BioPAX pathway converted from "MyD88 cascade initiated on plasma membrane" in the Reactome database. MyD88 cascade initiated on plasma membrane This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> TAK1-dependent IKK and NF-kappa-B activation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT CHUK, IKBKB and IKBKG form IKK complex IKBKA, IKBKB and IKBKG form IKK complex This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> CHUK Q28DZ1 Reactome DB_ID: 10487079 cytosol GENE ONTOLOGY GO:0005829 UniProt:Q28DZ1 Xenopus tropicalis NCBI Taxonomy 8364 UniProt Q28DZ1 1 EQUAL 745 EQUAL Reactome Database ID Release 82 10487079 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10487079 Reactome R-XTR-168104 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-168104.1 Reactome http://www.reactome.org ikbkb IKBKB A0A6I8S264 Reactome DB_ID: 10488953 UniProt:A0A6I8S264 ikbkb UniProt A0A6I8S264 1 EQUAL 756 EQUAL Reactome Database ID Release 82 10488953 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10488953 Reactome R-XTR-168114 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-168114.1 ikbkg IKBKG A0A6I8RKP9 Reactome DB_ID: 10483110 UniProt:A0A6I8RKP9 ikbkg UniProt A0A6I8RKP9 1 EQUAL 419 EQUAL Reactome Database ID Release 82 10483110 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483110 Reactome R-XTR-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-XTR-168108.1 CHUK:IKBKB:IKBKG Reactome DB_ID: 10488955 1 1 1 Reactome Database ID Release 82 10488955 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10488955 Reactome R-XTR-168113 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-168113.1 Reactome Database ID Release 82 10535043 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10535043 Reactome R-XTR-5609665 1 Reactome stable identifier. Use this 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-5609665.1 The multimeric I kappa B kinase (IKK) complex is a key regulator of NF-kappa-B signaling, which is responsible for the phosphorylation of inhibitor kB (IkB). The phosphorylation by IKK triggers K48-linked ubiquitination of IkB leading to proteasomal degradation of IkB, allowing translocation of NFkB factor to the nucleus, where it can activate transcription of a variety of genes participating in the immune and inflammatory response, cell adhesion, growth control, and protection against apoptosis (Alkalay I et al. 1995; Collins T et al. 1995; Kaltschmidt B et al. 2000; Oeckinghaus A and Ghosh S 2009). The IKK complex is composed of the two catalytic subunits, IKKa (IKBKA, IKK1 or CHUK) and IKKb (IKK2 or IKBKB) kinases, and a regulatory subunit, NF-kappa-B essential modulator (NEMO, IKKg or IKBKG). IKBKG (NEMO) associates with the C-termini of unphosphorylated IKKs and promotes the IKK complex activation (Rothwarf DM et al. 1998). The molecular composition and stoichiometry of the IKK complex remains debatable, although the core IKK complex that range from 700 to 900 kDa is thought to consist of an IKBKA:IKBKB heterodimer associated with an IKBKG dimer or higher oligomeric assemblies (DiDonato JA et al. 1997; May J et al. 2002; Tegethoff S et al. 2003; Marienfeld RB et al. 2006; Rushe M et al. 2008). 20066092 Pubmed 2009 The NF-kappaB family of transcription factors and its regulation Oeckinghaus, Andrea Ghosh, Sankar Cold Spring Harb Perspect Biol 1:a000034 7479848 Pubmed 1995 Stimulation-dependent I kappa B alpha phosphorylation marks the NF-kappa B inhibitor for degradation via the ubiquitin-proteasome pathway Alkalay, I Yaron, A Hatzubai, A Orian, A Ciechanover, A Ben-Neriah, Y Proc Natl Acad Sci U S A 92:10599-603 9751060 Pubmed 1998 IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex Rothwarf, D M Zandi, E Natoli, G Karin, M Nature 395:297-300 18462684 Pubmed 2008 Structure of a NEMO/IKK-associating domain reveals architecture of the interaction site Rushe, Mia Silvian, Laura Bixler, Sarah Chen, Ling Ling Cheung, Anne Bowes, Scott Cuervo, Hernan Berkowitz, Steven Zheng, Timothy Guckian, Kevin Pellegrini, Maria Lugovskoy, Alexey Structure 16:798-808 17000764 Pubmed 2006 Dimerization of the I kappa B kinase-binding domain of NEMO is required for tumor necrosis factor alpha-induced NF-kappa B activity Marienfeld, Ralf B Palkowitsch, Lysann Ghosh, Sankar Mol. Cell. Biol. 26:9209-19 inferred from electronic annotation EVIDENCE CODE ECO:0000203 LEFT-TO-RIGHT NF-kappa-B inhibitor binds NF-kappa-B 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> NFKB1(1-433), NFKB2(1-454):RELA Reactome DB_ID: 10483084 rela RELA A0A803JIP3 Reactome DB_ID: 10483072 UniProt:A0A803JIP3 rela UniProt A0A803JIP3 1 EQUAL 551 EQUAL Reactome Database ID Release 82 10483072 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483072 Reactome R-XTR-168172 1 Reactome stable identifier. Use this 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-168172.1 1 Converted from EntitySet in Reactome NFkB NFKB1(1-433), NFKB2(1-454) Nuclear factor NF-kappa-B Reactome DB_ID: 10483082 F6T195 ccdc71l NFKB1(1-433) Reactome DB_ID: 10483076 UniProt:F6T195 ccdc71l UniProt F6T195 1 EQUAL 433 EQUAL Reactome Database ID Release 82 10483076 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483076 Reactome R-XTR-168168 1 Reactome stable identifier. Use this 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-168168.1 nfkb2 NFKB2(1-454) A0A6I8PSP0 Reactome DB_ID: 10483080 UniProt:A0A6I8PSP0 nfkb2 UniProt A0A6I8PSP0 1 EQUAL 454 EQUAL Reactome Database ID Release 82 10483080 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483080 Reactome R-XTR-168144 1 Reactome stable identifier. Use this 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-168144.1 Reactome Database ID Release 82 10483082 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483082 Reactome R-XTR-177656 1 Reactome stable identifier. Use this 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-177656.1 1 Reactome Database ID Release 82 10483084 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483084 Reactome R-XTR-168155 1 Reactome stable identifier. Use this 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-168155.1 Converted from EntitySet in Reactome IkB NFkB inhibitor NF-kappaB inhibitor IkBA, IkBB NFKBIA, NFKBIB Reactome DB_ID: 10483094 nfkbia NFKBIA Q6GL40 Reactome DB_ID: 10483088 UniProt:Q6GL40 nfkbia UniProt Q6GL40 1 EQUAL 317 EQUAL Reactome Database ID Release 82 10483088 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483088 Reactome R-XTR-168151 1 Reactome stable identifier. Use this 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-168151.1 nfkbie NFKBIB A0A803JZI4 Reactome DB_ID: 10483092 UniProt:A0A803JZI4 nfkbie UniProt A0A803JZI4 1 EQUAL 356 EQUAL Reactome Database ID Release 82 10483092 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483092 Reactome R-XTR-168132 1 Reactome stable identifier. Use this 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-168132.1 Reactome Database ID Release 82 10483094 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483094 Reactome R-XTR-168143 1 Reactome stable identifier. Use this 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-168143.1 NFkB inhibitor:NFkB complex Reactome DB_ID: 10483096 1 1 Reactome Database ID Release 82 10483096 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483096 Reactome R-XTR-168130 1 Reactome stable identifier. Use this 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-168130.1 Reactome Database ID Release 82 10563074 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10563074 Reactome R-XTR-9630923 1 Reactome stable identifier. Use this 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-9630923.1 NF-kappa-B is sequestered in the cytosol of unstimulated cells through the interactions with a class of inhibitor proteins, called NF-kappa-B inhibitors (IkBs, NFKBIA or NFKBIB). IkBs proteins such as NFKBIA, NFKBIB or NFKBIE are characterized by the presence of six to seven ankyrin repeat motifs, which mediate interaction with the Rel homology domain (RHD). RHD mediates DNA binding, dimerization and nuclear localization (Jacobs MD & Harrison SC 1998; Manavalan B et al. 2010). NF-kappa-B inhibitors (IkBs) mask the nuclear localization signal (NLS) of the NF-kappa-B p65 subunit (ReLA, p65) preventing the nuclear translocation of NF-kappa-B (Jacobs MD & Harrison SC 1998; Cervantes CF et al. 2011). A key event in NF-kappa-B activation involves phosphorylation of IkB (at sites equivalent to Ser32 and Ser36 of NFKBIA (IkB-alpha) or Ser19 and Ser22 of NFKBIB (IkB-beta) by the IκB kinase (IKK) complex. The phosphorylated NFKBIA is recognized by the E3 ligase complex leading to K48-linked ubiquitination, and targeted for ubiquitin-mediated proteasomal degradation, releasing the NF-kappa-B dimer p50/p65 (RelA:NFKB1) into the nucleus to turn on target genes (Karin M & Ben-Neriah Y 2000, Kanarek N & Ben-Neriah Y 2012; Hoffmann A et al. 2006). Crystal structures of NF-kappa-B inhibitors:NF-kappaB complexes revealed that an NF-kappa-B dimer binds to one IkB molecule (Jacobs MD & Harrison SC 1998; Ghosh G et 2012). 22435548 Pubmed 2012 Regulation of NF-κB by ubiquitination and degradation of the IκBs Kanarek, Naama Ben-Neriah, Yinon Immunol. Rev. 246:77-94 9865693 Pubmed 1998 Structure of an IkappaBalpha/NF-kappaB complex Jacobs, M D Harrison, S C Cell 95:749-58 17072323 Pubmed 2006 Transcriptional regulation via the NF-kappaB signaling module Hoffmann, A Natoli, G Ghosh, G Oncogene 25:6706-16 10837071 Pubmed 2000 Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity Karin, M Ben-Neriah, Y Annu. Rev. Immunol. 18:621-63 22435546 Pubmed 2012 NF-κB regulation: lessons from structures Ghosh, Gourisankar Wang, Vivien Ya-Fan Huang, De-Bin Fusco, Amanda Immunol. Rev. 246:36-58 15145317 Pubmed 2004 The two NF-kappaB activation pathways and their role in innate and adaptive immunity Bonizzi, G Karin, M Trends Immunol 25:280-8 21203422 Pubmed 2010 Structure-function relationship of cytoplasmic and nuclear IκB proteins: an in silico analysis Manavalan, Balachandran Basith, Shaherin Choi, Yong-Min Lee, Gwang Choi, Sangdun PLoS ONE 5:e15782 21094161 Pubmed 2011 The RelA nuclear localization signal folds upon binding to IκBα Cervantes, Carla F Bergqvist, Simon Kjaergaard, Magnus Kroon, Gerard Sue, Shih-Che Dyson, H Jane Komives, Elizabeth A J. Mol. Biol. 405:754-64 LEFT-TO-RIGHT 2.7.11.1 Active IKBKB phosphorylates NF-kappa-B inhibitor 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> 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 82 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 4 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 82 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 4 Converted from EntitySet in Reactome Phospho-NF-kappaB Inhibitor Reactome DB_ID: 10483106 Q6GL40 phospho-nfkbia p-S32,S36-NFKBIA Reactome DB_ID: 10483100 32 EQUAL O-phospho-L-serine MOD MOD:00046 36 EQUAL 1 EQUAL 317 EQUAL Reactome Database ID Release 82 10483100 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483100 Reactome R-XTR-177677 1 Reactome stable identifier. Use this 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-177677.1 A0A803JZI4 phospho-nfkbie p-S19,S23-NFKBIB Reactome DB_ID: 10483104 19 EQUAL 23 EQUAL 1 EQUAL 356 EQUAL Reactome Database ID Release 82 10483104 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483104 Reactome R-XTR-177670 1 Reactome stable identifier. Use this 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-177670.1 Reactome Database ID Release 82 10483106 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483106 Reactome R-XTR-177678 1 Reactome stable identifier. Use this 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-177678.1 ACTIVATION activeUnit: #Protein14 CHUK:p-S177,S181-IKBKB:IKBKG Reactome DB_ID: 10488957 1 A0A6I8S264 phospho-ikbkb p-S177,S181-IKBKB Reactome DB_ID: 10483122 177 EQUAL 181 EQUAL 1 EQUAL 756 EQUAL Reactome Database ID Release 82 10483122 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483122 Reactome R-XTR-202506 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-202506.1 1 1 Reactome Database ID Release 82 10488957 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10488957 Reactome R-XTR-202513 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-202513.1 GENE ONTOLOGY GO:0004674 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 82 10566258 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10566258 Reactome Database ID Release 82 10566260 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10566260 Reactome R-XTR-9773803 1 Reactome stable identifier. Use this 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-9773803.1 In human, IkBs (NFKBIA, NFKBIB or NFKBIE) are inhibitory proteins that sequesters NF-kappa-B in the cytoplasm by masking a nuclear localization signal, located just at the C-terminal end of the RelA (p65) subunit of the RelA:NFKB1 heterodimer.<p>A key event in NF-kappa-B activation involves phosphorylation of IkB by an IkB kinase (IKK). The phosphorylation and ubiquitination of IkB kinase complex is mediated by two distinct pathways, either the classical or alternative pathway. In the classical NF-kappa-B signaling pathway, the activated IKK (IkB kinase) complex, predominantly acting through IKK beta (IKKb, IKBKB) in an IKK gamma (IKBKG, NEMO)-dependent manner, catalyzes the phosphorylation of IkBs (at sites equivalent to Ser32 and Ser36 of human NFKBIA (IkB-alpha) or Ser19 and Ser22 of NFKBIB (IkB-beta)). Once phosphorylated, IkB undergoes ubiquitin-mediated degradation, releasing NF-kappa-B.<br> 17047224 Pubmed 2006 Regulation and function of IKK and IKK-related kinases Hacker, H Karin, M Sci STKE 2006:re13 19666475 Pubmed 2009 The nemo binding domains of both IKKalpha and IKKbeta regulate IKK complex assembly and classical NFkappaB activation Solt, LA Madge, LA May, MJ J Biol Chem 10723127 Pubmed 2000 Activation of NF-kappa B by the dsRNA-dependent protein kinase, PKR involves the I kappa B kinase complex Gil, J Alcami, J Esteban, M Oncogene 19:1369-78 27701768 Pubmed 2017 Double phosphorylation-induced structural changes in the signal-receiving domain of IκBα in complex with NF-κB Yazdi, Samira Naumann, Michael Stein, Matthias Proteins 85:17-29 12221085 Pubmed 2002 IKKalpha, IKKbeta, and NEMO/IKKgamma are each required for the NF-kappa B-mediated inflammatory response program Li, X Massa, PE Hanidu, A Peet, GW Aro, P Savitt, A Mische, S Li, J Marcu, KB J Biol Chem 277:45129-40 INHIBITION Reactome Database ID Release 82 10483138 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483138 Converted from EntitySet in Reactome NKIRAS Reactome DB_ID: 10483135 nkiras1 NKIRAS1 A0A803JEN5 Reactome DB_ID: 10483129 UniProt:A0A803JEN5 nkiras1 UniProt A0A803JEN5 1 EQUAL 192 EQUAL Reactome Database ID Release 82 10483129 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483129 Reactome R-XTR-8952686 1 Reactome stable identifier. Use this 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-8952686.1 gtsf1 NKIRAS2 A0A7D9NJN9 Reactome DB_ID: 10483133 UniProt:A0A7D9NJN9 gtsf1 UniProt A0A7D9NJN9 1 EQUAL 191 EQUAL Reactome Database ID Release 82 10483133 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483133 Reactome R-XTR-8952684 1 Reactome stable identifier. Use this 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-8952684.1 Reactome Database ID Release 82 10483135 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483135 Reactome R-XTR-8952687 1 Reactome stable identifier. Use this 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-8952687.1 LEFT-TO-RIGHT NF-kappa-B complex is transported from cytosol to nucleus This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> NFKB1(1-433), NFKB2(1-454):RELA Reactome DB_ID: 10483167 nucleoplasm GENE ONTOLOGY GO:0005654 Converted from EntitySet in Reactome NFKB1, NFKB2 Nuclear factor NF-kappa-B p50 Reactome DB_ID: 10483163 F6T195 ccdc71l NFKB1(1-433) Reactome DB_ID: 10483159 1 EQUAL 433 EQUAL Reactome Database ID Release 82 10483159 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483159 Reactome R-XTR-177655 1 Reactome stable identifier. Use this 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-177655.1 nfkb2 NFKB2(1-454) A0A6I8PSP0 Reactome DB_ID: 10483161 1 EQUAL 454 EQUAL Reactome Database ID Release 82 10483161 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483161 Reactome R-XTR-177674 1 Reactome stable identifier. Use this 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-177674.1 Reactome Database ID Release 82 10483163 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483163 Reactome R-XTR-177662 1 Reactome stable identifier. Use this 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-177662.1 1 rela RELA A0A803JIP3 Reactome DB_ID: 10483165 1 EQUAL 551 EQUAL Reactome Database ID Release 82 10483165 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483165 Reactome R-XTR-177676 1 Reactome stable identifier. Use this 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-177676.1 1 Reactome Database ID Release 82 10483167 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483167 Reactome R-XTR-177673 1 Reactome stable identifier. Use this 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-177673.1 Reactome Database ID Release 82 10483205 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483205 Reactome R-XTR-168166 1 Reactome stable identifier. Use this 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-168166.1 NFkB is a family of transcription factors that play pivotal roles in immune, inflammatory, and antiapoptotic responses. There are five NF-kB/Rel family members, p65 (RelA), RelB, c-Rel, p50/p105 (NF-kappa-B1) and p52/p100 (NF-kappa-B2). All members of the NFkB family contain a highly conserved DNA-binding and dimerization domain called Rel-homology region (RHR). The RHR is responsible for homo- or heterodimerization. Therefore, NF-kappa-B exists in unstimulated cells as homo or heterodimers; the most common heterodimer is p65/p50. NF-kappa-B is sequestered in the cytosol of unstimulated cells through the interactions with a class of inhibitor proteins called IkBs, which mask the nuclear localization signal of NF-kB and prevent its nuclear translocation. Various stimuli induce the activation of the IkB kinase (IKK) complex, which then phosphorylates IkBs. The phosphorylated IkBs are ubiquitinated and then degraded through the proteasome-mediated pathway. The degradation of IkBs releases NF-kappa-B and and it can be transported into nucleus where it induces the expression of target genes.