y185-MAPK12 Reactome DB_ID: 9921350 183 EQUAL 185 EQUAL 1 EQUAL 367 EQUAL Reactome Database ID Release 81 9921350 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9921350 Reactome R-RNO-171021 1 Reactome stable identifier. Use this 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-171021.1 Reactome Database ID Release 81 9931952 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9931952 Reactome R-RNO-1250100 1 Reactome stable identifier. Use this 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-1250100.1 ACTIVATION GENE ONTOLOGY GO:0004708 Reactome Database ID Release 81 9931953 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9931953 Reactome Database ID Release 81 9931955 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9931955 Reactome R-RNO-1247960 1 Reactome stable identifier. Use this 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-1247960.1 p38 MAPK has 4 representative isoforms in humans, p38 alpha (Han et al. 1993), p38-beta (Jiang et al. 1996), p38-gamma (Lechner et al. 1996) and p38-delta (Hu et al. 1999). All are activated by phosphorylation on a canonical TxY motif by the dual-specificity kinase MKK6, which displays minimal substrate selectivity amongst the p38 isoforms (Zarubin & Han, 2005). p38 alpha and gamma are also activated by MKK3. 7693711 Pubmed 1993 Endotoxin induces rapid protein tyrosine phosphorylation in 70Z/3 cells expressing CD14 Han, J Lee, JD Tobias, PS Ulevitch, RJ J Biol Chem 268:25009-14 8633070 Pubmed 1996 ERK6, a mitogen-activated protein kinase involved in C2C12 myoblast differentiation Lechner, C Zahalka, MA Giot, JF Møller, NP Ullrich, A Proc Natl Acad Sci U S A 93:4355-9 9430721 Pubmed 1998 Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6 Enslen, H Raingeaud, J Davis, RJ J Biol Chem 273:1741-8 8663524 Pubmed 1996 Characterization of the structure and function of a new mitogen-activated protein kinase (p38beta) Jiang, Y Chen, C Li, Z Guo, W Gegner, JA Lin, S Han, J J Biol Chem 271:17920-6 15686620 Pubmed 2005 Activation and signaling of the p38 MAP kinase pathway Zarubin, T Han, J Cell Res 15:11-8 10066767 Pubmed 1999 Murine p38-delta mitogen-activated protein kinase, a developmentally regulated protein kinase that is activated by stress and proinflammatory cytokines Hu, MC Wang, YP Mikhail, A Qiu, WR Tan, TH J Biol Chem 274:7095-102 LEFT-TO-RIGHT AAMP binds NOD2 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> Aamp AAMP G3V7V2 Reactome DB_ID: 9989490 UniProt:G3V7V2 Aamp UniProt G3V7V2 1 EQUAL 434 EQUAL Reactome Database ID Release 81 9989490 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9989490 Reactome R-RNO-9674636 1 Reactome stable identifier. Use this 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-9674636.1 AAMP:NOD2 Reactome DB_ID: 9989536 1 1 Reactome Database ID Release 81 9989536 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9989536 Reactome R-RNO-9676152 1 Reactome stable identifier. Use this 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-9676152.1 Reactome Database ID Release 81 9989538 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9989538 Reactome R-RNO-9676160 1 Reactome stable identifier. Use this 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-9676160.1 AAMP (Angio-associated migratory cell protein) binds the human nucleotide-binding domain, leucine rich repeat containing (NLR) family member NOD2. The interaction involves WD40 domains 2-4 of AAMP. NOD2 is critically involved in innate immune protection against a variety of different bacterial pathogens. AAMP negatively regulates, through an unknown mechanism, NOD2-mediated NF-κB activation in HEK293T cells (Bielig et al. 2009). 19535145 Pubmed 2009 A function for AAMP in Nod2-mediated NF-kappaB activation Bielig, H Zurek, B Kutsch, A Menning, M Philpott, D J Sansonetti, P J Kufer, T A Mol. Immunol. 46:2647-54 Reactome Database ID Release 81 9993061 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9993061 Reactome R-RNO-168638 1 Reactome stable identifier. Use this 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-168638.1 GENE ONTOLOGY GO:0070423 gene ontology term for cellular process MI MI:0359 NOD1 is ubiquitously expressed, while NOD2 expression is restricted to monocytes, macrophages, dendritic cells, and intestinal Paneth cells (Inohara et al. 2005). NOD1 and NOD2 activation induces transcription of immune response genes, predominantly mediated by the proinflammatory transcriptional factor NFkappaB but also by AP-1 and Elk-1 (Inohara et al. 2005). NFkappaB translocates to the nucleus following release from IkappaB proteins. NOD1 and NOD2 signaling involves an interaction between their caspase-recruitment domain (CARD) and the CARD of the kinase RIPK2 (RIP2/RICK). This leads to the activation of the NFkappaB pathway and MAPK pathways (Windheim et al. 2007).<br>Activated NODs oligomerize via their NACHT domains, inducing physical proximity of RIP2 proteins that is believed to trigger their K63-linked polyubiquitination, facilitating recruitment of the TAK1 complex. RIP2 also recruits NEMO, bringing the TAK1 and IKK complexes into proximity, leading to NF-kappaB activation and activation of MAPK signaling. Recent studies have demonstrated that K63-linked regulatory ubiquitination of RIP2 is essential for the recruitment of TAK1 (Hasegawa et al. 2008, Hitosumatsu et al. 2008). As observed for toll-like receptor (TLR) signaling, ubiquitination can be removed by the deubiquitinating enzyme A20, thereby dampening NOD1/NOD2-induced NF-kappaB activation. NOD1 and NOD2 both induce K63-linked ubiquitination of RIP2, but NOD2-signaling appears to preferentially utilize the E3 ligase TRAF6, while TRAF2 and TRAF5 were shown to be important for NOD1-mediated signaling. In both cases, activation of NF-kappaB results in the upregulated transcription and production of inflammatory mediators. 18928408 Pubmed 2009 NOD-like receptors: role in innate immunity and inflammatory disease Chen, G Shaw, MH Kim, YG Nunez, G Annu Rev Pathol 4:365-98 18585455 Pubmed 2008 NOD-like receptors (NLRs): bona fide intracellular microbial sensors Shaw, MH Reimer, T Kim, YG Nunez, G Curr Opin Immunol 20:377-82 15952891 Pubmed 2005 NOD-LRR proteins: role in host-microbial interactions and inflammatory disease Inohara, N Chamaillard, M McDonald, C Nunez, G Annu Rev Biochem 74:355-83 18414735 Pubmed 2008 Signal transduction pathways used by NLR-type innate immune receptors Kufer, TA Mol Biosyst 4:380-6