BioPAX pathway converted from "MyD88-dependent cascade initiated on endosome membrane" in the Reactome database. MyD88-dependent cascade initiated on endosome membrane MyD88-dependent cascade initiated on endosome membrane Myeloid differentiation factor 88 (MyD88) is Toll/interleukin (IL)-1 (TIR)-domain containing adapter protein which plays a crucial role in TLR signaling. All TLRs except TLR3 can initiate downstream signaling through MyD88. In the MyD88-dependent pathway, once the adaptor is bound to TLR it leads to recruitment of proteins of the IL1 receptor associated kinase family - IRAK, followed by activation of tumor necrosis factor receptor-associated factor 6 (TRAF6). TRAF6 is an ubiquitin E3 ligase which in turn induces autophosphorylation of TGF-beta activating kinase 1 (TAK1). Activated TAK1 can ultimately mediate the induction of transcription factor NF-kB or 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.<p>The chicken MyD88 gene was cloned and its expression was detected in cecum, heart, spleen, liver, kidney, female reproductive tract, thymus and bursa. Over-expression of chicken MyD88 (299aa) significantly stimulated the activation of NF-kB in vitro. Chicken TLR21 was demonstrated to use a MyD88-dependent pathway to mediate IL1beta gene expression in HD11 chicken macrophages.(Ciraci C and Lamont SJ 2011) Besides, chTLR21 TIR domain was reported to contain a conserved proline residue at position 844 in its BB-loop (Keestra AM et al 2010), which is critical for activation of MyD88 dependent signaling of hTLR2, hTLR4 and also chTLR5. Authored: Shamovsky, V, 2010-11-30 Reviewed: D'Eustachio, P, 2010-12-06 Edited: Shamovsky, V, 2011-02-24 Activated TLR7 or 21 recruits MyD88 Activated TLR7 or 21 recruits MyD88 Cloning and analysis of full length chicken MyD88 revealed an open reading frame which encodes a predicted protein sequence of 368 amino acids (aa). Two more chicken MyD88 isoforms with 299 and 376 residues are described in the literature [Qiu Y et al 2008, Lynn et al 2003]. The amino acid sequences of the chMyD88 368 and 376 residue isoforms are 99% identical, 97% identical to the 299 aa chMyD88 predicted peptide and 68% identical to human MyD88 (296 aa).<p>Chicken MyD88 is recruited to the activated hetero or homodimer of chTLR that is located either on plasma membrane (TLR4, TLR2/1, TLR5 and TLR15) or endosome membrane (TLR7 and TLR21). Authored: Shamovsky, V, 2010-11-30 Reviewed: D'Eustachio, P, 2010-12-06 Edited: Shamovsky, V, 2011-02-24 Converted from EntitySet in Reactome Reactome DB_ID: 573279 1 endosome membrane GO 0010008 activated TLR7 or 21 bound to ligand [endosome membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome http://www.reactome.org Reactome DB_ID: 433987 2 cytosol GO 0005829 UniProt:A5HNF6 MYD88 MYD88 RCJMB04_14h3 MYD88 FUNCTION Adapter protein involved in the Toll-like receptor and IL-1 receptor signaling pathway in the innate immune response.TISSUE SPECIFICITY Expressed in spleen, liver, kidney, bursa of Fabricius, lung and brain (at protein level). Expressed in cecum, heart, spleen, liver, kidney, female reproductive tract, thymus, bursa of Fabricius, muscle and lung.DOMAIN The intermediate domain (ID) is required for the phosphorylation and activation of IRAK. Gallus gallus NCBI Taxonomy 9031 UniProt A5HNF6 Chain Coordinates 1 EQUAL 299 EQUAL Reactome DB_ID: 451459 1 activated TLR7/ or TLR21 : MyD88 complex [endosome membrane] activated TLR7/ or TLR21 : MyD88 complex Converted from EntitySet in Reactome Reactome DB_ID: 573279 1 Reactome DB_ID: 573258 2 1 EQUAL 299 EQUAL Reactome Database ID Release 82 451459 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451459 Reactome R-GGA-451459 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-451459.1 Reactome Database ID Release 82 451439 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451439 Reactome R-GGA-451439 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-451439.1 17676477 Pubmed 2007 Molecular cloning and expression analysis of chicken MyD88 and TRIF genes Wheaton, S Lambourne, MD Sarson, AJ Brisbin, JT