<br> 16056267 Pubmed 2005 Ubiquitin signalling in the NF-kappaB pathway Chen, ZJ Nat Cell Biol 7:758-65 ACTIVATION Reactome Database ID Release 82 10483206 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483206 AGER ligands:AGER Reactome DB_ID: 10483203 plasma membrane GENE ONTOLOGY GO:0005886 Converted from EntitySet in Reactome AGER ligands Reactome DB_ID: 10483201 AGE adducts:Peptide Reactome DB_ID: 879479 extracellular region GENE ONTOLOGY GO:0005576 Peptide Reactome DB_ID: 879484 peptide [ChEBI:16670] peptide peptido peptidos Peptid ChEBI CHEBI:16670 Reactome Database ID Release 82 879484 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=879484 Reactome R-ALL-879484 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-879484.2 1 Converted from EntitySet in Reactome AGE adducts Reactome DB_ID: 879487 NECML N(6)-carboxymethyl-lysine N(6)-carboxymethyl-L-lysine Reactome DB_ID: 879473 N(6)-carboxymethyl-L-lysine [ChEBI:53014] N(6)-carboxymethyl-L-lysine ChEBI CHEBI:53014 Reactome Database ID Release 82 879473 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=879473 Reactome R-ALL-879473 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-879473.3 N(6)-(1-carboxyethyl)-L-lysine N-epsilon-(1-(1-carboxy)ethyl)lysine Reactome DB_ID: 938699 N(6)-(1-carboxyethyl)-L-lysine [ChEBI:60125] N(6)-(1-carboxyethyl)-L-lysine ChEBI CHEBI:60125 Reactome Database ID Release 82 938699 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=938699 Reactome R-ALL-938699 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-938699.3 Reactome Database ID Release 82 879487 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=879487 Reactome R-ALL-879487 1 Reactome stable identifier. Use this 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-879487.1 1 Reactome Database ID Release 82 879479 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=879479 Reactome R-ALL-879479 1 Reactome stable identifier. Use this 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-879479.1 S100A12 dimer Reactome DB_ID: 10483183 Converted from EntitySet in Reactome Homologues of S100A12 Reactome DB_ID: 10483181 s100p S100A12 A0A6I8Q5Z6 Reactome DB_ID: 10483175 UniProt:A0A6I8Q5Z6 s100p UniProt A0A6I8Q5Z6 2 EQUAL 92 EQUAL Reactome Database ID Release 82 10483175 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483175 Reactome R-XTR-879450 1 Reactome stable identifier. Use this 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-879450.1 S100A12 A0A6I8RMX0 Reactome DB_ID: 10483179 UniProt:A0A6I8RMX0 UniProt A0A6I8RMX0 2 EQUAL 92 EQUAL Reactome Database ID Release 82 10483179 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483179 Reactome R-XTR-879450-2 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-879450-2.1 Reactome Database ID Release 82 10483181 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483181 Reactome R-XTR-879450-3 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-879450-3.1 2 Reactome Database ID Release 82 10483183 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483183 Reactome R-XTR-879439 1 Reactome stable identifier. Use this 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-879439.1 S100B homodimer Reactome DB_ID: 10483189 S100B A0A6I8R178 Reactome DB_ID: 10483187 UniProt:A0A6I8R178 UniProt A0A6I8R178 2 EQUAL 92 EQUAL Reactome Database ID Release 82 10483187 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483187 Reactome R-XTR-879433 1 Reactome stable identifier. Use this 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-879433.1 2 Reactome Database ID Release 82 10483189 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483189 Reactome R-XTR-879449 1 Reactome stable identifier. Use this 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-879449.1 hmgb1 HMGB1 Q6P4N5 Reactome DB_ID: 10483193 UniProt:Q6P4N5 hmgb1 UniProt Q6P4N5 2 EQUAL 215 EQUAL Reactome Database ID Release 82 10483193 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483193 Reactome R-XTR-879382 1 Reactome stable identifier. Use this 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-879382.1 app APP(672-713) A0A6I8RNI5 Reactome DB_ID: 10483197 UniProt:A0A6I8RNI5 app UniProt A0A6I8RNI5 672 EQUAL 713 EQUAL Reactome Database ID Release 82 10483197 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483197 Reactome R-XTR-879340 1 Reactome stable identifier. Use this 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-879340.1 Reactome Database ID Release 82 10483201 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483201 Reactome R-XTR-879455 1 Reactome stable identifier. Use this 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-879455.1 1 bcam AGER F6V7N4 Reactome DB_ID: 10483171 UniProt:F6V7N4 bcam UniProt F6V7N4 23 EQUAL 404 EQUAL Reactome Database ID Release 82 10483171 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483171 Reactome R-XTR-197639 1 Reactome stable identifier. Use this 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-197639.1 1 Reactome Database ID Release 82 10483203 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483203 Reactome R-XTR-879365 1 Reactome stable identifier. Use this 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-879365.1 Regulation of NF-kappa B signaling This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT IKBIP binds IKBKB and CHUK IKBIP binds IKBKB and IKBKA 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> ikbip IKBIP F7AQ13 Reactome DB_ID: 10565814 endoplasmic reticulum membrane GENE ONTOLOGY GO:0005789 UniProt:F7AQ13 ikbip UniProt F7AQ13 1 EQUAL 350 EQUAL Reactome Database ID Release 82 10565814 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10565814 Reactome R-XTR-9749482 1 Reactome stable identifier. Use this 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-9749482.1 CHUK:IKBKB:IKBIP Reactome DB_ID: 10565816 1 1 1 Reactome Database ID Release 82 10565816 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10565816 Reactome R-XTR-9749465 1 Reactome stable identifier. Use this 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-9749465.1 Reactome Database ID Release 82 10565818 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10565818 Reactome R-XTR-9749494 1 Reactome stable identifier. Use this 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-9749494.1 GENE ONTOLOGY GO:0043124 gene ontology term for cellular process MI MI:0359 The I-kappa-B-kinase (IKK) complex consists of two catalytic subunits, IKBKA (KKα or CHUK) and IKBKB (IKKβ), associated with a regulatory subunit IKBKG (NEMO). Yeast two-hybrid screening identified inhibitor of nuclear factor kappa-B kinase-interacting protein (IKBIP or IKIP) as an IKBKB-binding protein (Hofer-Warbinek R et al. 2004). IKBIP was found to downregulate NF-kappa-B activation and induction of proinflammatory cytokines in human and mouse myeloid cells in response to Toll-like receptor (TLR) ligands (Wu H et al. 2020). In addition, IKBIP deficiency resulted in prolonged phosphorylation of IKBKB, CHUK and p65, and increased expression of NF-kappaB-responsive genes in myeloid cells after stimulation with LPS, TNF-α, and IL-1β. Moreover, IKBIP co-immunoprecipitated with IKBKA (CHUK) and IKBKB subunits, but not with IKBKG, upon co-expression of tagged proteins in human embryonic kidney HEK293T cells (Wu H et al. 2020). Mutagenesis analysis revealed that the N-terminal region of IKBIP interacts with leucine zipper (LZ) and helix-loop-helix (HLH) domains of IKBKB. Confocal microscopy showed that IKBKB colocalizes with IKBIP in the endoplasmic reticulum (ER) upon co-expression of tagged proteins in Hela cells (Wu H et al. 2020). These data suggest that IKBIP negatively regulates NF-kappa-B activation via targeting IKBKB and CHUK and inhibiting their phosphorylation (Wu H et al. 2020). 31826938 Pubmed 2020 IKIP Negatively Regulates NF-κB Activation and Inflammation through Inhibition of IKKα/β Phosphorylation Wu, Haifeng Liu, Hansen Zhao, Xueying Zheng, Yi Liu, Bingyu Zhang, Lei Gao, Chengjiang J Immunol 204:418-427 15389287 Pubmed 2004 A highly conserved proapoptotic gene, IKIP, located next to the APAF1 gene locus, is regulated by p53 Hofer-Warbinek, R Schmid, J A Mayer, H Winsauer, G Orel, L Mueller, B Wiesner, Ch Binder, B R de Martin, R Cell Death Differ 11:1317-25 LEFT-TO-RIGHT LRRC14 binds IKBKB and CHUK LRRC14 binds IKBKB and IKBKA 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> lrrc14 LRRC14 F6UIV6 Reactome DB_ID: 10565822 UniProt:F6UIV6 lrrc14 UniProt F6UIV6 1 EQUAL 493 EQUAL Reactome Database ID Release 82 10565822 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10565822 Reactome R-XTR-9749455 1 Reactome stable identifier. Use this 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-9749455.1 CHUK:IKBKB:LRRC14 Reactome DB_ID: 10565824 1 1 1 Reactome Database ID Release 82 10565824 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10565824 Reactome R-XTR-9749467 1 Reactome stable identifier. Use this 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-9749467.1 Reactome Database ID Release 82 10565826 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10565826 Reactome R-XTR-9749505 1 Reactome stable identifier. Use this 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-9749505.1 Leucine-rich repeat-containing protein 14 (LRRC14) binds to the helix-loop-helix (HLH) domain of IKBKB (Wu C et al. 2016). This binding blocks IKBKB interaction with IKBKG (NEMO) disrupting IκB kinase (IKK) complex formation and NF-kappa-B activation (Wu C et al. 2016). 27426725 Pubmed 2016 LRRC14 attenuates Toll-like receptor-mediated NF-κB signaling through disruption of IKK complex Wu, Chenglei Yang, Yexin Ou, Jiayu Zhu, Liang Zhao, W Cui, Jun Exp Cell Res 347:65-73 LEFT-TO-RIGHT NLRX1 binds CHUK:IKBKB:IKBKG NLRX1 binds activated IKK complex This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> vwc2l K63polyUb-NLRX1 F6YYZ9 Reactome DB_ID: 10565806 UniProt:F6YYZ9 vwc2l UniProt F6YYZ9 ubiquitinylated lysine MOD MOD:01148 87 EQUAL 975 EQUAL Reactome Database ID Release 82 10565806 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10565806 Reactome R-XTR-9749510 1 Reactome stable identifier. Use this 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-9749510.1 CHUK:IKBKB:IKBKG:K63polyUb-NLRX1 Reactome DB_ID: 10565808 1 1 Reactome Database ID Release 82 10565808 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10565808 Reactome R-XTR-9749472 1 Reactome stable identifier. Use this 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-9749472.1 Reactome Database ID Release 82 10565810 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10565810 Reactome R-XTR-9749471 1 Reactome stable identifier. Use this 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-9749471.1 Nucleotide binding oligomerization domain (NOD)-like receptor (NLR) family member X1 (NLRX1) has been implicated in regulation of the Toll-like receptor (TLR)-mediated nuclear factor kappa-B (NF-kappa-B) signaling pathway. NLRX1 deficiency enhanced phosphorylation of catalytic subunits (CHUK and IKBKB) of the IkB kinase (IKK) complex and NF-kappa-B activation and led to elevated production of inflammatory cytokines in mouse cells in response to bacterial lipopolysaccharide (LPS, a TLR4 ligand) (Allen IC et al. 2011; Xia X et al. 2011; Ma D et al. 2019). NLRX1-knockdown mice showed enhanced susceptibility to LPS-induced septic shock thus further confirming that NLRX1 functions as a negative regulator of TLR signaling in vivo (Xia X et al. 2011). NLRX1 was shown to interact with TRAF6 (Allen et al. 2011; Xia X et al. 2011) and the IKK complex (CHUK:IKBKB:IKBKG) (Xia X et al. 2011) in human and mouse cells. Specifically, in unstimulated cells, NLRX1 was shown to associate with TRAF6 (Xia X et al. 2011). Upon stimulation with LPS, NLRX1 is thought to undergo K63-linked polyubiquitination. Although TRAF6 possesses E3 ubiquitin ligase activity, the TRAF6 deficiency did not affect NLRX1 ubiquitination in mouse embryonic fibroblast (MEF) (Xia X et al. 2011). Further studies are required to identify E3 ubiquitin ligase which is responsible for the ubiquitination of NLRX1. Ubiquitinated NLRX1 then binds to the IKK complex, blocking phosphorylation of the catalytic subunits CHUK (IKBKA) and IKBKB (Xia X et al. 2011). Mutagenesis studies showed that the C-terminal leucine-rich repeat (LRR) domain of NLRX1 binds to the kinase domain of IKBKB (Xia X et al. 2011). <p>The regulatory effects of NLRX1 are highly cell type specific (reviewed in Fekete T et al. 2021). As a regulator of inflammation, NLRX1 has been implicated in the pathology of diverse diseases (reviewed in Pickering RJ & Booty LM 2021).<p>This Reactome event shows interaction between NLRX1 and the IKK complex. 