BioPAX pathway converted from "NOD1/2 Signaling Pathway" in the Reactome database. NOD1/2 Signaling Pathway 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> iE-DAP elicits a NOD1 response 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> Reactome DB_ID: 10439342 1 cytosol GO 0005829 UniProt:F6PKK5 nod1 Reactome http://www.reactome.org Xenopus tropicalis NCBI Taxonomy 8364 UniProt F6PKK5 Chain Coordinates 1 EQUAL 953 EQUAL Reactome DB_ID: 622271 1 gamma-D-glutamyl-meso-diaminopimelic acid [ChEBI:59271] gamma-D-glutamyl-meso-diaminopimelic acid ChEBI 59271 Reactome DB_ID: 10439344 1 NOD1:iE-DAP [cytosol] NOD1:iE-DAP Reactome DB_ID: 10439342 1 1 EQUAL 953 EQUAL Reactome DB_ID: 622271 1 Reactome Database ID Release 81 10439344 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10439344 Reactome R-XTR-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-XTR-168408.1 Reactome Database ID Release 81 10439346 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10439346 Reactome R-XTR-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-XTR-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 by electronic annotation IEA GO IEA Activated NOD1 oligomerizes 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> Reactome DB_ID: 10439344 6 Reactome DB_ID: 10439348 1 NOD1:iE-DAP oligomer [cytosol] NOD1:iE-DAP oligomer Reactome DB_ID: 10439344 6 Reactome Database ID Release 81 10439348 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10439348 Reactome R-XTR-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-XTR-622306.1 Reactome Database ID Release 81 10459391 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10459391 Reactome R-XTR-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-XTR-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 inferred by electronic annotation IEA GO IEA Activated NOD oligomer recruites RIP2 (RICK) 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> Reactome DB_ID: 10439348 1 Reactome DB_ID: 10439352 6 UniProt:A0A6I8PV70 ripk2 UniProt A0A6I8PV70 1 EQUAL 540 EQUAL Reactome DB_ID: 10439354 1 PAMP:NOD oligomer:RIP2 [cytosol] PAMP:NOD oligomer:RIP2 Reactome DB_ID: 10439352 6 1 EQUAL 540 EQUAL Reactome DB_ID: 10439348 1 Reactome Database ID Release 81 10439354 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10439354 Reactome R-XTR-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-XTR-168409.1 Reactome Database ID Release 81 10439356 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10439356 Reactome R-XTR-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-XTR-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 inferred by electronic annotation IEA GO IEA RIP2 binds NEMO 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> Reactome DB_ID: 10439242 1 UniProt:A0A6I8RKP9 ikbkg UniProt A0A6I8RKP9 1 EQUAL 419 EQUAL Reactome DB_ID: 10439354 1 Reactome DB_ID: 10459467 1 PAMP:NOD oligomer:RIP2:NEMO [cytosol] PAMP:NOD oligomer:RIP2:NEMO Reactome DB_ID: 10439242 1 1 EQUAL 419 EQUAL Reactome DB_ID: 10439354 1 Reactome Database ID Release 81 10459467 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10459467 Reactome R-XTR-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-XTR-688994.1 Reactome Database ID Release 81 10459469 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10459469 Reactome R-XTR-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-XTR-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 inferred by electronic annotation IEA GO IEA CYLD deubiquitinates NEMO 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> Reactome DB_ID: 10459552 1 PAMP:NOD oligomer:RIP2:K63-Ub-K285-NEMO [cytosol] PAMP:NOD oligomer:RIP2:K63-Ub-K285-NEMO Reactome DB_ID: 10459550 1 ubiquitinylated lysine (K63polyUb [cytosol]) at 285 (in Homo sapiens) 285 EQUAL ubiquitinylated lysine [MOD:01148] 1 EQUAL 419 EQUAL Reactome DB_ID: 10439354 1 Reactome Database ID Release 81 10459552 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10459552 Reactome R-XTR-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-XTR-741389.1 Reactome DB_ID: 10459467 1 Reactome DB_ID: 10439404 1 K63polyUb [cytosol] K63polyUb PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10459556 UniProt:A0A6I8SGS6 cyld UniProt A0A6I8SGS6 1 EQUAL 956 EQUAL GO 0061578 GO molecular function Reactome Database ID Release 81 10459557 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10459557 Reactome Database ID Release 81 10459559 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10459559 Reactome R-XTR-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-XTR-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 inferred by electronic annotation IEA GO IEA RIP2 is K63 polyubiquitinated 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> Reactome DB_ID: 10459467 1 Reactome DB_ID: 10439404 6 Reactome DB_ID: 10457894 1 PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO [cytosol] PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO Reactome DB_ID: 10439242 1 1 EQUAL 419 EQUAL Reactome DB_ID: 10457892 1 PAMP:NOD oligomer:K63-Ub-RIP2 [cytosol] PAMP:NOD oligomer:K63-Ub-RIP2 Reactome DB_ID: 10439348 1 Reactome DB_ID: 10457890 6 ubiquitinylated lysine (K63polyUb [cytosol]) at 209 (in Homo sapiens) 209 EQUAL 1 EQUAL 540 EQUAL Reactome Database ID Release 81 10457892 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10457892 Reactome R-XTR-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-XTR-706482.1 Reactome Database ID Release 81 10457894 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10457894 Reactome R-XTR-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-XTR-706480.