Mayameei, A Sharif, S DNA Seq 18:480-6 18582498 Pubmed 2008 Molecular cloning and functional characterization of a novel isoform of chicken myeloid differentiation factor 88 (MyD88) Qiu, Y Shen, Y Li, X Ding, C Ma, Z Dev Comp Immunol 32:1522-30 19002681 Pubmed 2009 Differential mRNA expression of the avian-specific toll-like receptor 15 between heterophils from Salmonella-susceptible and -resistant chickens Nerren, JR Swaggerty, CL MacKinnon, KM Genovese, KJ He, H Pevzner, I Kogut, MH Immunogenetics 61:71-7 IRAK4 binds to the activated TLR7 or 21 IRAK4 binds to the activated TLR7 or 21 Mammalian IL-1 receptor-associated kinases IRAK-1, IRAK-2 and IRAK-4 form a multigene family. Those proteins are Ser/Thr protein kinases that are required for TLR mediated pathways leading to NFkB activation. Another IRAK family member IRAK-M has been identified as an inhibitor of TLR signaling.<p>Mammalian IRAK-4 is the homolog of Drosophila melanogaster Pelle. Like Pelle and unlike the other mammalian IRAKs, IRAK-4 is considered to be a central TIR signalling mediator in innate immunity. Mutagenesis analysis showed that any interference with IRAK-4's kinase activity virtually abolished downstream events. This is not the case with other members of the IRAK family.<p>Formation of MyD88:IRAKs multimer relies on homotypic interactions of death domains (DD). It triggers a cascade of phosphorylation reactions that leads to activation of NF-kB/AP-1 and transcription of multiple genes involved in the immune response.<p>The predicted chicken full-length IRAK-4 protein contains 414aa and is 58% identical to human IRAK-4. Chicken IRAK-4 contains a conserved N-terminal death domain and C-terminal protein kinase domain. Authored: Shamovsky, V, 2010-11-30 Reviewed: D'Eustachio, P, 2010-12-06 Edited: Shamovsky, V, 2011-02-24 Reactome DB_ID: 433873 2 UniProt:Q5ZJM6 RCJMB04_17b10 RCJMB04_17b10 RCJMB04_17b10 <submittedName> <fullName>Putative uncharacterized protein</fullName> </submittedName> UniProt Q5ZJM6 1 EQUAL 373 EQUAL Reactome DB_ID: 451459 1 Reactome DB_ID: 451434 1 activated TLR7/or TLR21 : MyD88 : IRAK4 complex [endosome membrane] activated TLR7/or TLR21 : MyD88 : IRAK4 complex Reactome DB_ID: 451459 1 Reactome DB_ID: 993981 2 1 EQUAL 373 EQUAL Reactome Database ID Release 82 451434 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451434 Reactome R-GGA-451434 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-451434.1 Reactome Database ID Release 82 451461 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451461 Reactome R-GGA-451461 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-451461.1 19539094 Pubmed 2009 The avian Toll-Like receptor pathway--subtle differences amidst general conformity Cormican, P Lloyd, AT Downing, T Connell, SJ Bradley, D O'Farrelly, C Dev Comp Immunol 33:967-73 12814703 Pubmed 2003 In silico identification of components of the Toll-like receptor (TLR) signaling pathway in clustered chicken expressed sequence tags (ESTs) Lynn, DJ Lloyd, AT O'Farrelly, C Vet Immunol Immunopathol 93:177-84 11960013 Pubmed 2002 IRAK-4: a novel member of the IRAK family with the properties of an Li, S Strelow, A Fontana, EJ Wesche, H Proc Natl Acad Sci U S A 99:5567-72 19167362 Pubmed 2009 Contribution of globular death domains and unstructured linkers to MyD88.IRAK-4 heterodimer formation: an explanation for the antagonistic activity of MyD88s Mendoza-Barberá, E Corral-Rodriguez, Maria Ýngeles Soares-Schanoski, A Velarde, M Macieira, S Messerschmidt, A López-Collazo, E Fuentes-Prior, P Biochem Biophys Res Commun 380:183-7 2.7.11.1 Autophosphorylation of IRAK4 bound to the activated TLR7 or 21complex. Autophosphorylation of IRAK4 bound to the activated TLR7 or 21complex. Chicken IRAK4 shows 66% amino acid identity to human IRAK4. It is assumed here that chicken IRAK4 is activated by autophosphorylation like its human homologue. Authored: Shamovsky, V, 2010-11-30 Reviewed: D'Eustachio, P, 2010-12-06 Edited: Shamovsky, V, 2011-02-24 Reactome DB_ID: 451434 1 Reactome DB_ID: 113592 2 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 