30861394 Pubmed 2019 NLRX1 alleviates lipopolysaccharide-induced apoptosis and inflammation in chondrocytes by suppressing the activation of NF-κB signaling Ma, Ding Zhao, Yangxue She, Jiang Zhu, Yandong Zhao, Y Liu, Liang Zhang, Yingang Int Immunopharmacol 71:7-13 33525671 Pubmed 2021 Focusing on the Cell Type Specific Regulatory Actions of NLRX1 Fekete, Tünde Bencze, Dóra Bíró, Eduárd Benko, Szilvia Pázmándi, Kitti Int J Mol Sci 22: 21703539 Pubmed 2011 NLRX1 negatively regulates TLR-induced NF-κB signaling by targeting TRAF6 and IKK Xia, Xiaojun Cui, Jun Wang, Helen Y Zhu, Liang Matsueda, Satoko Wang, Qinfu Yang, Xiaoang Hong, Jun Songyang, Z Chen, Zhijian J Wang, Rong-Fu Immunity 34:843-53 33314068 Pubmed 2021 NLR in eXile: Emerging roles of NLRX1 in immunity and human disease Pickering, Robert J Booty, Lee M Immunology 162:268-280 21703540 Pubmed 2011 NLRX1 protein attenuates inflammatory responses to infection by interfering with the RIG-I-MAVS and TRAF6-NF-κB signaling pathways Allen, Irving C Moore, Chris B Schneider, Monika Lei, Yu Davis, Beckley K Scull, Margaret A Gris, Denis Roney, Kelly E Zimmermann, Albert G Bowzard, John B Ranjan, Priya Monroe, Kathryn M Pickles, Raymond J Sambhara, Suryaprakash Ting, Jenny P Y Immunity 34:854-65 LEFT-TO-RIGHT NLRC5 binds IKBKB and CHUK NLRC5 binds IKBKB and IKBKA 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> nlrc5 NLRC5 A0A803J229 Reactome DB_ID: 10565862 UniProt:A0A803J229 nlrc5 UniProt A0A803J229 1 EQUAL 1866 EQUAL Reactome Database ID Release 82 10565862 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10565862 Reactome R-XTR-937324 1 Reactome stable identifier. Use this 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-937324.1 CHUK:IKBKB:NLRC5 Reactome DB_ID: 10565864 1 1 1 Reactome Database ID Release 82 10565864 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10565864 Reactome R-XTR-9750228 1 Reactome stable identifier. Use this 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-9750228.1 Reactome Database ID Release 82 10565873 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10565873 Reactome R-XTR-9750226 1 Reactome stable identifier. Use this 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-9750226.1 The I-kappa-B-kinase (IKK) complex, a key regulator of the nuclear factor kappa B (NF-kB) signaling pathway, consists of two catalytic subunits, IKBKA (KKα or CHUK) and IKBKB (IKKβ), associated with a regulatory subunit IKBKG (NEMO). The IKK complex is responsible for the phosphorylation of inhibitors of NF-kB (IkBs), such as NFKBIA or NFKBIB. Once phosphorylated, IkB undergoes ubiquitin-mediated degradation, releasing the transcription factor NF-kB thereby allowing translocation of NF-kB to the nucleus to regulate gene expression (Oeckinghaus A and Ghosh S 2009). NOD-like receptor C5 (NLRC5), the transcriptional activator of genes coding for MHC-I, has been implicated in the regulation of inflammatory pathways and IFN-dependent antiviral defense (Benko S et al. 2010; Cui J et al. 2010). Overexpression of NLRC5 inhibited NFkB-luciferase reporter activity in human embryonic kidney 293T (HEK293T) cells treated with interleukin (IL)-1β, TNF-α or toll-like receptor (TLR) agonists such as bacterial LPS (TLR4 ligand) or R848 (TLR7/8 ligand) (Cui J et al. 2010). Similar findings were obtained with human monocytic THP-1 cells and murine embryonic fibroblasts (MEFs) (Cui J et al. 2010). Further, NLRC5 deficiency resulted in enhanced phosphorylation of IKBKB, CHUK, and increased expression of NF-kB-responsive cytokines (such as TNF-α and IL-6), in LPS-stimulated THP-1 and mouse macrophage RAW264.7 cells (Cui J et al. 2010). NLRC5 deficiency enhanced NF‐kB activation in mouse cells in response to TLR3, TLR4, TLR7, TLR9 ligands (Tong Y et al. 2012) and TLR2 ligand (Wang M et al. 2019). Knockdown of NLRC5 also enhanced cytokine response and antiviral immunity in vesicular stomatitis virus (VSV)-treated primary human monocytes, primary murine macrophages and RAW264.7 cells. Studies with NLRC5-deficient mice confirmed the regulatory role of NLRC5 in the induction of NF-kB and type I interferon in response to LPS or VSV infection (Tong Y et al. 2012). Moreover, NLRC5 co-immunoprecipitated with IKBKA (CHUK) and IKBKB subunits, but not with IKBKG, upon co-expression of tagged proteins in HEK293T cells (Cui J et al. 2010). Mutagenesis analysis revealed that human NLRC5 targets the amino-terminal kinase domain (KD) of IKBKB. Fractionation of RAW264.7 cells extracts on a size-exclusion column followed by immunoblotting analysis showed that both CHUK:IKBKB:IKBKG and CHUK:IKBKB:NLRC5 complexes co-exist in unstimulated cells suggesting that NLRC5 inhibits the interaction between IKBKG (NEMO) and IKBKB/CHUK (Cui J et al. 2010). The dynamics of NLRC5 interaction with IKBKB/CHUK upon stimulation is regulated by TRAF2/TRAF6-dependent ubiquitination of NLRC5 (Meng Q et al. 2015). These data suggest that NLRC5 negatively regulates NF-kappa-B activation via targeting IKBKB and CHUK. 20610642 Pubmed 2010 NLRC5 limits the activation of inflammatory pathways Benko, Szilvia Magalhaes, Joao G Philpott, Dana J Girardin, Stephen E J Immunol 185:1681-91 22473004 Pubmed 2012 Enhanced TLR-induced NF-κB signaling and type I interferon responses in NLRC5 deficient mice Tong, Yanzheng Cui, Jun Li, Qingtian Zou, Jia Wang, Helen Y Wang, Rong-Fu Cell Res 22:822-35 26620909 Pubmed 2015 Reversible ubiquitination shapes NLRC5 function and modulates NF-κB activation switch Meng, Qingcai Cai, Chunmei Sun, Tingzhe Wang, Qianliang Xie, Weihong Wang, Rongfu Cui, Jun J Cell Biol 211:1025-40 20434986 Pubmed 2010 NLRC5 negatively regulates the NF-kappaB and type I interferon signaling pathways Cui, J Zhu, Lijun Xia, X Wang, HY Legras, X Hong, J Ji, J Shen, P Zheng, S Chen, ZJ Wang, RF Cell 141:483-96 30945291 Pubmed 2019 NLRC5 negatively regulates LTA-induced inflammation via TLR2/NF-κB and participates in TLR2-mediated allergic airway inflammation Wang, Muzi Wang, Lixia Fang, Lei Li, Shuai Liu, Rongyu J Cell Physiol 234:19990-20001 ACTIVATION Reactome Database ID Release 82 10565875 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10565875 usp14 USP14 A0A6I8QN69 Reactome DB_ID: 10565871 UniProt:A0A6I8QN69 usp14 UniProt A0A6I8QN69 1 EQUAL 494 EQUAL Reactome Database ID Release 82 10565871 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10565871 Reactome R-XTR-5689541 1 Reactome stable identifier. Use this 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-5689541.1 INHIBITION Reactome Database ID Release 82 10565874 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10565874 nlrc5 K63polyUb-NLRC5 A0A803J229 Reactome DB_ID: 10565867 1178 EQUAL 87 EQUAL 975 EQUAL Reactome Database ID Release 82 10565867 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10565867 Reactome R-XTR-9750938 1 Reactome stable identifier. Use this 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-9750938.1 LEFT-TO-RIGHT 6.3.2.19 TRAF2,6 ubiquitinates NLRC5 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 Ub ubiquitin Reactome DB_ID: 10472693 A0A803J2V9 RPS27A(1-76) Reactome DB_ID: 10472665 UniProt:A0A803J2V9 UniProt A0A803J2V9 1 EQUAL 76 EQUAL Reactome Database ID Release 82 10472665 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10472665 Reactome R-XTR-939205 1 Reactome stable identifier. Use this 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-939205.1 rps27a UBA52(1-76) Q28FM7 Reactome DB_ID: 10472667 UniProt:Q28FM7 rps27a UniProt Q28FM7 1 EQUAL 76 EQUAL Reactome Database ID Release 82 10472667 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10472667 Reactome R-XTR-939203 1 Reactome stable identifier. Use this 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-939203.1 ubc UBB(1-76) Q6GL58 Reactome DB_ID: 10472669 UniProt:Q6GL58 ubc UniProt Q6GL58 1 EQUAL 76 EQUAL Reactome Database ID Release 82 10472669 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10472669 Reactome R-XTR-939214 1 Reactome stable identifier. Use this 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-939214.1 uba52 UBC(1-76) Q6AZL4 Reactome DB_ID: 10472675 UniProt:Q6AZL4 uba52 UniProt Q6AZL4 1 EQUAL 76 EQUAL Reactome Database ID Release 82 10472675 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10472675 Reactome R-XTR-939188 1 Reactome stable identifier. Use this 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-939188.1 Reactome Database ID Release 82 10472693 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10472693 Reactome R-XTR-113595 1 Reactome stable identifier. Use this 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-113595.1 3 ACTIVATION Converted from EntitySet in Reactome TRAF2, TRAF6 Reactome DB_ID: 10555011 traf2 TRAF2 A0A803JE99 Reactome DB_ID: 10478259 UniProt:A0A803JE99 traf2 UniProt A0A803JE99 2 EQUAL 501 EQUAL Reactome Database ID Release 82 10478259 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10478259 Reactome R-XTR-66370 1 Reactome stable identifier. Use this 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-66370.1 traf6 TRAF6 Q28DL4 Reactome DB_ID: 10486521 UniProt:Q28DL4 traf6 UniProt Q28DL4 1 EQUAL 522 EQUAL Reactome Database ID Release 82 10486521 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10486521 Reactome R-XTR-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-XTR-166366.1 Reactome Database ID Release 82 10555011 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10555011 Reactome R-XTR-918188 1 Reactome stable identifier. Use this 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-918188.1 GENE ONTOLOGY GO:0004842 Reactome Database ID Release 82 10565900 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10565900 Reactome Database ID Release 82 10565902 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10565902 Reactome R-XTR-9750946 1 Reactome stable identifier. Use this 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-9750946.1 NOD-like receptor C5 (NLRC5) functions as negative regulator of the NF-kappa B signaling pathway by targeting the I-kappa-B-kinase (IKK) complex (Cui J et al. 2010). The IKK complex consists of two catalytic subunits, IKBKA (KKα or CHUK) and IKBKB (IKKβ), associated with a regulatory subunit IKBKG (NEMO). NLRC5 directly binds to CHUK and IKBKB inhibiting their phosphorylation and interaction with IKBKG (Cui J et al. 2010). The dynamics of NLRC5 interaction with IKBKB/CHUK is regulated by TRAF2 or TRAF6-dependent ubiquitination of NLRC5 (Meng Q et al. 2015). Active TRAF2/6 catalyzed K63-linked polyubiquitination of NLRC5 at K1178 in human and mouse cells in response to LPS stimulation. The ubiquitinated NLRC5 (K63-polyUb-NLRC5) blocked NLRC5 interaction with IKBKB/CHUK thereby resulting in a decreased inhibitory function of NLRC5. The TRAF2/TRAF6-mediated ubiquitination of NLRC5 was reversely regulated by USP14 (Meng Q et al. 2015). LEFT-TO-RIGHT USP14 deubiquitinates NLRC5 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> H2O water Reactome DB_ID: 29356 water [ChEBI:15377] water ChEBI CHEBI:15377 Reactome Database ID Release 82 29356 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29356 Reactome R-ALL-29356 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29356.5 COMPOUND C00001 3 ACTIVATION GENE ONTOLOGY GO:0061578 Reactome Database ID Release 82 10565897 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10565897 Reactome Database ID Release 82 10565899 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10565899 Reactome R-XTR-9750942 1 Reactome stable identifier. Use this 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-9750942.1 NLRC5 functions as negative regulator of the NF-kappa B signaling pathway by targeting the I-kappa-B-kinase (IKK) complex (Cui J et al. 2010). The IKK complex consists of two catalytic subunits, IKBKA (KKα or CHUK) and IKBKB (IKKβ), associated with a regulatory subunit IKBKG (NEMO). NLRC5 directly binds to CHUK and IKBKB inhibiting their phosphorylation and interaction with IKBKG (Cui J et al. 2010). The dynamics of NLRC5 interaction with IKBKB/CHUK is regulated by TRAF2 or TRAF6-dependent K63-linked polyubiquitination of NLRC5 at K1178 (Meng Q et al. 2015). The ubiquitinated NLRC5 (K63-polyUb-NLRC5) showed lower ability to interact with IKBKB/CHUK thereby resulting in a decreased inhibitory function of NLRC5. Ubiquitin-specific protease 14 (USP14) was found to remove the polyUb chains from NLRC5 and thereby enhanced the NLRC5-mediated inhibition of NF-kB signaling (Meng Q et al. 2015). LEFT-TO-RIGHT USP18 binds IKBKG within IKK complex This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> usp18 USP18 A0A1B8Y9B0 Reactome DB_ID: 10504483 UniProt:A0A1B8Y9B0 usp18 UniProt A0A1B8Y9B0 1 EQUAL 372 EQUAL Reactome Database ID Release 82 10504483 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10504483 Reactome R-XTR-912325 1 Reactome stable identifier. Use this 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-912325.1 CHUK:IKBKB:IKBKG:USP18 Reactome DB_ID: 10566180 1 1 Reactome Database ID Release 82 10566180 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10566180 Reactome R-XTR-9761338 1 Reactome stable identifier. Use this 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-9761338.1 Reactome Database ID Release 82 10566182 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10566182 Reactome R-XTR-9761344 1 Reactome stable identifier. Use this 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-9761344.1 Expression of ubiquitin-specific protease 18 (USP18) is induced by various Toll-like receptor (TLR) ligands in human monocytes and macrophages (Yang Z et al. 2015). A nuclear factor kappa B (NF-kappa-B, NF-κB) luciferase reporter gene assay showed that expression of tagged USP18 negatively regulates TLR-mediated activation of NF-kappa B in human embryonic kidney HEK293T cells. USP18 also inhibited the degradation of endogenous IκBα protein in HEK293T cells (Yang Z et al. 2015). Further, knockdown of USP18 by USP18-specific small interfering RNAs (siRNA) enhanced NF-kappaB activity in LPS- stimulated human monocyte-like THP-1 cells (Yang Z et al. 2015). Co-immunoprecipitation and immunoblot analysis revealed that USP18 targets the regulatory subunit IKBKG (NEMO) of the IKK (CHUK:IKBKB:IKBKG) complex upon co-expression of tagged proteins in HEK293T cells. Mutagenesis analysis using HEK293T cells showed that USP18 directly binds to the UBAN motif of IKBKG inhibiting K63-linked ubiquitination of IKBKG by masking the ubiquitination sites at K325 and K326 (Yang Z et al. 2015). In addition, USP18 targets the TAK1-TAB1 complex and cleaves the K63-linked polyubiquitin chains of TAK1 in a protease-dependent manner (Liu X et al. 2013; Yang Z et al. 2015). These data suggest that USP18 functions as a negative regulator of NF-kappa-B activation.<p>This Reactome events shows USP18 binding to IKBKG within the IKK (CHUK:IKBKB:IKBKG) complex. 23825189 Pubmed 2013 USP18 inhibits NF-κB and NFAT activation during Th17 differentiation by deubiquitinating the TAK1-TAB1 complex Liu, Xikui Li, Hongxiu Zhong, Bo Blonska, Marzenna Gorjestani, Sara Yan, Ming Tian, Qiang Zhang, Dong-Er Lin, Xin Dong, Chen J. Exp. Med. 210:1575-90 26240016 Pubmed 2015 USP18 negatively regulates NF-κB signaling by targeting TAK1 and NEMO for deubiquitination through distinct mechanisms Yang, Zhifen Xian, Huifang Hu, Jiajia Tian, Shuo Qin, Yunfei Wang, Rong-Fu Cui, Jun Sci Rep 5:12738 LEFT-TO-RIGHT N4BP1 binds IKBKG 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> n4bp1 N4BP1 Q6DJS0 Reactome DB_ID: 10566070 UniProt:Q6DJS0 n4bp1 UniProt Q6DJS0 1 EQUAL 896 EQUAL Reactome Database ID Release 82 10566070 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10566070 Reactome R-XTR-9757941 1 Reactome stable identifier. Use this 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-9757941.1 IKBKG:N4BP1 Reactome DB_ID: 10566079 1 1 Reactome Database ID Release 82 10566079 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10566079 Reactome R-XTR-9757950 1 Reactome stable identifier. Use this 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-9757950.1 Reactome Database ID Release 82 10566081 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10566081 Reactome R-XTR-9757954 1 Reactome stable identifier. Use this 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-9757954.1 NEDD4-binding protein 1 (N4BP1) negatively regulates Toll-like receptor (TLR)-induced activation of NF-kappaB and cytokine production in human and mouse cells (Shi H et al. 2021; Gitlin AD et al. 2020). N4BP1 was found to target IKBKG (NEMO, IKKg), the regulatory subunit of the IkB kinase (IKK) complex, which is essential for NF-kappa-B activation. N4BP1 co-immunoprecipitated with IKBKG (NEMO) upon co-expression of tagged proteins in human embryonic kidney 293T (HEK293T) cells (Shi H et al. 2021). The interaction between endogenous N4BP1 and IKBKG was also detected in mouse peritoneal macrophages (Shi H et al. 2021). Linear and K63-linked polyubiquitin chains promoted the interaction between N4BP1 and IKBKG. Binding of N4BP1 to IKBKG is thought to block homooligomerization of IKBKG thereby leading to destabilization of the IKK complex (Shi H et al. 2021). In addition, N4BP1 deficiency in mice and mouse cells increased the production of select NF-kappa-B-dependent cytokines via TICAM1 (TRIF)-independent TLR2, TLR7 or TLR9 signaling pathways, but not upon engagement of TLR3 or TLR4 which utilize the adaptor protein TICAM1 (Shi H et al. 2021; Gitlin AD et al. 2020). Similar results were observed in human monocytic THP-1 cells (Shi H et al. 2021). Further, TLR3- or TRL4-induced TICAM1-dependent activation of caspase-8 (CASP8) was found to inactivate N4BP1 via the proteolytic cleavage thus promoting NF-kappa-B activation (Gitlin AD et al. 2020; Shi H et al. 2021). Downregulation of N4BP1 was not observed in TICAM-1-deficient mouse macrophages treated with LPS (Shi H et al. 2021). These data suggest that N4BP1 limits TICAM1-independent TLR-induced NF-kappa-B activation by blocking the function of the IKK complex, while TICAM1-dependent TLR signaling leads to CASP8-mediated inactivation of N4BP1(Shi H et al. 2021; Gitlin AD et al. 2020). 