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10459508 RIP2 ubiquitin ligases [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity itch [cytosol] UniProt L7N3Q1 GO 0019787 GO molecular function Reactome Database ID Release 81 10459509 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10459509 Reactome Database ID Release 81 10459511 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10459511 Reactome R-XTR-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-XTR-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 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 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 inferred by electronic annotation IEA GO IEA TAK1 is activated 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> Reactome DB_ID: 10459515 1 plasma membrane GO 0005886 PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO:TAK1 complex [plasma membrane] PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO:TAK1 complex Reactome DB_ID: 10459513 1 TAK1 complex [plasma membrane] TAK1 complex Reactome DB_ID: 10457898 1 Ghost homologue of TAB1 [cytosol] Ghost homologue of TAB1 Reactome DB_ID: 10445092 1 UniProt:F6YEZ3 tab2 UniProt F6YEZ3 1 EQUAL 693 EQUAL Reactome DB_ID: 10457896 1 UniProt:A0A6I8QTD1 map3k7 UniProt A0A6I8QTD1 1 EQUAL 606 EQUAL Reactome Database ID Release 81 10459513 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10459513 Reactome R-XTR-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-XTR-8947970.1 Reactome DB_ID: 10457894 1 Reactome Database ID Release 81 10459515 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10459515 Reactome R-XTR-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-XTR-706478.1 Reactome DB_ID: 10457904 1 PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO:activated TAK1 complex [cytosol] PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO:activated TAK1 complex Reactome DB_ID: 10457894 1 Reactome DB_ID: 10457902 1 TAK1 complex [cytosol] TAK1 complex Reactome DB_ID: 10457898 1 Reactome DB_ID: 10457896 1 1 EQUAL 606 EQUAL Reactome DB_ID: 10457900 1 1 EQUAL 693 EQUAL Reactome Database ID Release 81 10457902 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10457902 Reactome R-XTR-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-XTR-446878.1 Reactome Database ID Release 81 10457904 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10457904 Reactome R-XTR-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-XTR-706477.1 Reactome Database ID Release 81 10459517 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10459517 Reactome R-XTR-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-XTR-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 inferred by electronic annotation IEA GO IEA NOD1 induced apoptosis is mediated by RIP2 and CARD8 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> Reactome DB_ID: 10439344 1 Converted from EntitySet in Reactome Reactome DB_ID: 10459471 1 Long prodomain caspases [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity casp8 [cytosol] UniProt A0A6I8Q0P2 Reactome DB_ID: 10459473 1 NOD1:iE-DAP:Long prodomain caspases [cytosol] NOD1:iE-DAP:Long prodomain caspases Reactome DB_ID: 10439344 1 Converted from EntitySet in Reactome Reactome DB_ID: 10459471 1 Reactome Database ID Release 81 10459473 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10459473 Reactome R-XTR-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-XTR-622417.1 Reactome Database ID Release 81 10459475 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10459475 Reactome R-XTR-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-XTR-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 inferred by electronic annotation IEA GO IEA 2.7.12.2 Activation of p38 MAPK 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 Reactome DB_ID: 10469016 1 p38 MAPK [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 113592 8 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 29370 8 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 Converted from EntitySet in Reactome Reactome DB_ID: 10469022 1 Phospho-p38 MAPK [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10457881 UniProt:A0A7D9NLW8 map2k6 UniProt A0A7D9NLW8 O-phospho-L-serine at 207 (in Homo sapiens) 207 EQUAL O-phospho-L-serine [MOD:00046] O-phospho-L-threonine at 211 (in Homo sapiens) 211 EQUAL O-phospho-L-threonine [MOD:00047] 1 EQUAL 334 EQUAL GO 0004708 GO molecular function Reactome Database ID Release 81 10469023 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10469023 Reactome Database ID Release 81 10469025 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10469025 Reactome R-XTR-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-XTR-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 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 81 10523146 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10523146 Reactome R-XTR-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-XTR-168638.1 GO 0070423 GO biological process 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 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 18414735 Pubmed 2008 Signal transduction pathways used by NLR-type innate immune receptors Kufer, TA Mol Biosyst 4:380-6 inferred by electronic annotation IEA GO IEA