571317 1 activated TLR7/or TLR21: MyD88 : p-IRAK4 complex [endosome membrane] activated TLR7/or TLR21: MyD88 : p-IRAK4 complex Reactome DB_ID: 451459 1 Reactome DB_ID: 993980 2 O-phospho-L-serine at unknown position O-phospho-L-serine [MOD:00046] O-phospho-L-threonine at unknown position O-phospho-L-threonine [MOD:00047] 1 EQUAL 373 EQUAL Reactome Database ID Release 82 571317 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=571317 Reactome R-GGA-571317 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-571317.1 Reactome DB_ID: 29370 2 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 451434 GO 0004674 GO molecular function Reactome Database ID Release 82 571325 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=571325 Reactome Database ID Release 82 571316 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=571316 Reactome R-GGA-571316 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-571316.1 18438411 Pubmed 2008 Sequential control of Toll-like receptor-dependent responses by IRAK1 and IRAK2 Kawagoe, T Sato, S Matsushita, K Kato, H Matsui, Kuniko Kumagai, Y Saitoh, T Kawai, T Takeuchi, O Akira, Shizuo Nat Immunol 9:684-91 14625308 Pubmed 2004 Sequential autophosphorylation steps in the interleukin-1 Receptor-associated Kinase-1 Regulate its Availability as an Adapter in Interleukin-1 Signaling Kollewe, C Mackensen, AC Neumann, D Knop, J Cao, P Li, S Wesche, H Martin, MU J Biol Chem 279:5227-36 IRAK2 binds to p-IRAK4:MyD88:activated TLR7 or 21 complex IRAK2 binds to p-IRAK4:MyD88:activated TLR7 or 21 complex In mammals activated IRAK4 phosphorylates both IRAK1 and IRAK2. Activated IRAK1 and IRAK2 in turn induce NFkB and AP-1 intracellular signaling cascades mediated by TRAF6.<p>Bioinformatic analysis reveals no evidence of IRAK1 in the chicken genome. It is possible that the chicken TLR pathway utilizes only IRAK-2, which shares 47% amino acid sequence identity with human IRAK2. Authored: Shamovsky, V, 2010-04-02 Reviewed: D'Eustachio, P, 2010-12-06 Edited: Shamovsky, V, 2011-02-24 Reactome DB_ID: 571317 1 Reactome DB_ID: 434068 2 UniProt:Q5F382 RCJMB04_29d24 RCJMB04_29d24 RCJMB04_29d24 <submittedName> <fullName>Putative uncharacterized protein</fullName> </submittedName> UniProt Q5F382 1 EQUAL 691 EQUAL Reactome DB_ID: 571321 1 IRAK2:p-IRAK4:MyD88:activated TLR7 /or 21 complex [endosome membrane] IRAK2:p-IRAK4:MyD88:activated TLR7 /or 21 complex Reactome DB_ID: 993993 2 1 EQUAL 691 EQUAL Reactome DB_ID: 451434 1 Reactome Database ID Release 82 571321 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=571321 Reactome R-GGA-571321 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-571321.1 Reactome Database ID Release 82 571324 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=571324 Reactome R-GGA-571324 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-571324.1 19224918 Pubmed 2009 Interleukin-1 receptor-associated kinase 2 is critical for lipopolysaccharide-mediated post-transcriptional control Wan, Y Xiao, H Affolter, J Kim, TW Bulek, K Chaudhuri, S Carlson, D Hamilton, T Mazumder, B Stark, GR Thomas, J Li, X J Biol Chem 284:10367-75 2.7.11.1 IRAK2 phosphorylation bound to the activated TLR7 (or TLR21) complex IRAK2 phosphorylation bound to the activated TLR7 (or TLR21) complex In mammals activated IRAK4 phosphorylates both IRAK1 and IRAK2. Activated IRAK1 and IRAK2 in turn induce NFkB and AP-1 intracellular signaling cascades mediated by TRAF6.<p>Bioinformatic analysis reveals no evidence of IRAK1 in the chicken genome. It is possible that the chicken TLR pathway utilizes only IRAK-2, which shares 47% amino acid sequence identity with human IRAK2. Authored: Shamovsky, V, 2010-11-30 Reviewed: D'Eustachio, P, 2010-12-06 Edited: Shamovsky, V, 2011-02-24 Reactome DB_ID: 571321 1 Reactome DB_ID: 113592 2 Reactome DB_ID: 994003 1 p-IRAK2 : p-IRAK4 : MyD88: activated TLR7 or 21 [endosome membrane] p-IRAK2 : p-IRAK4 : MyD88: activated TLR7 or 21 Reactome DB_ID: 994002 2 phosphorylated residue at unknown position phosphorylated residue [MOD:00696] phosphorylated residue at unknown