32971525 Pubmed 2020 Integration of innate immune signalling by caspase-8 cleavage of N4BP1 Gitlin, Alexander D Heger, Klaus Schubert, Alexander F Reja, Rohit Yan, Donghong Pham, Victoria C Suto, Eric Zhang, Juan Kwon, Youngsu C Freund, Emily C Kang, Jing Pham, Anna Caothien, Roger Bacarro, Natasha Hinkle, Trent Xu, Min McKenzie, Brent S Haley, Benjamin Lee, Wyne P Lill, Jennie R Roose-Girma, Merone Dohse, Monika Webster, Joshua D Newton, Kim Dixit, Vishva M Nature 587:275-280 33654074 Pubmed 2021 N4BP1 negatively regulates NF-κB by binding and inhibiting NEMO oligomerization Shi, Hexin Sun, Lei Wang, Ying Liu, Aijie Zhan, Xiaoming Li, Xiaohong Tang, Miao Anderton, Priscilla Hildebrand, Sara Quan, Jiexia Ludwig, Sara Moresco, Eva Marie Y Beutler, B Nat Commun 12:1379 INHIBITION Reactome Database ID Release 82 10566082 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10566082 active caspase-8 Reactome DB_ID: 10480165 Caspase-8 dimer Reactome DB_ID: 10480163 casp8 CASP8(217-374) A0A6I8Q0P2 Reactome DB_ID: 10480159 UniProt:A0A6I8Q0P2 casp8 UniProt A0A6I8Q0P2 217 EQUAL 374 EQUAL Reactome Database ID Release 82 10480159 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10480159 Reactome R-XTR-75975 1 Reactome stable identifier. Use this 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-75975.1 1 casp8 CASP8(385-479) A0A6I8Q0P2 Reactome DB_ID: 10480161 385 EQUAL 479 EQUAL Reactome Database ID Release 82 10480161 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10480161 Reactome R-XTR-76158 1 Reactome stable identifier. Use this 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-76158.1 1 Reactome Database ID Release 82 10480163 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10480163 Reactome R-XTR-139950 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-139950.1 2 Reactome Database ID Release 82 10480165 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10480165 Reactome R-XTR-2562550 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-2562550.1 LEFT-TO-RIGHT 3.4 CASP8 cleaves N4BP1 at D424, D490 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2 n4bp1 N4BP1(1-424) Q6DJS0 Reactome DB_ID: 10566072 1 EQUAL 424 EQUAL Reactome Database ID Release 82 10566072 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10566072 Reactome R-XTR-9757940 1 Reactome stable identifier. Use this 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-9757940.1 ACTIVATION GENE ONTOLOGY GO:0008234 Reactome Database ID Release 82 10566075 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10566075 Reactome Database ID Release 82 10566077 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10566077 Reactome R-XTR-9757951 1 Reactome stable identifier. Use this 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-9757951.1 GENE ONTOLOGY GO:0043122 NEDD4-binding protein 1 (N4BP1) limits the activation of NF-kappaB downstream of TICAM1 (TRIF)-independent Toll-like receptor 2 (TLR2), TLR7 or TLR9 signaling pathways, but not upon engagement of TLR3 or TLR4 which utilize the adaptor protein TICAM1 (Shi H et al. 2021; Gitlin AD et al. 2020). TLR3- or TRL4-induced TICAM1-dependent activation of caspase-8 (CASP8) was found to inactivate N4BP1 via the proteolytic cleavage thus promoting NF-kappa-B activation (Gitlin AD et al. 2020; Shi H et al. 2021). Functional studies of N4BP1 mutants expressed in human embryonic kidney 293T (HEK293T) cells suggest that human N4BP1 is cleaved after D424 and/or D490 (Shi H et al. 2021). Reactome Database ID Release 82 10569412 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10569412 Reactome R-XTR-9758274 1 Reactome stable identifier. Use this 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-9758274.1 Nuclear factor kappa B (NF-kappa-B, NF-κB) is activated by a diverse range of stimuli including cytokines, ligands of pattern-recognition receptors (PRRs) such as Toll-like receptors (TLRs) in myeloid cells, antigen-activated TCR in T-cells and by DNA damage (reviewed in Yu H et al. 2020; Zhang T et al. 2021). NF-kappa-B regulates the transcription of genes that are involved in immune and inflammatory responses, cell cycle, cell proliferation and apoptosis (Bhatt D & Ghosh S 2014; Liu T et al. 2017; Yu H et al. 2020). In unstimulated cells, NF-κB is sequestered in the cytosol through interactions with a class of inhibitor proteins, called NF-κB inhibitors (IkBs, such as NFKBIA or NFKBIB) (Jacobs MD & Harrison SC 1998). IkBs mask the nuclear localization signal (NLS) of NF-κB preventing its nuclear translocation (Cervantes CF et al. 2011). A key event in NF-κB activation involves phosphorylation of IkBs by the IκB kinase (IKK) complex which consists of CHUK, IKBKB and IKBKG subunits (Israël A 2010). The activated NF-κB signaling is tightly controlled at multiple levels (Dorrington MG & Fraser IDC 2019; Prescott JA et al. 2021). Dysregulated NF-κB activity can cause tissue damage associated with inflammatory diseases and is also linked to tumorigenesis (Aggarwal BB & Sung B 2011; Liu T et al.2017; Barnabei L et al. 2021). The regulation of NF-κB is cell-type-, context- , and stimulus-dependent and is crucial for orchestrating specific cellular responses (Mussbacher M et al. 2019).<p>This Reactome module describes several molecular mechanisms that regulate TLR-mediated NF-κB signaling at the level of the IKK signaling complex. <br><br> 34977871 Pubmed 2021 NF-κB signaling in inflammation and cancer Zhang, Tao Ma, Chao Zhang, Zhiqiang Zhang, Huiyuan Hu, Hongbo MedComm (2020) 2:618-653 24611065 Pubmed 2014 Regulation of the NF-κB-Mediated Transcription of Inflammatory Genes Bhatt, Dev Ghosh, Sankar Front Immunol 5:71 22586649 Pubmed 2011 NF-κB in cancer: a matter of life and death Aggarwal, Bharat B Sung, Bokyung Cancer Discov 1:469-71 34269817 Pubmed 2021 Inhibitory feedback control of NF-κB signalling in health and disease Prescott, Jack A Mitchell, Jennifer P Cook, Simon J Biochem J 478:2619-2664 32958760 Pubmed 2020 Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study Yu, Hui Lin, Liangbin Zhang, Zhiqiang Zhang, Huiyuan Hu, Hongbo Signal Transduct Target Ther 5:209 31024544 Pubmed 2019 NF-κB Signaling in Macrophages: Dynamics, Crosstalk, and Signal Integration Dorrington, Michael G Fraser, Iain D C Front Immunol 10:705 29158945 Pubmed 2017 NF-κB signaling in inflammation Liu, Ting Zhang, Lingyun Joo, Donghyun Sun, Shao-Cong Signal Transduct Target Ther 2: 34434197 Pubmed 2021 NF-κB: At the Borders of Autoimmunity and Inflammation Barnabei, Laura Laplantine, Emmanuel Mbongo, William Rieux-Laucat, Frederic Weil, Robert Front Immunol 12:716469 30778349 Pubmed 2019 Cell Type-Specific Roles of NF-κB Linking Inflammation and Thrombosis Mussbacher, Marion Salzmann, Manuel Brostjan, Christine Hoesel, Bastian Schoergenhofer, Christian Datler, Hannes Hohensinner, Philipp Basílio, José Petzelbauer, Peter Assinger, Alice Schmid, Johannes A Front Immunol 10:85 20300203 Pubmed 2010 The IKK complex, a central regulator of NF-kappaB activation Israel, A Cold Spring Harb Perspect Biol 2:a000158 Reactome Database ID Release 82 10567114 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10567114 Reactome R-XTR-445989 1 Reactome stable identifier. Use this 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-445989.1 GENE ONTOLOGY GO:0051092 NF-kappa-B is sequestered in the cytoplasm in a complex with inhibitor of NF-kappa-B (IkB). Almost all NF-kappa-B activation pathways are mediated by IkB kinase (IKK), which phosphorylates IkB resulting in dissociation of NF-kappa-B from the complex. This allows translocation of NF-kappa-B to the nucleus where it regulates gene expression. 15837794 Pubmed 2005 Simultaneous blockade of NFkappaB, JNK, and p38 MAPK by a kinase-inactive mutant of the protein kinase TAK1 sensitizes cells to apoptosis and affects a distinct spectrum of tumor necrosis factor [corrected] target genes Thiefes, A Wolter, S Mushinski, JF Hoffmann, E Dittrich-Breiholz, O Graue, N Dörrie, A Schneider, H Wirth, D Luckow, B Resch, K Kracht, M J Biol Chem 280:27728-41 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 MAP kinase activation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT 2.7.11.1 Activated TAK1 phosphorylates MKK4/MKK7 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2 MAP2K4 A0A6I8RP65 Reactome DB_ID: 10501767 UniProt:A0A6I8RP65 UniProt A0A6I8RP65 1 EQUAL 399 EQUAL Reactome Database ID Release 82 10501767 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10501767 Reactome R-XTR-168107 1 Reactome stable identifier. Use this 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-168107.1 2 A0A6I8RP65 phospho-p-S257,T261-MAP2K4 Reactome DB_ID: 10483154 257 EQUAL 261 EQUAL O-phospho-L-threonine MOD MOD:00047 1 EQUAL 399 EQUAL Reactome Database ID Release 82 10483154 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483154 Reactome R-XTR-168170 1 Reactome stable identifier. Use this 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-168170.1 ACTIVATION activeUnit: #Protein55 Converted from EntitySet in Reactome Activated TAK complexes Reactome DB_ID: 10501794 PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO:activated TAK1 complex Reactome DB_ID: 10501784 PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO Reactome DB_ID: 10501774 PAMP:NOD oligomer:K63-Ub-RIP2 Reactome DB_ID: 10501772 ripk2 Ub-209-RIPK2 A0A6I8PV70 Reactome DB_ID: 10501770 UniProt:A0A6I8PV70 ripk2 UniProt A0A6I8PV70 209 EQUAL 1 EQUAL 540 EQUAL Reactome Database ID Release 82 10501770 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10501770 Reactome R-XTR-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-XTR-706483.1 6 NOD1:iE-DAP oligomer Reactome DB_ID: 10483216 NOD1:iE-DAP Reactome DB_ID: 10483212 iE-DAP intracellular D-gamma-Glutamyl-meso-diamino-pimelic acid gamma-D-glutamyl-meso-diaminopimelic acid Reactome DB_ID: 622271 gamma-D-glutamyl-meso-diaminopimelic acid [ChEBI:59271] gamma-D-glutamyl-meso-diaminopimelic acid ChEBI CHEBI:59271 Reactome Database ID Release 82 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 1 nod1 NOD1 F6PKK5 Reactome DB_ID: 10483210 UniProt:F6PKK5 nod1 UniProt F6PKK5 1 EQUAL 953 EQUAL Reactome Database ID Release 82 10483210 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483210 Reactome R-XTR-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-XTR-168407.1 1 Reactome Database ID Release 82 10483212 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483212 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 6 Reactome Database ID Release 82 10483216 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483216 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 1 Reactome Database ID Release 82 10501772 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10501772 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 1 1 Reactome Database ID Release 82 10501774 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10501774 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 1 TAK1 complex Reactome DB_ID: 10501782 tab2 TAB2 F6YEZ3 Reactome DB_ID: 10501780 UniProt:F6YEZ3 tab2 UniProt F6YEZ3 1 EQUAL 693 EQUAL Reactome Database ID Release 82 10501780 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10501780 Reactome R-XTR-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-XTR-168117.1 1 Ghost homologue of TAB1 Reactome DB_ID: 10501778 Reactome Database ID Release 82 10501778 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10501778 Reactome R-XTR-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-XTR-167923.1 1 MAP3K7 A0A6I8QTD1 Reactome DB_ID: 10501776 UniProt:A0A6I8QTD1 UniProt A0A6I8QTD1 1 EQUAL 606 EQUAL Reactome Database ID Release 82 10501776 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10501776 Reactome R-XTR-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-XTR-168156.1 1 Reactome Database ID Release 82 10501782 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10501782 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 1 Reactome Database ID Release 82 10501784 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10501784 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 K63pUb-TRAF6:TAB1:TAB2,TAB3:free pUb:p-T-TAK1 Reactome DB_ID: 10501786 2 traf6 K63polyUb-TRAF6 Q28DL4 Reactome DB_ID: 10488960 124 EQUAL 1 EQUAL 522 EQUAL Reactome Database ID Release 82 10488960 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10488960 Reactome R-XTR-2685681 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-2685681.1 1 A0A6I8QTD1 phospho-p-T184,T187-MAP3K7 Reactome DB_ID: 10488972 184 EQUAL 187 EQUAL 1 EQUAL 606 EQUAL Reactome Database ID Release 82 10488972 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10488972 Reactome R-XTR-202527 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-202527.1 2 K63polyUb Reactome DB_ID: 10483272 Reactome Database ID Release 82 10483272 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483272 Reactome R-XTR-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-XTR-450152.1 2 2 Reactome Database ID Release 82 10501786 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10501786 Reactome R-XTR-847073 1 Reactome stable identifier. Use this 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-847073.1 p-IRAK2:K63-linked pUb oligo-TRAF6:free K63-linked pUb:p-TAK1complex Reactome DB_ID: 10501792 p-IRAK2:K63-linked pUb oligo-TRAF6 Reactome DB_ID: 10501790 3 Ghost homologue of p-IRAK2 Reactome DB_ID: 10501788 Reactome Database ID Release 82 10501788 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10501788 Reactome R-XTR-446636 1 Reactome stable identifier. Use this 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-446636.1 1 Reactome Database ID Release 82 10501790 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10501790 Reactome R-XTR-937064 1 Reactome stable identifier. Use this 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-937064.1 1 3 3 Reactome Database ID Release 82 10501792 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10501792 Reactome R-XTR-937060 1 Reactome stable identifier. Use this 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-937060.1 Reactome Database ID Release 82 10501794 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10501794 Reactome R-XTR-772536 1 Reactome stable identifier. Use this 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-772536.1 Reactome Database ID Release 82 10501795 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10501795 Reactome Database ID Release 82 10501797 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10501797 Reactome R-XTR-450337 1 Reactome stable identifier. Use this 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-450337.1 In human, phosphorylation of MKK4 (MAP2K4) and MKK7 (MAP2K7) by TAK1 occurs at the typical Ser-Xaa-Ala-Xaa-Thr motif in their activation loops.<p>Residues involved in activation of these protein kinases correspond to human Ser271, Thr275 in MKK7 and Ser257, Thr261 in MKK4.<p>Cell lines lacking MKK4 exhibit defective activation of JNK and AP-1 dependent transcription activity in response to some cellular stresses; JNK and p38 MAPK activities were decreased by around 80% and 20%, respectively, following deletion of the mkk4 gene. 8533096 Pubmed 1995 Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction Yamaguchi, K Shirakabe, K Shibuya, H Irie, K Oishi, I Ueno, N Taniguchi, T Nishida, E Matsumoto, K Science 270:2008-11 17875933 Pubmed 2007 Targeted deletion of the mitogen-activated protein kinase kinase 4 gene in the nervous system causes severe brain developmental defects and premature death Wang, X Nadarajah, B Robinson, AC McColl, BW Jin, JW Dajas-Bailador, F Boot-Handford, RP Tournier, C Mol Cell Biol 27:7935-46 16186825 Pubmed 2005 Essential function for the kinase TAK1 in innate and adaptive immune responses Sato, S Sanjo, H Takeda, K Ninomiya-Tsuji, J Yamamoto, M Kawai, T Matsumoto, K Takeuchi, O Akira, Shizuo Nat Immunol 6:1087-95 LEFT-TO-RIGHT 2.7.11 Phosphorylation of human JNKs by activated MKK4/MKK7 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2 Converted from EntitySet in Reactome MAPK8,9,10 JNKs: MAPK8_MAPK9_MAPK10 Reactome DB_ID: 10483142 mapk8 MAPK8 A0A6I8R4U4 Reactome DB_ID: 10480189 UniProt:A0A6I8R4U4 mapk8 UniProt A0A6I8R4U4 1 EQUAL 427 EQUAL Reactome Database ID Release 82 10480189 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10480189 Reactome R-XTR-168141 1 Reactome stable identifier. Use this 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-168141.1 mapk10 MAPK10 A0A6I8SML4 Reactome DB_ID: 10483140 UniProt:A0A6I8SML4 mapk10 UniProt A0A6I8SML4 1 EQUAL 464 EQUAL Reactome Database ID Release 82 10483140 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483140 Reactome R-XTR-450352 1 Reactome stable identifier. Use this 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-450352.1 Reactome Database ID Release 82 10483142 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483142 Reactome R-XTR-450289 1 Reactome stable identifier. Use this 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-450289.1 2 Converted from EntitySet in Reactome p-MAPK8,9,10 phosphorylated JNKs: MAPK8_MAPK9_MAPK10 Reactome DB_ID: 10483148 A0A6I8R4U4 phospho-mapk8 p-T,Y-MAPK8 Reactome DB_ID: 10483144 O4'-phospho-L-tyrosine MOD MOD:00048 1 EQUAL 427 EQUAL Reactome Database ID Release 82 10483144 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483144 Reactome R-XTR-194371 1 Reactome stable identifier. Use this 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-194371.1 A0A6I8SML4 phospho-mapk10 p-T221,Y223-MAPK10 Reactome DB_ID: 10483146 221 EQUAL 223 EQUAL 1 EQUAL 464 EQUAL Reactome Database ID Release 82 10483146 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483146 Reactome R-XTR-450214 1 Reactome stable identifier. Use this 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-450214.1 Reactome Database ID Release 82 10483148 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483148 Reactome R-XTR-450226 1 Reactome stable identifier. Use this 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-450226.1 ACTIVATION GENE ONTOLOGY GO:0008545 Reactome Database ID Release 82 10483155 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483155 Reactome Database ID Release 82 10483157 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483157 Reactome R-XTR-168162 1 Reactome stable identifier. Use this 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-168162.1 Activated human JNK kinases (MKK4 and MKK7) phosphorylate Thr183 and Tyr185 residues in the characteristic Thr-Pro-Tyr phosphoacceptor loop of each JNK. <p>JNK is differentially regulated by MKK4 and MKK7 depending on the stimulus. MKK7 is the primary activator of JNK in TNF, LPS, and PGN responses. However, TLR3 cascade requires both MKK4 and MKK7. Some studies reported that in three JNK isoforms tested MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking preference for the threonine residue (Thr-183). 13130464 Pubmed 2003 Expression of the MAPK kinases MKK-4 and MKK-7 in rheumatoid arthritis and their role as key regulators of JNK Sundarrajan, M Boyle, DL Chabaud-Riou, M Hammaker, D Firestein, GS Arthritis Rheum 48:2450-60 11062067 Pubmed 2000 Synergistic activation of stress-activated protein kinase 1/c-Jun N-terminal kinase (SAPK1/JNK) isoforms by mitogen-activated protein kinase kinase 4 (MKK4) and MKK7 Fleming, Y Armstrong, CG Morrice, N Paterson, A Goedert, M Cohen, P Biochem J 352:145-54 9162092 Pubmed 1997 Characterization of the mitogen-activated protein kinase kinase 4 (MKK4)/c-Jun NH2-terminal kinase 1 and MKK3/p38 pathways regulated by MEK kinases 2 and 3. MEK kinase 3 activates MKK3 but does not cause activation of p38 kinase in vivo. Deacon, K Blank, JL J Biol Chem 272:14489-96 18713996 Pubmed 2008 Synoviocyte innate immune responses: I. Differential regulation of interferon responses and the JNK pathway by MAPK kinases Yoshizawa, T Hammaker, D Sweeney, SE Boyle, DL Firestein, GS J Immunol 181:3252-8 LEFT-TO-RIGHT Activated human JNKs migrate to nucleoplasm 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 p-MAPK8,9,10 Phosphorylated JNKs: MAPK8, MAPK9, MAPK10 Reactome DB_ID: 10483065 A0A6I8R4U4 phospho-mapk8 p-T,Y-MAPK8 Reactome DB_ID: 10483057 1 EQUAL 427 EQUAL Reactome Database ID Release 82 10483057 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483057 Reactome R-XTR-216349 1 Reactome stable identifier. Use this 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-216349.1 A0A6I8SML4 phospho-mapk10 p-T221,Y223-MAPK10 Reactome DB_ID: 10483063 1 EQUAL 464 EQUAL Reactome Database ID Release 82 10483063 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483063 Reactome R-XTR-450311 1 Reactome stable identifier. Use this 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-450311.1 Reactome Database ID Release 82 10483065 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483065 Reactome R-XTR-450253 1 Reactome stable identifier. Use this 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-450253.1 Reactome Database ID Release 82 10501803 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10501803 Reactome R-XTR-450348 1 Reactome stable identifier. Use this 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-450348.1 c-Jun NH2 terminal kinase (JNK) plays a role in conveying signals from the cytosol to the nucleus, where they associate and activate their target transcription factors. 9195981 Pubmed 1997 A novel mechanism of JNK1 activation. Nuclear translocation and activation of JNK1 during ischemia and reperfusion. Mizukami, Y Yoshioka, K Morimoto, S Yoshida, K J Biol Chem 272:16657-62 12193592 Pubmed 2002 Evidence of functional modulation of the MEKK/JNK/cJun signaling cascade by the low density lipoprotein receptor-related protein (LRP) Lutz, C Nimpf, J Jenny, M Boecklinger, K Enzinger, C Utermann, G Baier-Bitterlich, G Baier, G J Biol Chem 277:43143-51 Reactome Database ID Release 82 10567112 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10567112 Reactome R-XTR-450321 1 Reactome stable identifier. Use this 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-450321.1 GENE ONTOLOGY GO:0007254 C-Jun NH2 terminal kinases (JNKs) are an evolutionarily conserved family of serine/threonine protein kinases, that belong to mitogen activated protein kinase family (MAPKs - also known as stress-activated protein kinases, SAPKs). The JNK pathway is activated by heat shock, or inflammatory cytokines, or UV radiation. <p>The JNKs are encoded by at least three genes: JNK1/SAPK-gamma, JNK2/SAPK-alpha and JNK3/ SAPK-beta. The first two are ubiquitously expressed, whereas the JNK3 protein is found mainly in brain and to a lesser extent in heart and testes. As a result of alternative gene splicing all cells express distinct active forms of JNK from 46 to 55 kDa in size. Sequence alignment of these different products shows homologies of >80%. In spite of this similarity, the multiple JNK isoforms differ in their ability to bind and phosphorylate different target proteins, thus leading to the distinctive cellular processes: induction of apoptosis, or enhancment of cell survival, or proliferation.<p>Activation of JNKs is mediated by activated TAK1 which phosphorylates two dual specificity enzymes MKK4 (MAPK kinase 4) and MKK7(MAPK kinase 7). 9851932 Pubmed 1998 Defective T cell differentiation in the absence of Jnk1 Dong, C Yang, DD Wysk, M Whitmarsh, AJ Davis, RJ Flavell, RA Science 282:2092-5 26988982 Pubmed 2016 IL-17 mediates inflammatory reactions via p38/c-Fos and JNK/c-Jun activation in an AP-1-dependent manner in human nucleus pulposus cells Li, Jing-kun Nie, Lin Zhao, Yun-peng Zhang, Yuan-qiang Wang, Xiaoqing Wang, Shuai-shuai Liu, Yi Zhao, Hua Cheng, Lei J Transl Med 14:77 16937364 Pubmed 2006 The isoform-specific functions of the c-Jun N-terminal Kinases (JNKs): differences revealed by gene targeting Bogoyevitch, MA Bioessays 28:923-34 8177321 Pubmed 1994 The stress-activated protein kinase subfamily of c-Jun kinases Kyriakis, JM Banerjee, P Nikolakaki, E Dai, T Rubie, EA Ahmad, MF Avruch, Joseph Woodgett, JR Nature 369:156-60 activated TAK1 mediates p38 MAPK activation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT 2.7.11.1 activated human TAK1 phosphorylates MKK3/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> 2 MAP2K6 A0A7D9NLW8 Reactome DB_ID: 10501799 UniProt:A0A7D9NLW8 UniProt A0A7D9NLW8 1 EQUAL 334 EQUAL Reactome Database ID Release 82 10501799 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10501799 Reactome R-XTR-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-XTR-167998.1 A0A7D9NLW8 phospho-p-S207,T211-MAP2K6 Reactome DB_ID: 10501761 207 EQUAL 211 EQUAL 1 EQUAL 334 EQUAL Reactome Database ID Release 82 10501761 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10501761 Reactome R-XTR-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-XTR-206255.1 2 ACTIVATION activeUnit: #Protein55 Reactome Database ID Release 82 10501801 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10501801 Reactome R-XTR-450346 1 Reactome stable identifier. Use this 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-450346.1 Human MKK3 (MAP2K4) and MKK6 (MAP2K6) are two closely related dual-specificity protein kinases. Both are activated by cellular stress and inflammatory cytokines, and both phosphorylate and activate p38 MAP kinase at its activation site Thr-Gly-Tyr but do not phosphorylate or activate Erk1/2 or SAPK/JNK.<p> Activation of MKK3 and MKK6 occurs through phosphorylation of serine and threonine residues at the typical Ser-Xaa-Ala-Xaa-Thr motif in their activation loop. Residues involved into these protein kinases activation correspond to human sites Ser189 and Thr193 for MKK3 and Ser207 and Thr211 for MKK6 . 8622669 Pubmed 1996 MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway Raingeaud, J Whitmarsh, AJ Barrett, T Derijard, B Davis, RJ Mol Cell Biol 16:1247-55 LEFT-TO-RIGHT Phosphorylated MKK3/MKK6 migrates to nucleus This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> A0A7D9NLW8 phospho-p-S207,T211-MAP2K6 Reactome DB_ID: 10501763 1 EQUAL 334 EQUAL Reactome Database ID Release 82 10501763 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10501763 Reactome R-XTR-450258 1 Reactome stable identifier. Use this 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-450258.1 Reactome Database ID Release 82 10501765 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10501765 Reactome R-XTR-450296 1 Reactome stable identifier. Use this 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-450296.1 The p38 activators MKK3 (MAP2K3) and MKK6 (MAP2K6) were present in both the nucleus and the cytoplasm, consistent with a role in activating p38 in the nucleus. 9768359 Pubmed 1998 Nuclear export of the stress-activated protein kinase p38 mediated by its substrate MAPKAP kinase-2 Ben-Levy, R Hooper, S Wilson, R Paterson, HF Marshall, CJ Curr Biol 8:1049-57 7535770 Pubmed 1995 Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine Raingeaud, J Gupta, S Rogers, JS Dickens, M Han, J Ulevitch, RJ Davis, RJ J Biol Chem 270:7420-6 Reactome Database ID Release 82 10568044 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10568044 Reactome R-XTR-450302 1 Reactome stable identifier. Use this 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-450302.1 GENE ONTOLOGY GO:0038066 p38 mitogen-activated protein kinase (MAPK) belongs to a highly conserved family of serine/threonine protein kinases. <p>The p38 MAPK-dependent signaling cascade is activated by pro-inflammatory or stressful stimuli such as ultraviolet radiation, oxidative injury, heat shock, cytokines, and other pro-inflammatory stimuli. p38 MAPK exists as four isoforms (alpha, beta, gamma, and delta). Of these, p38alpha and p38beta are ubiquitously expressed while p38gamma and p38delta are differentially expressed depending on tissue type. Each isoform is activated by upstream kinases including MAP kinase kinases (MKK) 3, 4, and 6, which in turn are phosphorylated by activated TAK1 at the typical Ser-Xaa-Ala-Xaa-Thr motif in their activation loops.<p>Once p38 MAPK is phosphorylated it activates numerous downstream substrates, including MAPK-activated protein kinase-2 and 3 (MAPKAPK-2 or 3) and mitogen and stress-activated kinase-1/2 (MSK1/2). MAPKAPK-2/3 and MSK1/2 function to phosphorylate heat shock protein 27 (HSP27) and cAMP-response element binding protein transcriptional factor, respectively. Other transcription factors, including activating transcription factor 2, Elk, CHOP/GADD153, and myocyte enhancer factor 2, are known to be regulated by these kinases. 10878576 Pubmed 2000 p38 MAPK signalling cascades: ancient roles and new functions Martin-Blanco, E Bioessays 22:637-45 MAP3K8 (TPL2)-dependent MAPK1/3 activation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT NFKB p105, TPL2 (COT) and ABIN2 form a stable 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> tnip2 TNIP2 A0A803JDE1 Reactome DB_ID: 10502066 UniProt:A0A803JDE1 tnip2 UniProt A0A803JDE1 1 EQUAL 429 EQUAL Reactome Database ID Release 82 10502066 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10502066 Reactome R-XTR-451661 1 Reactome stable identifier. Use this 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-451661.1 F6T195 ccdc71l NFKB1(1-968) Reactome DB_ID: 10502062 1 EQUAL 968 EQUAL Reactome Database ID Release 82 10502062 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10502062 Reactome R-XTR-451607 1 Reactome stable identifier. Use this 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-451607.1 map3k8 MAP3K8 A0A6I8SN59 Reactome DB_ID: 10497104 UniProt:A0A6I8SN59 map3k8 UniProt A0A6I8SN59 1 EQUAL 467 EQUAL Reactome Database ID Release 82 10497104 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10497104 Reactome R-XTR-389388 1 Reactome stable identifier. Use this 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-389388.1 NFKB1:MAP3K8:TNIP2 Reactome DB_ID: 10502068 1 1 1 Reactome Database ID Release 82 10502068 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10502068 Reactome R-XTR-451638 1 Reactome stable identifier. Use this 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-451638.1 Reactome Database ID Release 82 10502080 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10502080 Reactome R-XTR-451634 1 Reactome stable identifier. Use this 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-451634.1 The C-terminal half of NFKB1 p105 forms a high-affinity stoichiometric association with MAP3K8 (TPL2) via two distinct interactions (Belich et al. 1999; Beinke et al. 2003). The Tpl2 C-terminus (residues 398-467) binds to a region N-terminal to the p105 ankyrin repeat region (human p105 residues 497-534), whereas the Tpl2 kinase domain interacts with the p105 death domain (Beinke et al. 2003). In unstimulated macrophages, all detectable Tpl2 is associated with p105 (Belich et al. 1999; Lang et al. 2004). Binding to p105 maintains the stability of Tpl2 but inhibits Tpl2 MEK kinase activity by preventing access to MEK (Beinke et al. 2003; Waterfield et al. 2003). Tpl2 phosphorylation at Thr-290 may also play a role in the activation of Tpl2 (Cho & Tsichlis 2005). <br><br>A20-binding inhibitor of NFkappaB2 (ABIN-2 ot TNIP2) interacts with Tpl2 and p105 but preferentially forms a ternary complex with both proteins. As ABIN2 is a polyubiquitin binding protein, it has been suggested that it may facilitate recruitment of the p105/Tpl2 complex to the activated IKK complex, allowing IKK2 induced p105 phosphorylation and consequent Tpl2 activation.