position 1 EQUAL 691 EQUAL Reactome DB_ID: 571317 1 Reactome Database ID Release 82 994003 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=994003 Reactome R-GGA-994003 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-994003.1 Reactome DB_ID: 29370 2 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 571321 Reactome Database ID Release 82 571329 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=571329 Reactome Database ID Release 82 571327 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=571327 Reactome R-GGA-571327 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-571327.1 NFkB and MAPK activation mediated by TRAF6 upon TLR7 or TLR21 stimulation NFkB and MAPK activation mediated by TRAF6 upon TLR7 or TLR21 stimulation Expression of chicken TLR21 in HEK293 was shown to upregulate NF-kB activation in response to synthetic CpG DNA (Keestra et al 2010). PKC, MEK1/2, p38MAPK and NF-kB signaling pathways were also reported to mediate nitric oxide production by avian HD11 macrophage cells in response to CpG DNA. (He H and Kogut MH 2003). Authored: Shamovsky, V, 2010-11-30 Reviewed: D'Eustachio, P, 2010-12-06 Edited: Shamovsky, V, 2011-02-24 TRAF6 binds to p-IRAK2 complexed with activated TLR7 or TLR21 TRAF6 binds to p-IRAK2 complexed with activated TLR7 or TLR21 There is little experimental data about mammalian IRAK2 mediated signaling. It is possible that phosphorylated IRAK2, like IRAK1, dissociates from upstream adapters such as MyD88 but leaves its interaction with the downstream adapter TRAF6 unaffected. Furthermore Keating et al. [2007] showed that IRAK2 can promote TRAF6 ubiquitination. Other studies [Wan et al 2009] detected IRAK2-TRAF6 interaction upon LPS stimulation.<p>In this reaction we assume that chicken IRAK2 behaves like its mammalian homolog IRAK2. Authored: Shamovsky, V, 2010-03-01 Reviewed: D'Eustachio, P, 2010-12-06 Edited: Shamovsky, V, 2011-02-24 Reactome DB_ID: 994003 1 Reactome DB_ID: 433886 2 UniProt:E1C626 TRAF6 TRAF6 TRAF6 SIMILARITY: Contains 1 MATH domain. UniProt E1C626 Reactome DB_ID: 532635 1 TRAF6 bound to activated TLR7 or 21 [endosome membrane] TRAF6 bound to activated TLR7 or 21 Reactome DB_ID: 994003 1 Reactome DB_ID: 433792 2 Reactome Database ID Release 82 532635 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=532635 Reactome R-GGA-532635 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-532635.1 Reactome Database ID Release 82 532632 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=532632 Reactome R-GGA-532632 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-532632.1 18070982 Pubmed 2008 TRAF6 distinctively mediates MyD88- and IRAK-1-induced activation of NF-kappaB Muroi, M Tanamoto, K J Leukoc Biol 83:702-7 17878161 Pubmed 2007 IRAK-2 participates in multiple toll-like receptor signaling pathways to NFkappaB via activation of TRAF6 ubiquitination Keating, SE Maloney, GM Moran, EM Bowie, AG J Biol Chem 282:33435-43 p-IRAK2- TRAF6 dissociates from the activated TRL7 or 21 p-IRAK2- TRAF6 dissociates from the activated TRL7 or 21 There is little experimental data about mammalian IRAK2 mediated signaling. It is possible that phosphorylated IRAK2, like IRAK1, dissociates from upstream adapters such as MyD88 but leaves its interaction with the downstream adapter TRAF6 unaffected. Furthermore Keating et al. [2007] showed that IRAK2 can promote TRAF6 ubiquitination. Other studies [Wan et al 2009] detected IRAK2-TRAF6 interaction upon LPS stimulation.<p>In this reaction we assume that chicken IRAK2 behaves like its mammalian homolog IRAK2. Authored: Shamovsky, V, 2010-11-30 Reviewed: D'Eustachio, P, 2010-12-06 Edited: Shamovsky, V, 2011-02-24 Reactome DB_ID: 532635 1 Reactome DB_ID: 993986 2 TRAF6:p-IRAK2 [endosome membrane] TRAF6:p-IRAK2 Reactome DB_ID: 994002 1 phosphorylated residue at unknown position phosphorylated residue at unknown position 1 EQUAL 691 EQUAL Reactome DB_ID: 433792 1 Reactome Database ID Release 82 993986 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=993986 Reactome R-GGA-993986 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-993986.1 Reactome DB_ID: 571317 1 Reactome Database ID Release 82 532630 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=532630 Reactome R-GGA-532630 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-532630.1 TRAF6 binding to IRAK2 stimulates its oligomerizartion upon TLR7 or TLR21 stimulation TRAF6 binding to IRAK2 stimulates its oligomerizartion upon TLR7 or TLR21 stimulation There is little experimental data about mammalian IRAK2 mediated signaling. It is possible that phosphorylated IRAK2, like IRAK1, dissociates from upstream adapters such as MyD88 but leaves its interaction with the downstream adapter TRAF6 unaffected. Furthermore Keating et al. [2007] showed that IRAK2 can promote TRAF6 ubiquitination. Other studies [Wan et al 2009] detected IRAK2-TRAF6 interaction upon LPS stimulation.<p>In this reaction we assume that chicken IRAK2 behaves like its mammalian homolog IRAK2. Authored: Shamovsky, V, 2010-11-30 Reviewed: D'Eustachio, P, 2010-12-06 Edited: Shamovsky, V, 2011-02-24 Reactome DB_ID: 993986 1 Reactome DB_ID: 433792 2 Reactome DB_ID: 994001 1 oligo TRAF6 : p-IRAK2 [endosome membrane] oligo TRAF6 : p-IRAK2 Reactome DB_ID: 994002 1 phosphorylated residue at unknown position phosphorylated residue at unknown position 1 EQUAL 691 EQUAL Reactome DB_ID: 433792 3 Reactome Database ID Release 82 994001 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=994001 Reactome R-GGA-994001 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-994001.1 Reactome Database ID Release 82 573297 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=573297 Reactome R-GGA-573297 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-573297.1 6.3.2.19 Autoubiquitination of oligoTRAF6 bound to p-IRAK2 Autoubiquitination of oligoTRAF6 bound to p-IRAK2 TRAF6 possesses ubiquitin ligase activity and undergoes K-63-linked auto-ubiquitination after its oligomerization. In the first step, ubiquitin is activated by an E1 ubiquitin activating enzyme. The activated ubiquitin is transferred to a E2 conjugating enzyme (a heterodimer of proteins Ubc13 and Uev1A) forming the E2-Ub thioester. Finally, in the presence of ubiquitin-protein ligase E3 (TRAF6, a RING-domain E3), ubiquitin is attached to the target protein (TRAF6 on residue Lysine 124) through an isopeptide bond between the C-terminus of ubiquitin and the epsilon-amino group of a lysine residue in the target protein. In contrast to K-48-linked ubiquitination that leads to the proteosomal degradation of the target protein, K-63-linked polyubiquitin chains act as a scaffold to assemble protein kinase complexes and mediate their activation through proteosome-independent mechanisms. This K63 polyubiquitinated TRAF6 activates the TAK1 kinase complex. Authored: Shamovsky, V, 2010-11-30 Reviewed: D'Eustachio, P, 2010-12-06 Edited: Shamovsky, V, 2011-02-24 Reactome DB_ID: 994001 1 Converted from EntitySet in Reactome Reactome DB_ID: 434147 8 Ubiquitin [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity ubiquitin (RPS27A) [cytosol] ubiquitin (UBB 4) [cytosol] ubiquitin (UBB 1) [cytosol] ubiquitin (UBB 2) [cytosol] ubiquitin (UBB 3) [cytosol] ubiquitin (UBA52) [cytosol] UniProt P79781 UniProt P0CG62 UniProt P62985 Reactome DB_ID: 993982 1 oligo pUb-TRAF6 : p-IRAK2 [endosome membrane] oligo pUb-TRAF6 : p-IRAK2 Reactome DB_ID: 434011 3 pUb_TRAF6 [endosome membrane] pUb_TRAF6 Reactome DB_ID: 433989 1 K63_polyubiquitin chain [endosome membrane] K63_polyubiquitin chain Reactome DB_ID: 433792 1 Reactome Database ID Release 82 434011 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434011 Reactome R-GGA-434011 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-434011.1 Reactome DB_ID: 994003 1 Reactome Database ID Release 82 993982 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=993982 Reactome R-GGA-993982 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-993982.