<br> 12667451 Pubmed 2003 NF-kappaB1/p105 regulates lipopolysaccharide-stimulated MAP kinase signaling by governing the stability and function of the Tpl2 kinase Waterfield, MR Zhang, M Norman, LP Sun, SC Mol Cell 11:685-94 15699325 Pubmed 2005 Phosphorylation at Thr-290 regulates Tpl2 binding to NF-kappaB1/p105 and Tpl2 activation and degradation by lipopolysaccharide Cho, J Tsichlis, PN Proc Natl Acad Sci U S A 102:2350-5 12832462 Pubmed 2003 NF-kappaB1 p105 negatively regulates TPL-2 MEK kinase activity Beinke, S Deka, J Lang, V Belich, MP Walker, PA Howell, S Smerdon, SJ Gamblin, SJ Ley, SC Mol Cell Biol 23:4739-52 15169888 Pubmed 2004 ABIN-2 forms a ternary complex with TPL-2 and NF-kappa B1 p105 and is essential for TPL-2 protein stability Lang, V Symons, A Watton, SJ Janzen, J Soneji, Y Beinke, S Howell, S Ley, SC Mol Cell Biol 24:5235-48 9950430 Pubmed 1999 TPL-2 kinase regulates the proteolysis of the NF-kappaB-inhibitory protein NF-kappaB1 p105 Belich, MP Salmeron, A Johnston, LH Ley, SC Nature 397:363-8 INHIBITION Reactome Database ID Release 82 10502082 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10502082 3xUb, 2xp-S-NFKB1(1-968):p-S,T-MAP3K8:TNIP2 Reactome DB_ID: 10502078 1 F6T195 phospho-ccdc71l 3xUb-p-S927,S932-NFKB1(1-968) Reactome DB_ID: 10502073 927 EQUAL 932 EQUAL 1 EQUAL 968 EQUAL Reactome Database ID Release 82 10502073 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10502073 Reactome R-XTR-451619 1 Reactome stable identifier. Use this 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-451619.1 1 A0A6I8SN59 phospho-map3k8 p-S400,T290-MAP3K8 Reactome DB_ID: 10502076 290 EQUAL 400 EQUAL 1 EQUAL 467 EQUAL Reactome Database ID Release 82 10502076 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10502076 Reactome R-XTR-5684259 1 Reactome stable identifier. Use this 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-5684259.1 1 Reactome Database ID Release 82 10502078 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10502078 Reactome R-XTR-5684242 1 Reactome stable identifier. Use this 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-5684242.1 INHIBITION Reactome Database ID Release 82 10502081 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10502081 LEFT-TO-RIGHT 2.7.11.10 IKBKB phosphorylates TPL2 (MAP3K8) at Ser400 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> NFKB1:p-S400-MAP3K8:TNIP2 Reactome DB_ID: 10539378 1 1 A0A6I8SN59 phospho-map3k8 p-S400-MAP3K8 Reactome DB_ID: 10497107 1 EQUAL 467 EQUAL Reactome Database ID Release 82 10497107 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10497107 Reactome R-XTR-389738 1 Reactome stable identifier. Use this 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-389738.1 1 Reactome Database ID Release 82 10539378 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10539378 Reactome R-XTR-5687880 1 Reactome stable identifier. Use this 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-5687880.1 ACTIVATION activeUnit: #Protein14 GENE ONTOLOGY GO:0008384 Reactome Database ID Release 82 10539372 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10539372 Reactome Database ID Release 82 10539380 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10539380 Reactome R-XTR-5684275 1 Reactome stable identifier. Use this 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-5684275.1 The activity of tumor progression locus-2 (TPL2, also known as COT and MAP3K8) is regulated by means of phosphorylation. MAP3K8 undergoes phosphorylated on S400 in its C-terminal tail to activate MAP2Ks (MEK1/2) following LPS stimulation of macrophages. Different experimental systems have suggested that S400 is either autophosphosphorylated by MAPK3P8 (IL-1?-stimulated IL-1R-293T cells) or transphosphorylated by an unknown kinase (LPS-stimulated RAW264.7 macrophages). 19754427 Pubmed 2009 IRAK1-independent pathways required for the interleukin-1-stimulated activation of the Tpl2 catalytic subunit and its dissociation from ABIN2 Handoyo, Hosea Stafford, Margaret J McManus, Eamon Baltzis, Dionissios Peggie, Mark Cohen, P Biochem. J. 424:109-18 16806191 Pubmed 2006 Interleukin-1 stimulated activation of the COT catalytic subunit through the phosphorylation of Thr290 and Ser62 Stafford, Margaret J Morrice, Nick A Peggie, Mark W Cohen, P FEBS Lett. 580:4010-4 22988300 Pubmed 2012 I?B kinase 2 regulates TPL-2 activation of extracellular signal-regulated kinases 1 and 2 by direct phosphorylation of TPL-2 serine 400 Roget, Karine Ben-Addi, Abduelhakem Mambole-Dema, Agnes Gantke, Thorsten Yang, Huei-Ting Janzen, Julia Morrice, N Abbott, Derek W Ley, Steven C Mol. Cell. Biol. 32:4684-90 LEFT-TO-RIGHT MAP3K8 is phosphorylated TPL2 (MAP3K8) is phosphorylated at T290 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> NFKB1:p-T290-MAP3K8:TNIP2 Reactome DB_ID: 10539367 1 1 1 Reactome Database ID Release 82 10539367 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10539367 Reactome R-XTR-5684265 1 Reactome stable identifier. Use this 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-5684265.1 Reactome Database ID Release 82 10539369 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10539369 Reactome R-XTR-5684261 1 Reactome stable identifier. Use this 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-5684261.1 The activity of tumor progression locus-2 (TPL2, also known as COT and MAP3K8) is regulated by means of phosphorylation (Gantke T 2011).<p>The catalytic subunit of MAP3K8 (TPL2) was reported to undergo phosphorylation at Thr290 in human embryonic kidney 293 (HEK293) cells transfected with MAP3K8 (Luciano BS et al. 2004; Cho J et al. 2005; Stafford MJ et al. 2006). Mutation of this residue to alanine prevented the LPS-stimulated activation of MAP3K8 in mouse macrophages (Cho J et al. 2005). Experiments with a small-molecule inhibitor of MAP3K8 have suggested that Thr290 is autophosphosphorylated after IL-1 beta stimulation of IL-1R-expressing HEK293T cells (Handoyo H et al. 2009). However, a catalytically inactive mutant of MAP3K8 (Tpl2-K167M) was reported to become phosphorylated at Thr290 in transfected HEK-293 cells, suggesting that Thr290 phosphorylation did not occur as a result of autophosphorylation (Cho J et al. 2005) In addition, the phosphorylation at Thr290 was also reported to be catalysed by IKBKB, based on small interfering RNA(siRNA)-knockdown studies and the use of high concentrations of the IKBKB inhibitor PS1145 (Cho J et al. 2005). However, the other work showed that lower concentrations of PS1145, but nevertheless sufficient to completely inhibit IKBKB, did not affect the IL-1-stimulated phosphorylation of transfected MAP3K8 at Thr290, suggesting that the IL-1 beta stimulated phosphorylation of Thr290 is catalysed by a protein kinase distinct from IKBKB. (Stafford MJ et al. 2006). Thus, phosphorylation at Thr290 is required for the physiological activation of MAP3K8 by external signals, although the mode of the modification remains to be clarified.<p> Activation of MAP3K8 may also occur trough phosphorylation on Ser62 and Ser400 (Stafford MJ et al. 2006; Roget K et al. 2012). 21135874 Pubmed 2011 Regulation and function of TPL-2, an I?B kinase-regulated MAP kinase kinase kinase Gantke, Thorsten Sriskantharajah, Srividya Ley, Steven C Cell Res. 21:131-45 15466476 Pubmed 2004 Phosphorylation of threonine 290 in the activation loop of Tpl2/Cot is necessary but not sufficient for kinase activity Luciano, Brenda S Hsu, Sang Channavajhala, Padma L Lin, Lih-Ling Cuozzo, John W J. Biol. Chem. 279:52117-23 15778223 Pubmed 2005 Tpl2 (tumor progression locus 2) phosphorylation at Thr290 is induced by lipopolysaccharide via an Ikappa-B Kinase-beta-dependent pathway and is required for Tpl2 activation by external signals Cho, Jeonghee Melnick, Michael Solidakis, Georgios P Tsichlis, Philip N J. Biol. Chem. 280:20442-8 LEFT-TO-RIGHT 2.7.11.10 IKBKB phosphorylates NFkB p105 within the NFkB p105:TPL2:ABIN2 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> 2 2 p-S927,S932-NFKB1(1-968):MAP3K8:TNIP2 Reactome DB_ID: 10539371 1 F6T195 phospho-ccdc71l p-S927,S932-NFKB1(1-968) Reactome DB_ID: 10539356 1 EQUAL 968 EQUAL Reactome Database ID Release 82 10539356 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10539356 Reactome R-XTR-451611 1 Reactome stable identifier. Use this 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-451611.1 1 1 Reactome Database ID Release 82 10539371 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10539371 Reactome R-XTR-5687885 1 Reactome stable identifier. Use this 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-5687885.1 ACTIVATION activeUnit: #Protein14 Reactome Database ID Release 82 10539374 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10539374 Reactome R-XTR-5684267 1 Reactome stable identifier. Use this 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-5684267.1 NFkappaB p105 protein (p105) is a precursor of the NFkappaB p50 subunit and an inhibitor of NFkappaB. The IkappaB kinase (IKK) complex phosphorylates p105 on S927 within the PEST region. TNF-alpha-induced p105 proteolysis additionally requires the phosphorylation of S932. Purified IKK (IKK1) or IKKB (IKK2) can phosphorylate both these regulatory serines in vitro. 12482991 Pubmed 2003 betaTrCP-mediated proteolysis of NF-kappaB1 p105 requires phosphorylation of p105 serines 927 and 932 Lang, V Janzen, J Fischer, GZ Soneji, Y Beinke, S Salmeron, A Allen, H Hay, RT Ben-Neriah, Y Ley, SC Mol Cell Biol 23:402-13 LEFT-TO-RIGHT SCF betaTrCP1,2 binds p-NFkB p105:TPL2:ABIN2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> p-S927,S932-NFKB1(1-968):p-S,T-MAP3K8:TNIP2 Reactome DB_ID: 10539358 1 1 1 Reactome Database ID Release 82 10539358 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10539358 Reactome R-XTR-5684268 1 Reactome stable identifier. Use this 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-5684268.1 Converted from EntitySet in Reactome SCF-beta-TrCp1,2 (BTRC:CUL1:SKP1),(FBXW11:CUL1:SKP1) SCF-beta-TrCp1 or SCF-beta-TrCP2 Reactome DB_ID: 10511994 BTRC:CUL1:SKP1 Reactome DB_ID: 10484067 cul1 CUL1 A0A803K281 Reactome DB_ID: 10484061 UniProt:A0A803K281 cul1 UniProt A0A803K281 1 EQUAL 776 EQUAL Reactome Database ID Release 82 10484061 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10484061 Reactome R-XTR-174230 1 Reactome stable identifier. Use this 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-174230.1 1 skp1 SKP1 Q28CT2 Reactome DB_ID: 10484059 UniProt:Q28CT2 skp1 UniProt Q28CT2 2 EQUAL 163 EQUAL Reactome Database ID Release 82 10484059 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10484059 Reactome R-XTR-174150 1 Reactome stable identifier. Use this 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-174150.1 1 btrc BTRC A0A6I8R8Q1 Reactome DB_ID: 10484065 UniProt:A0A6I8R8Q1 btrc UniProt A0A6I8R8Q1 1 EQUAL 605 EQUAL Reactome Database ID Release 82 10484065 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10484065 Reactome R-XTR-174237 1 Reactome stable identifier. Use this 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-174237.1 1 Reactome Database ID Release 82 10484067 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10484067 Reactome R-XTR-174155 1 Reactome stable identifier. Use this 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-174155.1 CUL1:FBXW11:SKP1 Reactome DB_ID: 10511992 1 FBXW11 pafah1b1 Q6NZH4 Reactome DB_ID: 10509960 UniProt:Q6NZH4 pafah1b1 UniProt Q6NZH4 1 EQUAL 542 EQUAL Reactome Database ID Release 82 10509960 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10509960 Reactome R-XTR-976035 1 Reactome stable identifier. Use this 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-976035.1 1 1 Reactome Database ID Release 82 10511992 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10511992 Reactome R-XTR-1168592 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-1168592.1 Reactome Database ID Release 82 10511994 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10511994 Reactome R-XTR-1168601 1 Reactome stable identifier. Use this 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-1168601.1 SCF-beta-TrCP1,2:p-S927,S932-NFKB1:p-S,T-MAP3K8:TNIP2 Reactome DB_ID: 10539360 1 1 Reactome Database ID Release 82 10539360 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10539360 Reactome R-XTR-5684270 1 Reactome stable identifier. Use this 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-5684270.1 Reactome Database ID Release 82 10539362 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10539362 Reactome R-XTR-5684248 1 Reactome stable identifier. Use this 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-5684248.1 IKK-mediated NFkB p105 phosphorylation generates a binding site for betaTrCP, the receptor subunit of the SCF-type beta-TrCP ubiquitin E3 ligase complex. 11158290 Pubmed 2001 Shared pathways of IkappaB kinase-induced SCF(betaTrCP)-mediated ubiquitination and degradation for the NF-kappaB precursor p105 and IkappaBalpha Heissmeyer, V Krappmann, D Hatada, E N Scheidereit, C Mol. Cell. Biol. 21:1024-35 14673179 Pubmed 2004 Dual effects of IkappaB kinase beta-mediated phosphorylation on p105 Fate: SCF(beta-TrCP)-dependent degradation and SCF(beta-TrCP)-independent processing Cohen, S Achbert-Weiner, H Ciechanover, A Mol Cell Biol 24:475-86 LEFT-TO-RIGHT 6.3.2.19 SCF betaTrCP ubiquitinates NFKB p105 within p-S927, S932-NFkB p105:TPL2:ABIN2 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> 9 ACTIVATION activeUnit: #Complex34 Reactome Database ID Release 82 10539363 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10539363 Reactome Database ID Release 82 10539365 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10539365 Reactome R-XTR-5684250 1 Reactome stable identifier. Use this 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-5684250.1 Beta-TrCP ubiquitinates p105 at several lysine residues within the C-terminal region 660-968. The level of ubiquitination is variable; in this reaction p105 is represented with 3 ubiquitinated lysine residues. Removal of all lysines within this region abolishes subsequent p105 degradation. 9535861 Pubmed 1998 Enzymes catalyzing ubiquitination and proteolytic processing of the p105 precursor of nuclear factor kappaB1 Coux, O Goldberg, A L J Biol Chem 273:8820-8 LEFT-TO-RIGHT 3xUb,p-S-NFkB p105:TPL2:ABIN2 dissociates due to degradation of p105 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> 9 Reactome Database ID Release 82 10539376 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10539376 Reactome R-XTR-5684273 1 Reactome stable identifier. Use this 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-5684273.1 IKBKB-induced proteolysis of NFkB p105 to p50 releases MAP3K8 (TPL2) from the complex with NFkB p105 and ABIN2. On TLR or IL1beta stimulation, dissociated MAP3K8 with an adequate phosphorylation state activates MAP2K (MKK1/2) and consequently MAPK1/3 (ERK1/2). Reactome Database ID Release 82 10568062 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10568062 Reactome R-XTR-5684264 1 Reactome stable identifier. Use this 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-5684264.1 Tumor progression locus-2 (TPL2, also known as COT and MAP3K8) functions as a mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) in various stress-responsive signaling cascades. MAP3K8 (TPL2) mediates phosphorylation of MAP2Ks (MEK1/2) which in turn phosphorylate MAPK (ERK1/2) (Gantke T et al., 2011).<p>In the absence of extra-cellular signals, cytosolic MAP3K8 (TPL2) is held inactive in the complex with ABIN2 (TNIP2) and NFkB p105 (NFKB1) (Beinke S et al., 2003; Waterfield MR et al., 2003; Lang V et al., 2004). This interaction stabilizes MAP3K8 (TPL2) but also prevents MAP3K8 and NFkB from activating their downstream signaling cascades by inhibiting the kinase activity of MAP3K8 and the proteolysis of NFkB precursor protein p105. Upon activation of MAP3K8 by various stimuli (such as LPS, TNF-alpha, and IL-1 beta), IKBKB phosphorylates NFkB p105 (NFKB1) at Ser927 and Ser932, which trigger p105 proteasomal degradation and releases MAP3K8 from the complex (Beinke S et al., 2003, 2004; Roget K et al., 2012). Simultaneously, MAP3K8 is activated by auto- and/or transphosphorylation (Gantke T et al. 2011; Yang HT et al. 2012). The released active MAP3K8 phosphorylates its substrates, MAP2Ks. The free MAP3K8, however, is also unstable and is targeted for proteasome-mediated degradation, thus restricting prolonged activation of MAP3K8 (TPL2) and its downstream signaling pathways (Waterfield MR et al. 2003; Cho J et al., 2005). Furthermore, partially degraded NFkB p105 (NFKB1) into p50 can dimerize with other NFkB family members to regulate the transcription of target genes.<p>MAP3K8 activity is thought to regulate the dynamics of transcription factors that control an expression of diverse genes involved in growth, differentiation, and inflammation. Suppressing the MAP3K8 kinase activity with selective inhibitors, such as C8-chloronaphthyridine-3-carbonitrile, caused a significant reduction in TNFalpha production in LPS- and IL-1beta-induced both primary human monocytes and human blood (Hall JP et al. 2007). Similar results have been reported for mouse LPS-stimulated RAW264.7 cells (Hirata K et al. 2010). Moreover, LPS-stimulated macrophages derived from Map3k8 knockout mice secreted lower levels of pro-inflammatory cytokines such as TNFalpha, Cox2, Pge2 and CXCL1 (Dumitru CD et al. 2000; Eliopoulos AG et al. 2002). Additionally, bone marrow-derived dendritic cells (BMDCs) and macrophages from Map3k8 knockout mice showed significantly lower expression of IL-1beta in response to LPS, poly IC and LPS/MDP (Mielke et al., 2009). However, several other studies seem to contradict these findings and Map3k8 deficiency in mice has been also reported to enhance pro-inflammatory profiles. Map3k8 deficiency in LPS-stimulated macrophages was associated with an increase in nitric oxide synthase 2 (NOS2) expression (López-Peláez et al., 2011). Similarly, expression of IRAK-M, whose function is to compete with IL-1R-associated kinase (IRAK) family of kinases, was decreased in Map3k8-/- macrophages while levels of TNF and IL6 were elevated (Zacharioudaki et al., 2009). Moreover, significantly higher inflammation level was observed in 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated Map3k8-/- mouse skin compared to WT skin (DeCicco-Skinner K. et al., 2011). Additionally, MAP3K8 activity is associated with NFkB inflammatory pathway. High levels of active p65 NFkB were observed in the nucleus of Map3k8 -/- mouse keratinocytes that dramatically increased within 15-30 minutes of TPA treatment. Similarly, increased p65 NFkB was observed in Map3k8-deficient BMDC both basally and after stimulation with LPS when compared to wild type controls (Mielke et al., 2009). The data opposes the findings that Map3k8-deficient mouse embryo fibroblasts and human Jurkat T cells with kinase domain-deficient protein have a reduction in NFkB activation but only when certain stimuli are administered (Lin et al., 1999; Das S et al., 2005). Thus, it is possible that whether MAP3K8 serves more of a pro-inflammatory or anti-inflammatory role may depend on cell- or tissue type and on stimuli (LPS vs. TPA, etc.) (Mielke et al., 2009; DeCicco-Skinner K. et al., 2012).