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 994001 GO 0004842 GO molecular function Reactome Database ID Release 82 532634 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=532634 Reactome Database ID Release 82 571318 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=571318 Reactome R-GGA-571318 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-571318.1 17135271 Pubmed 2007 Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation Lamothe, B Besse, A Campos, AD Webster, WK Wu, H Darnay, BG J Biol Chem 282:4102-12 Activated TRAF6 synthesizes free K63 linked pUb chains. Activated TRAF6 synthesizes free K63 linked pUb chains. TRAF6 generates unanchored Lys63-linked polyubiquitin chains that bind to the regulatory subunits of the TAK1 (TAB2 or TAB3), leading to the activation of TAK1[Xia et al. 2009]. Authored: Shamovsky, V, 2010-11-30 Reviewed: D'Eustachio, P, 2010-12-06 Edited: Shamovsky, V, 2011-02-24 Converted from EntitySet in Reactome Reactome DB_ID: 434147 3 Reactome DB_ID: 451962 1 free K63_polyubiquitin chain [cytosol] free K63_polyubiquitin chain PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 993982 GO 0034450 GO molecular function Reactome Database ID Release 82 433984 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433984 Reactome Database ID Release 82 573294 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=573294 Reactome R-GGA-573294 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-573294.1 17496917 Pubmed 2007 Ubiquitin-mediated activation of TAK1 and IKK Adhikari, A Xu, M Chen, ZJ Oncogene 26:3214-26 19675569 Pubmed 2009 Direct activation of protein kinases by unanchored polyubiquitin chains Xia, ZP Sun, L Chen, X Pineda, G Jiang, X Adhikari, A Zeng, W Chen, ZJ Nature GO 0010994 GO biological process Activated TRAF6 recruits TAK1 kinase complex upon TLR7 or TLR21 stimulation Activated TRAF6 recruits TAK1 kinase complex upon TLR7 or TLR21 stimulation Polyubiquitinated TRAF6 activates TAK1 by binding to the ubiquitin receptor TAB2 (also known as MAP3K7IP2). This binding leads to autophosphorylation and activation of TAK1. Authored: Shamovsky, V, 2010-11-30 Reviewed: D'Eustachio, P, 2010-12-06 Edited: Shamovsky, V, 2011-02-24 Reactome DB_ID: 993982 1 Reactome DB_ID: 451962 2 Reactome DB_ID: 433839 2 TAK1 : TAB1 : TAB2/TAB3 complex [cytosol] TAK1 : TAB1 : TAB2/TAB3 complex Converted from EntitySet in Reactome Reactome DB_ID: 975711 1 chicken TAB2/TAB3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity TAB2 [cytosol] TAB3 [cytosol] ENSEMBL ENSGALP00000020155 ENSEMBL ENSGALP00000026205 Reactome DB_ID: 433882 1 UniProt:Q5ZJW3 RCJMB04_15c17 RCJMB04_15c17 RCJMB04_15c17 <submittedName> <fullName>Putative uncharacterized protein</fullName> </submittedName> UniProt Q5ZJW3 1 EQUAL 438 EQUAL Reactome DB_ID: 433825 1 ENSEMBL:ENSGALP00000025101 TGF-beta- activated kinase 1 TGF-beta- activated kinase 1 MAP3K7 ENSEMBL ENSGALP00000025101 1 EQUAL 617 EQUAL Reactome Database ID Release 82 433839 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433839 Reactome R-GGA-433839 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-433839.1 Reactome DB_ID: 993989 1 p-IRAK2:oligo pUb TRAF6 : TAK1 :TAB1 : TAB2/TAB3 : free K63 pUb chains [endosome membrane] p-IRAK2:oligo pUb TRAF6 : TAK1 :TAB1 : TAB2/TAB3 : free K63 pUb chains Reactome DB_ID: 433931 2 TAK1 : TAB1 : TAB2/TAB3 complex [endosome membrane] TAK1 : TAB1 : TAB2/TAB3 complex Reactome DB_ID: 434141 1 1 EQUAL 438 EQUAL Reactome DB_ID: 433956 1 1 EQUAL 617 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 993984 1 chicken TAB2/TAB3 [endosome membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity TAB3 [endosome membrane] TAB2 [endosome membrane] Reactome Database ID Release 82 433931 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433931 Reactome R-GGA-433931 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-433931.1 Reactome DB_ID: 993982 1 Reactome DB_ID: 451962 2 Reactome Database ID Release 82 993989 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=993989 Reactome R-GGA-993989 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-993989.1 Reactome Database ID Release 82 573296 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=573296 Reactome R-GGA-573296 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-573296.1 2.7.11.1 Activation of recruited TAK1 within the complex p-IRAK2: pUb-TRAF6:TAB2/TAB3:TAB1:TAK1 upon TLR7 or 21 stimulation Activation of recruited TAK1 within the complex p-IRAK2: pUb-TRAF6:TAB2/TAB3:TAB1:TAK1 upon TLR7 or 21 stimulation Polyubiquitinated TRAF6 activates TAK1 by binding to the ubiquitin receptor TAB2 (also known as MAP3K7IP2). This binding leads to autophosphorylation and activation of TAK1. Chicken TAK1 complex proteins TAK1, TAB1, TAB2 and TAB3, confirmed by transcript evidence, show 89%, 88% , 87%, 85% amino acid identity with their human counterparts respectively.<p>Embryonic fibroblasts and B cells derived from TAK1-deficient mice show reduced NF-kappaB, JNK and p38 activation in response to various TLR ligands. Furthermore, ERK1 and ERK2 activation was also reduced in TAK1-deficient mouse B cells [Sato S et al 2005].<p>Although there are no experimental data showing a TAK1 functional role in chicken innate immune response, its kinase activity was demonstrated to be essential for BCR (B cell antigen receptor)-mediated IKK and JNK activation in chicken DT40 B cells [Shinohara H et al 2005]. When BCR-mediated NF-kappaB activation was abolished, JNK phosphorylation was completely abolished, while ERK was activated normally in a TAK1-deficient chicken DT40 B cell line. <p>Thus, TAK1 is believed to activate the IKK complex that leads to NF-kappaB activation. Also TAK1 phosphorylates members of the MAP kinase kinase family, MKK4, MKK3 and MKK6, which subsequently activate JNK and p38. ERK is also activated in response to TLR ligands through the activation of MEK1 and MEK2, although an upstream kinase activating MEK1 and MEK2 in TLR signaling remains unknown. Authored: Shamovsky, V, 2010-01-05 Reviewed: D'Eustachio, P, 2010-12-06 Edited: Shamovsky, V, 2011-02-24 Reactome DB_ID: 993989 1 Reactome DB_ID: 113592 4 Reactome DB_ID: 993983 1 p-IRAK2: pUb_oligo TRAF6 : phospho TAK1 :TAB1 : TAB2/TAB3 : K63linked free pUb chain [endosome membrane] p-IRAK2: pUb_oligo TRAF6 : phospho TAK1 :TAB1 : TAB2/TAB3 : K63linked free pUb chain Reactome DB_ID: 434141 2 1 EQUAL 438 EQUAL Reactome DB_ID: 993982 1 Reactome DB_ID: 433952 2 O-phospho-L-threonine at unknown position O-phospho-L-threonine at unknown position 1 EQUAL 617 EQUAL Reactome DB_ID: 451962 2 Converted from EntitySet in Reactome Reactome DB_ID: 993984 2 Reactome Database ID Release 82 993983 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=993983 Reactome R-GGA-993983 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-993983.1 Reactome DB_ID: 29370 4 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 993989 Reactome Database ID Release 82 993988 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=993988 Reactome Database ID Release 82 994000 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=994000 Reactome R-GGA-994000 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-994000.1 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 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 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 16260493 Pubmed 2005 TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo Shim, JH Xiao, C Paschal, AE Bailey, ST Rao, P Hayden, MS Lee, KY Bussey, C Steckel, M Tanaka, N Yamada, G Akira, Shizuo Matsumoto, K Ghosh, S Genes Dev 19:2668-81 16301747 Pubmed 2005 PKC beta regulates BCR-mediated IKK activation by facilitating the interaction between TAK1 and CARMA1 Shinohara, H Yasuda, T Aiba, Y Sanjo, H Hamadate, M Watarai, H Sakurai, H Kurosaki, T J Exp Med 202:1423-31 Activated TAK1 leaves endosome membrane Activated TAK1 leaves endosome membrane It's believed that TAK1 dissociates from the membrane in to cytosol where it regulates NF-kB and MAPKs activation. Authored: Shamovsky, V, 2010-10-02 Reviewed: D'Eustachio, P, 2010-12-06 Edited: Shamovsky, V, 2011-02-24 Reactome DB_ID: 993983 1 Reactome DB_ID: 1094885 1 p-IRAK2: pUb_oligo TRAF6 : phospho TAK1 :TAB1 : TAB2/TAB3 : K63linked free pUb chain [cytosol] p-IRAK2: pUb_oligo TRAF6 : phospho TAK1 :TAB1 : TAB2/TAB3 : K63linked free pUb chain Reactome