<p>MAP3K8 has been also studied in the context of carcinogenesis, however the physiological role of MAP3K8 in the etiology of human cancers is also convoluted (Vougioukalaki M et al., 2011; DeCicco-Skinner K. et al., 2012). 12234923 Pubmed 2002 Induction of COX-2 by LPS in macrophages is regulated by Tpl2-dependent CREB activation signals Eliopoulos, Aristides G Dumitru, Calin D Wang, Chun-Chi Cho, Jeonghee Tsichlis, Philip N EMBO J. 21:4831-40 19414798 Pubmed 2009 Adiponectin promotes endotoxin tolerance in macrophages by inducing IRAK-M expression Zacharioudaki, Vassiliki Androulidaki, Ariadne Arranz, Alicia Vrentzos, George Margioris, Andrew N Tsatsanis, Christos J. Immunol. 182:6444-51 10072079 Pubmed 1999 The proto-oncogene Cot kinase participates in CD3/CD28 induction of NF-kappaB acting through the NF-kappaB-inducing kinase and IkappaB kinases Lin, X Cunningham, E T Mu, Y Geleziunas, R Greene, W C Immunity 10:271-80 22733995 Pubmed 2012 Coordinate regulation of TPL-2 and NF-?B signaling in macrophages by NF-?B1 p105 Yang, Huei-Ting Papoutsopoulou, Stamatia Belich, Monica Brender, Christine Janzen, Julia Gantke, Thorsten Handley, Matt Ley, Steven C Mol. Cell. Biol. 32:3438-51 978-953-51-0633-3 ISBN 2012 The Role of Tpl2 Protein Kinase in Carcinogenesis and Inflammation DeCicco-Skinner, Kathleen L. Deshpande, Monika Wiest, Jonathan Advances in Protein Kinases (Book) 21377269 Pubmed 2011 Tpl2 kinase signal transduction in inflammation and cancer Vougioukalaki, Maria Kanellis, Dimitris C Gkouskou, Kalliopi Eliopoulos, Aristides G Cancer Lett. 304:80-9 11163183 Pubmed 2000 TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway Dumitru, C D Ceci, J D Tsatsanis, C Kontoyiannis, D Stamatakis, K Lin, J H Patriotis, C Jenkins, N A Copeland, N G Kollias, G Tsichlis, P N Cell 103:1071-83 21469113 Pubmed 2011 Cot/tpl2 activity is required for TLR-induced activation of the Akt p70 S6k pathway in macrophages: Implications for NO synthase 2 expression López-Peláez, Marta Soria-Castro, Irene Boscá, Lisardo Fernández, Margarita Alemany, Susana Eur. J. Immunol. 41:1733-41 15485931 Pubmed 2004 Lipopolysaccharide activation of the TPL-2/MEK/extracellular signal-regulated kinase mitogen-activated protein kinase cascade is regulated by IkappaB kinase-induced proteolysis of NF-kappaB1 p105 Beinke, S Robinson, M J Hugunin, M Ley, S C Mol. Cell. Biol. 24:9658-67 19933865 Pubmed 2009 Tumor progression locus 2 (Map3k8) is critical for host defense against Listeria monocytogenes and IL-1 beta production Mielke, Lisa A Elkins, Karen L Wei, Lai Starr, Robyn Tsichlis, Philip N O'Shea, John J Watford, Wendy T J. Immunol. 183:7984-93 20606319 Pubmed 2010 Inhibition of tumor progression locus 2 protein kinase decreases lipopolysaccharide-induced tumor necrosis factor alpha production due to the inhibition of the tip-associated protein induction in RAW264.7 cells Hirata, Kazuya Miyashiro, Masahiko Ogawa, Hirofumi Taki, Hirofumi Tobe, Kazuyuki Sugita, Takahisa Biol. Pharm. Bull. 33:1233-7 17848581 Pubmed 2007 Pharmacologic inhibition of tpl2 blocks inflammatory responses in primary human monocytes, synoviocytes, and blood Hall, J Perry Kurdi, Yahya Hsu, Sang Cuozzo, John Liu, Julie Telliez, Jean-Baptiste Seidl, Katherine J Winkler, Aaron Hu, Yonghan Green, Neal Askew, G Roger Tam, Steve Clark, James D Lin, Lih-Ling J. Biol. Chem. 282:33295-304 MAPK targets/ Nuclear events mediated by MAP kinases 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> ERK/MAPK targets 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 2.7.11.1 ERK1/2/5 activate RSK1/2/3 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> ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 29358 Reactome Database ID Release 82 29358 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29358 Reactome R-ALL-29358 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29358.3 COMPOUND C00002 6 Converted from EntitySet in Reactome Ribosomal protein S6 kinase Reactome DB_ID: 10487119 RPS6KA1 A0A6I8SXX2 Reactome DB_ID: 10487109 UniProt:A0A6I8SXX2 UniProt A0A6I8SXX2 1 EQUAL 735 EQUAL Reactome Database ID Release 82 10487109 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10487109 Reactome R-XTR-199860 1 Reactome stable identifier. Use this 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-199860.1 RPS6KA2 A0A803JCT7 Reactome DB_ID: 10487113 UniProt:A0A803JCT7 UniProt A0A803JCT7 1 EQUAL 733 EQUAL Reactome Database ID Release 82 10487113 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10487113 Reactome R-XTR-199861 1 Reactome stable identifier. Use this 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-199861.1 RPS6KA3 A0A6I8S147 Reactome DB_ID: 10487117 UniProt:A0A6I8S147 UniProt A0A6I8S147 1 EQUAL 740 EQUAL Reactome Database ID Release 82 10487117 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10487117 Reactome R-XTR-199869 1 Reactome stable identifier. Use this 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-199869.1 Reactome Database ID Release 82 10487119 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10487119 Reactome R-XTR-199858 1 Reactome stable identifier. Use this 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-199858.1 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 113582 Reactome Database ID Release 82 113582 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113582 Reactome R-ALL-113582 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113582.3 COMPOUND C00008 6 Converted from EntitySet in Reactome Phospho-Ribosomal protein S6 kinase Reactome DB_ID: 10487145 A0A6I8SXX2 phospho-p-4S,T359,T573-RPS6KA1 Reactome DB_ID: 10487127 221 EQUAL 363 EQUAL 380 EQUAL 732 EQUAL 359 EQUAL 573 EQUAL 1 EQUAL 735 EQUAL Reactome Database ID Release 82 10487127 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10487127 Reactome R-XTR-199829 1 Reactome stable identifier. Use this 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-199829.1 A0A803JCT7 phospho-p-4S,T356,T570-RPS6KA2 Reactome DB_ID: 10487135 218 EQUAL 360 EQUAL 377 EQUAL 730 EQUAL 356 EQUAL 570 EQUAL 1 EQUAL 733 EQUAL Reactome Database ID Release 82 10487135 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10487135 Reactome R-XTR-199871 1 Reactome stable identifier. Use this 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-199871.1 A0A6I8S147 phospho-p-4S,T231,T365-RPS6KA3 Reactome DB_ID: 10487143 227 EQUAL 369 EQUAL 386 EQUAL 715 EQUAL 231 EQUAL 365 EQUAL 1 EQUAL 740 EQUAL Reactome Database ID Release 82 10487143 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10487143 Reactome R-XTR-199830 1 Reactome stable identifier. Use this 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-199830.1 Reactome Database ID Release 82 10487145 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10487145 Reactome R-XTR-199849 1 Reactome stable identifier. Use this 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-199849.1 ACTIVATION Converted from EntitySet in Reactome p-ERK1/2/5 dimers p-MAPK3/MAPK1/MAPK7 dimers Reactome DB_ID: 10487153 p-Y185,Y187 MAPK1 dimer Reactome DB_ID: 10487149 Q28H11 phospho-p-T185,Y187-MAPK1 Reactome DB_ID: 10487147 UniProt:Q28H11 UniProt Q28H11 185 EQUAL 187 EQUAL 2 EQUAL 360 EQUAL Reactome Database ID Release 82 10487147 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10487147 Reactome R-XTR-112354 1 Reactome stable identifier. Use this 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-112354.1 2 Reactome Database ID Release 82 10487149 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10487149 Reactome R-XTR-109856 1 Reactome stable identifier. Use this 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-109856.1 p-T1218, Y220 MAPK7 dimer Reactome DB_ID: 10487151 F7E265 phospho-p-T218,Y220-MAPK7 Reactome DB_ID: 10487103 UniProt:F7E265 UniProt F7E265 218 EQUAL 220 EQUAL 2 EQUAL 816 EQUAL Reactome Database ID Release 82 10487103 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10487103 Reactome R-XTR-198738 1 Reactome stable identifier. Use this 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-198738.1 2 Reactome Database ID Release 82 10487151 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10487151 Reactome R-XTR-9610768 1 Reactome stable identifier. Use this 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-9610768.1 Reactome Database ID Release 82 10487153 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10487153 Reactome R-XTR-199878 1 Reactome stable identifier. Use this 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-199878.1 Reactome Database ID Release 82 10487154 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10487154 Reactome Database ID Release 82 10487156 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10487156 Reactome R-XTR-198746 1 Reactome stable identifier. Use this 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-198746.1 The p90 ribosomal S6 kinases (RSK1-4) comprise a family of serine/threonine kinases that lie at the terminus of the ERK pathway. RSK family members are unusual among serine/threonine kinases in that they contain two distinct kinase domains, both of which are catalytically functional . The C-terminal kinase domain is believed to be involved in autophosphorylation, a critical step in RSK activation, whereas the N-terminal kinase domain, which is homologous to members of the AGC superfamily of kinases, is responsible for the phosphorylation of all known exogenous substrates of RSK.<br>RSKs can be activated by the ERKs (ERK1, 2, 5) in the cytoplasm as well as in the nucleus, they both have cytoplasmic and nuclear substrates, and they are able to move from nucleus to cytoplasm. Efficient RSK activation by ERKs requires its interaction through a docking site located near the RSK C terminus. The mechanism of RSK activation has been studied mainly with regard to ERK1 and ERK2. RSK activation leads to the phosphorylation of four essential residues Ser239, Ser381, Ser398, and Thr590, and two additional sites, Thr377 and Ser749 (the amino acid numbering refers to RSK1). ERK is thought to play at least two roles in RSK1 activation. First, activated ERK phosphorylates RSK1 on Thr590, and possibly on Thr377 and Ser381, and second, ERK brings RSK1 into close proximity to membrane-associated kinases that may phosphorylate RSK1 on Ser381 and Ser398.<br>Moreover, RSKs and ERK1/2 form a complex that transiently dissociates upon growth factor signalling. Complex dissociation requires phosphorylation of RSK1 serine 749, a growth factor regulated phosphorylation site located near the ERK docking site. Serine 749 is phosphorylated by the N-terminal kinase domain of RSK1 itself. ERK1/2 docking to RSK2 and RSK3 is also regulated in a similar way. The length of RSK activation following growth factor stimulation depends on the duration of the RSK/ERK complex, which, in turn, differs among the different RSK isoforms. RSK1 and RSK2 readily dissociate from ERK1/2 following growth factor stimulation stimulation, but RSK3 remains associated with active ERK1/2 longer, and also remains active longer than RSK1 and RSK2. <br> 12832467 Pubmed 2003 Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity Roux, PP Richards, SA Blenis, J Mol Cell Biol 23:4796-804 16626623 Pubmed 2006 The MAP kinase ERK5 binds to and phosphorylates p90 RSK Ranganathan, A Pearson, GW Chrestensen, CA Sturgill, TW Cobb, MH Arch Biochem Biophys 449:8-16 ERKs are inactivated This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT 3.1.3.48 ERKs are inactivated by dual-specific phosphatases (DUSPs) 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> H2O water Reactome DB_ID: 113518 Reactome Database ID Release 82 113518 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113518 Reactome R-ALL-113518 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113518.3 COMPOUND C00001 Converted from EntitySet in Reactome ERK1/2/5 MAPK3/MAPK1/MAPK7 dimers Reactome DB_ID: 10488028 MAPK1 dimer Reactome DB_ID: 10488022 MAPK1 Q28H11 Reactome DB_ID: 10488020 2 EQUAL 360 EQUAL Reactome Database ID Release 82 10488020 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10488020 Reactome R-XTR-199960 1 Reactome stable identifier. Use this 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-199960.1 2 Reactome Database ID Release 82 10488022 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10488022 Reactome R-XTR-5675356 1 Reactome stable identifier. Use this 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-5675356.1 MAPK7 dimer Reactome DB_ID: 10488026 MAPK7 F7E265 Reactome DB_ID: 10488024 2 EQUAL 816 EQUAL Reactome Database ID Release 82 10488024 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10488024 Reactome R-XTR-199961 1 Reactome stable identifier. Use this 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-199961.1 2 Reactome Database ID Release 82 10488026 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10488026 Reactome R-XTR-9610770 1 Reactome stable identifier. Use this 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-9610770.1 Reactome Database ID Release 82 10488028 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10488028 Reactome R-XTR-199955 1 Reactome stable identifier. Use this 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-199955.1 Pi Orthophosphate hydrogenphosphate Phosphate Inorganic Phosphate Reactome DB_ID: 113550 hydrogenphosphate [ChEBI:43474] hydrogenphosphate hydrogen phosphate phosphate [PO3(OH)](2-) INORGANIC PHOSPHATE GROUP HYDROGENPHOSPHATE ION HPO4(2-) [P(OH)O3](2-) ChEBI CHEBI:43474 Reactome Database ID Release 82 113550 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113550 Reactome R-ALL-113550 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-113550.4 COMPOUND C00009 ACTIVATION Converted from EntitySet in Reactome ERK-specific DUSP Reactome DB_ID: 10489360 dusp4 DUSP4 Q28F83 Reactome DB_ID: 10489350 UniProt:Q28F83 dusp4 UniProt Q28F83 1 EQUAL 394 EQUAL Reactome Database ID Release 82 10489350 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10489350 Reactome R-XTR-203794 1 Reactome stable identifier. Use this 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-203794.1 dusp7 DUSP7 Q28EB3 Reactome DB_ID: 10489354 UniProt:Q28EB3 dusp7 UniProt Q28EB3 1 EQUAL 419 EQUAL Reactome Database ID Release 82 10489354 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10489354 Reactome R-XTR-203791 1 Reactome stable identifier. Use this 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-203791.1 dusp6 DUSP6 Q28E94 Reactome DB_ID: 10489358 UniProt:Q28E94 dusp6 UniProt Q28E94 1 EQUAL 381 EQUAL Reactome Database ID Release 82 10489358 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10489358 Reactome R-XTR-2871619 1 Reactome stable identifier. Use this 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-2871619.1 Reactome Database ID Release 82 10489360 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10489360 Reactome R-XTR-203792 1 Reactome stable identifier. Use this 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-203792.1 GENE ONTOLOGY GO:0004725 Reactome Database ID Release 82 10489361 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10489361 Reactome Database ID Release 82 10489363 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10489363 Reactome R-XTR-203797 1 Reactome stable identifier. Use this 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-203797.1 Over 10 dual specificity phosphatases (DUSPs) active on MAP kinases are known. Among them, some possess good ERK docking sites and so are more specific for the ERKS (DUSP 3, 4, 6, 7), others are more specific for p38MAPK (DUSP1 and 10), while others do not seem to discriminate. It is noteworthy that transcription of DUSP genes is induced by growth factor signaling itself, so that these phosphatases provide feedback attenuation of signaling. Moreover, differential activation of DUSPs by different stimuli is thought to contribute to pathway specificity. 17322878 Pubmed 2007 A module of negative feedback regulators defines growth factor signaling Amit, I Citri, A Shay, T Lu, Y Katz, M Zhang, F Tarcic, G Siwak, D Lahad, J Jacob-Hirsch, J Amariglio, N Vaisman, N Segal, E Rechavi, G Alon, U Mills, GB Domany, E Yarden, Y Nat Genet 39:503-12 Reactome Database ID Release 82 10567528 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10567528 Reactome R-XTR-202670 1 Reactome stable identifier. Use this 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-202670.1 MAP Kinases are inactivated by a family of protein named MAP Kinase Phosphatases (MKPs). They act through dephosphorylation of threonine and/or tyrosine residues within the signature sequence -pTXpY- located in the activation loop of MAP kinases (pT=phosphothreonine and pY=phosphotyrosine). MKPs are divided into three major categories depending on their preference for dephosphorylating; tyrosine, serine/threonine and both the tyrosine and threonine (dual specificity phoshatases or DUSPs). The tyrosine-specific MKPs include PTP-SL, STEP and HePTP, serine/threonine-specific MKPs are PP2A and PP2C, and many DUSPs acting on MAPKs are known. Activated MAP kinases trigger activation of transcription of MKP genes. Therefore, MKPs provide a negative feedback regulatory mechanism on MAPK signaling, by inactivating MAPKs via dephosphorylation, in the cytoplasm and the nucleus. Some MKPs are more specific for ERKs, others for JNK or p38MAPK. 15115656 Pubmed 2004 Structure and regulation of MAPK phosphatases Farooq, A Zhou, MM Cell Signal 16:769-79 Reactome Database ID Release 82 10567446 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10567446 Reactome R-XTR-198753 1 Reactome stable identifier. Use this 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-198753.1 ERK/MAPK kinases have a number of targets within the nucleus, usually transcription factors or other kinases. The best known targets, ELK1, ETS1, ATF2, MITF, MAPKAPK2, MSK1, RSK1/2/3 and MEF2 are annotated here. CREB phosphorylation 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 2.7.11.1 RSK1/2/3 phosphorylates CREB at Serine 133 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> creb1 CREB1 A0A6I8S0G7 Reactome DB_ID: 10487899 UniProt:A0A6I8S0G7 creb1 UniProt A0A6I8S0G7 1 EQUAL 341 EQUAL Reactome Database ID Release 82 10487899 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10487899 Reactome R-XTR-52777 1 Reactome stable identifier. Use this 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-52777.1 A0A6I8S0G7 phospho-creb1 p-S133-CREB1 Reactome DB_ID: 10487902 133 EQUAL 1 EQUAL 341 EQUAL Reactome Database ID Release 82 10487902 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10487902 Reactome R-XTR-111910 1 Reactome stable identifier. Use this 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-111910.1 ACTIVATION Reactome Database ID Release 82 10488009 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10488009 Reactome Database ID Release 82 10488011 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10488011 Reactome R-XTR-199895 1 Reactome stable identifier. Use this 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-199895.1 CREB is phosphorylated at Serine 133 by RSK1/2/3. 9770464 Pubmed 1998 Rsk-2 activity is necessary for epidermal growth factor-induced phosphorylation of CREB protein and transcription of c-fos gene De Cesare, D Jacquot, S Hanauer, A Sassone-Corsi, P Proc Natl Acad Sci U S A 95:12202-7 Reactome Database ID Release 82 10567468 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10567468 Reactome R-XTR-199920 1 Reactome stable identifier. Use this 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-199920.1 Nerve growth factor (NGF) activates multiple signalling pathways that mediate the phosphorylation of CREB at the critical regulatory site, serine 133. CREB phosphorylation at serine 133 is a crucial event in neurotrophin signalling, being mediated by ERK/RSK, ERK/MSK1 and p38/MAPKAPK2 pathways. Several kinases, such as MSK1, RSK1/2/3 (MAPKAPK1A/B/C), and MAPKAPK2, are able to directly phosphorylate CREB at S133. MSK1 is also able to activate ATF (Cyclic-AMP-dependent transcription factor). However, the NGF-induced CREB phosphorylation appears to correlate better with activation of MSK1 rather than RSK1/2/3, or MAPKAPK2. In retrograde signalling, activation of CREB occurs within 20 minutes after neurotrophin stimulation of distal axons. Activation of the AP-1 family of transcription factors 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 2.7.11 Activated JNKs phosphorylate c-JUN 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> jun JUN A0A803K0W9 Reactome DB_ID: 10483049 UniProt:A0A803K0W9 jun UniProt A0A803K0W9 1 EQUAL 331 EQUAL Reactome Database ID Release 82 10483049 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483049 Reactome R-XTR-450250 1 Reactome stable identifier. Use this 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-450250.1 2 2 A0A803K0W9 phospho-jun p-S63,S73-JUN Reactome DB_ID: 10483053 63 EQUAL 73 EQUAL 1 EQUAL 331 EQUAL Reactome Database ID Release 82 10483053 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483053 Reactome R-XTR-450237 1 Reactome stable identifier. Use this 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-450237.1 ACTIVATION GENE ONTOLOGY GO:0004705 Reactome Database ID Release 82 10483066 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483066 Reactome Database ID Release 82 10483068 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483068 Reactome R-XTR-168136 1 Reactome stable identifier. Use this 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-168136.1 JNK (c-Jun N-terminal Kinase) phosphorylates several transcription factors including c-Jun after translocation to the nucleus. 9561845 Pubmed 1998 Signal transduction by the c-Jun N-terminal kinase (JNK)--from inflammation to development Ip, YT Davis, RJ Curr Opin Cell Biol 10:205-19 18793328 Pubmed 2008 c-Jun expression, activation and function in neural cell death, inflammation and repair Raivich, G J Neurochem 107:898-906 10871633 Pubmed 2000 c-Jun inhibits transforming growth factor beta-mediated transcription by repressing Smad3 transcriptional activity Dennler, S Prunier, C Ferrand, N Gauthier, JM Atfi, A J Biol Chem 275:28858-65 Reactome Database ID Release 82 10567066 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10567066 Reactome R-XTR-450341 1 Reactome stable identifier. Use this 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-450341.1 GENE ONTOLOGY GO:0051090 Activator protein-1 (AP-1) is a collective term referring to a group of transcription factors that bind to promoters of target genes in a sequence-specific manner. AP-1 family consists of hetero- and homodimers of bZIP (basic region leucine zipper) proteins, mainly of Jun-Jun, Jun-Fos or Jun-ATF. <p>AP-1 members are involved in the regulation of a number of cellular processes including cell growth, proliferation, survival, apoptosis, differentiation, cell migration. The ability of a single transcription factor to determine a cell fate critically depends on the relative abundance of AP-1 subunits, the composition of AP-1 dimers, the quality of stimulus, the cell type, the co-factor assembly. </p><p>AP-1 activity is regulated on multiple levels; transcriptional, translational and post-translational control mechanisms contribute to the balanced production of AP-1 proteins and their functions. Briefly, regulation occurs through:<ol><li>effects on jun, fos, atf gene transcription and mRNA turnover.<li> AP-1 protein members turnover. <li>post-translational modifications of AP-1 proteins that modulate their transactivation potential (effect of protein kinases or phosphatases).<li>interactions with other transcription factors that can either induce or interfere with AP-1 activity.</ol> 7622446 Pubmed 1995 The regulation of AP-1 activity by mitogen-activated protein kinases Karin, M J Biol Chem 270:16483-6 19167516 Pubmed 2009 Translational regulation mechanisms of AP-1 proteins Vesely, PW Staber, PB Hoefler, G Kenner, L Mutat Res 682:7-12 15564374 Pubmed 2004 AP-1 subunits: quarrel and harmony among siblings Hess, J Angel, P Schorpp-Kistner, M J Cell Sci 117:5965-73 9069263 Pubmed 1997 AP-1 function and regulation Karin, M Liu, Z Zandi, E Curr Opin Cell Biol 9:240-6 Reactome Database ID Release 82 10567068 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10567068 Reactome R-XTR-450282 1 Reactome stable identifier. Use this 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-450282.1 MAPKs are protein kinases that, once activated, phosphorylate their specific cytosolic or nuclear substrates at serine and/or threonine residues. Such phosphorylation events can either positively or negatively regulate substrate, and thus entire signaling cascade activity. <p>The major cytosolic target of activated ERKs are RSKs (90 kDa Ribosomal protein S6 Kinase). Active RSKs translocates to the nucleus and phosphorylates such factors as c-Fos(on Ser362), SRF (Serum Response Factor) at Ser103, and CREB (Cyclic AMP Response Element-Binding protein) at Ser133. In the nucleus activated ERKs phosphorylate many other targets such as MSKs (Mitogen- and Stress-activated protein kinases), MNK (MAP interacting kinase) and Elk1 (on Serine383 and Serine389). ERK can directly phosphorylate CREB and also AP-1 components c-Jun and c-Fos. Another important target of ERK is NF-KappaB. Recent studies reveals that nuclear pore proteins are direct substrates for ERK (Kosako H et al, 2009). Other ERK nuclear targets include c-Myc, HSF1 (Heat-Shock Factor-1), STAT1/3 (Signal Transducer and Activator of Transcription-1/3), and many more transcription factors.</p><p>Activated p38 MAPK is able to phosphorylate a variety of substrates, including transcription factors STAT1, p53, ATF2 (Activating transcription factor 2), MEF2 (Myocyte enhancer factor-2), protein kinases MSK1, MNK, MAPKAPK2/3, death/survival molecules (Bcl2, caspases), and cell cycle control factors (cyclin D1).</p><p>JNK, once activated, phosphorylates a range of nuclear substrates, including transcription factors Jun, ATF, Elk1, p53, STAT1/3 and many other factors. JNK has also been shown to directly phosphorylate many nuclear hormone receptors. For example, peroxisome proliferator-activated receptor 1 (PPAR-1) and retinoic acid receptors RXR and RAR are substrates for JNK. Other JNK targets are heterogeneous nuclear ribonucleoprotein K (hnRNP-K) and the Pol I-specific transcription factor TIF-IA, which regulates ribosome synthesis. Other adaptor and scaffold proteins have also been characterized as nonnuclear substrates of JNK. 17158707 Pubmed 2006 Uses for JNK: the many and varied substrates of the c-Jun N-terminal kinases Bogoyevitch, MA Kobe, B Microbiol Mol Biol Rev 70:1061-95 16393692 Pubmed 2006 The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions Yoon, S Seger, R Growth Factors 24:21-44 17637696 Pubmed 2007 Coordinating TLR-activated signaling pathways in cells of the immune system Banerjee, A Gerondakis, S Immunol Cell Biol 85:420-4 12471242 Pubmed 2002 Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases Johnson, GL Lapadat, R Science 298:1911-2 19767751 Pubmed 2009 Phosphoproteomics reveals new ERK MAP kinase targets and links ERK to nucleoporin-mediated nuclear transport Kosako, H Yamaguchi, N Aranami, C Ushiyama, M Kose, S Imamoto, N Taniguchi, H Nishida, E Hattori, S Nat Struct Mol Biol 16:1026-35 Reactome Database ID Release 82 10567070 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10567070 Reactome R-XTR-450294 1 Reactome stable identifier. Use this 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-450294.1 GENE ONTOLOGY GO:0051403 The mitogen activated protein kinase (MAPK) cascade, one of the most ancient and evolutionarily conserved signaling pathways, is involved in many processes of immune responses. The MAP kinases cascade transduces signals from the cell membrane to the nucleus in response to a wide range of stimuli (Chang and Karin, 2001; Johnson et al, 2002). <p>There are three major groups of MAP kinases<ul><li>the extracellular signal-regulated protein kinases ERK1/2, <li>the p38 MAP kinase<li> and the c-Jun NH-terminal kinases JNK.</ul><p>ERK1 and ERK2 are activated in response to growth stimuli. Both JNKs and p38-MAPK are activated in response to a variety of cellular and environmental stresses. The MAP kinases are activated by dual phosphorylation of Thr and Tyr within the tripeptide motif Thr-Xaa-Tyr. The sequence of this tripeptide motif is different in each group of MAP kinases: ERK (Thr-Glu-Tyr); p38 (Thr-Gly-Tyr); and JNK (Thr-Pro-Tyr).<p>MAPK activation is mediated by signal transduction in the conserved three-tiered kinase cascade: MAPKKKK (MAP4K or MKKKK or MAPKKK Kinase) activates the MAPKKK. The MAPKKKs then phosphorylates a dual-specificity protein kinase MAPKK, which in turn phosphorylates the MAPK.<p>The dual specificity MAP kinase kinases (MAPKK or MKK) differ for each group of MAPK. The ERK MAP kinases are activated by the MKK1 and MKK2; the p38 MAP kinases are activated by MKK3, MKK4, and MKK6; and the JNK pathway is activated by MKK4 and MKK7. The ability of MAP kinase kinases (MKKs, or MEKs) to recognize their cognate MAPKs is facilitated by a short docking motif (the D-site) in the MKK N-terminus, which binds to a complementary region on the MAPK. MAPKs then recognize many of their targets using the same strategy, because many MAPK substrates also contain D-sites.<p>The upstream signaling events in the TLR cascade that initiate and mediate the ERK signaling pathway remain unclear. 11242034 Pubmed 2001 Mammalian MAP kinase signalling cascades Chang, L Karin, M Nature 410:37-40 11861597 Pubmed 2002 MAP kinases in the immune response Dong, C Davis, RJ Flavell, RA Annu Rev Immunol 20:55-72 19196711 Pubmed 2009 Selectivity of docking sites in MAPK kinases Bardwell, AJ Frankson, E Bardwell, L J Biol Chem 284:13165-73 Reactome Database ID Release 82 10567082 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10567082 Reactome R-XTR-975871 1 Reactome stable identifier. Use this 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-975871.1 GENE ONTOLOGY GO:0002755 Mammalian myeloid differentiation factor 88 (MyD88) is Toll/interleukin (IL)-1 (TIR)-domain containing adapter protein which plays crucial role in TLR signaling. All TLRs, with only one exception of TLR3, can initiate downstream signaling trough MyD88. In the MyD88 - dependent pathway, once the adaptor is bound to TLR it leads to recruitment of IL1 receptor associated kinase family IRAK which is followed by activation of tumour necrosis factor receptor-associated factor 6 (TRAF6) . TRAF6 is an ubiquitin E3 ligase which in turn induces TGF-beta activating kinase 1 (TAK1) auto phosphorylation. Once activated TAK1 can ultimately mediate the induction of the transcription factor NF-kB or the mitogen-activated protein kinases (MAPK), such as JNK, p38 and ERK. This results in the translocation of the activated NF-kB and MAPKs to the nucleus and the initiation of appropriate gene transcription leading to the production of many proinflammatory cytokines and antimicrobial peptides. 10435584 Pubmed 1999 Unresponsiveness of MyD88-deficient mice to endotoxin Kawai, T Adachi, O Ogawa, T Takeda, K Immunity 11:115-22 15728506 Pubmed 2005 Human TLR10 is a functional receptor, expressed by B cells and plasmacytoid dendritic cells, which activates gene transcription through MyD88 Hasan, U Chaffois, C Gaillard, C Saulnier, V Merck, E Tancredi, S Guiet, C Briere, F Vlach, J Lebecque, S Trinchieri, G Bates, EE J Immunol 174:2942-50 9430229 Pubmed 1997 MyD88: an adapter that recruits IRAK to the IL-1 receptor complex Wesche, H Henzel, WJ Shillinglaw, W Li, S Cao, Z Immunity 7:837-47 16239509 Pubmed 2005 Human airway epithelial cells sense Pseudomonas aeruginosa infection via recognition of flagellin by Toll-like receptor 5 Zhang, Z Louboutin, JP Weiner, DJ Goldberg, JB Wilson, JM Infect Immun 73:7151-60