DB_ID: 993982 1 Reactome DB_ID: 433952 2 O-phospho-L-threonine at unknown position O-phospho-L-threonine at unknown position 1 EQUAL 617 EQUAL Reactome DB_ID: 451962 2 Converted from EntitySet in Reactome Reactome DB_ID: 975711 2 Reactome DB_ID: 433882 2 1 EQUAL 438 EQUAL Reactome Database ID Release 82 1094885 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1094885 Reactome R-GGA-1094885 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-1094885.1 Reactome Database ID Release 82 1008270 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1008270 Reactome R-GGA-1008270 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-1008270.1 12609980 Pubmed 2003 Poly(I-C)-induced Toll-like receptor 3 (TLR3)-mediated activation of NFkappa B and MAP kinase is through an interleukin-1 receptor-associated kinase (IRAK)-independent pathway employing the signaling components TLR3-TRAF6-TAK1-TAB2-PKR Jiang, Z Zamanian-Daryoush, M Nie, H Silva, AM Williams, BR Li, X J Biol Chem 278:16713-9 17218788 Pubmed 2006 TGF-beta activated kinase-1: new insights into the diverse roles of TAK1 in development and immunity Delaney, JR Mlodzik, M Cell Cycle 5:2852-5 19898473 Pubmed 2010 Different modes of ubiquitination of the adaptor TRAF3 selectively activate the expression of type I interferons and proinflammatory cytokines Tseng, PH Matsuzawa, A Zhang, W Mino, T Vignali, DA Karin, M Nat Immunol 11:70-5 TAK1 activates NFkB by phosphorylation and activation of IKKs complex TAK1 activates NFkB by phosphorylation and activation of IKKs complex 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. Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 2.7.11.1 Phosphorylation of IKKs complex by activated TAK1 Phosphorylation of IKKs complex by activated TAK1 The IKKs - IkB kinase (IKK) complex serves as the master regulator for the activation of NF-kB by various stimuli. It contains two catalytic subunits, IKK alpha and IKK beta, and a regulatory subunit, IKKgamma/NEMO. The activation of IKK complex and the NFkB mediated antiviral response are dependent on the phosphorylation of IKK alpha/beta at its activation loop and the K63-linked ubiquitination of NEMO[Solt et al 2009; Li et al 2002]. NEMO ubiquitination by TRAF6 is required for optimal activation of IKKalpha/beta. This basic trimolecular complex is referred to as the IKK complex. <p>Each catalytic IKK subunit has an N-terminus kinase domain, a leucine zipper (LZ) motif, a helix-loop-helix (HLH) and a C-terminus NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs.<p>IKK beta is the major IKK catalytic subunit for NF-kB activation. Phosphorylation in the activation loop of IKK beta requires Ser177 and Ser181 (data for human proteins) and thus activates the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation.<p>Chicken IKK alpha and IKK beta showed 81% and 68% identity to the corresponding human IKK kinases (UniProtKB sequence data using NCBI BLASTP 2.2.20). Multiple sequence alignment of the proteins by ClustalW demonstrated that chicken IKK alpha serine residues 190 and 194 correspond to human Ser176 and Ser180, that are required for the activation. It is unclear what serine residues of chicken IKK beta are involved into the phosphorylation.<p>Chicken IKK gamma or NEMO is considered as avian lost.[Cormican et al 2009]. Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 434005 1 IKKs_complex (Inhibitor of kappa B kinases) [cytosol] IKKs_complex (Inhibitor of kappa B kinases) Reactome DB_ID: 433865 1 UniProt:Q5ZI83 RCJMB04_29g15 RCJMB04_29g15 RCJMB04_29g15 <submittedName> <fullName>Putative uncharacterized protein</fullName> </submittedName> UniProt Q5ZI83 1 EQUAL 739 EQUAL Reactome DB_ID: 433915 1 UniProt:Q5ZJB4 CHUK CHUK RCJMB04_19h23 CHUK IKKA FUNCTION Phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF-kappa-B complex and ultimately the degradation of the inhibitor. Phosphorylates 'Ser-10' of histone H3 at NF-kappa-B-regulated promoters during inflammatory responses triggered by cytokines.ACTIVITY REGULATION Activated when phosphorylated and inactivated when dephosphorylated.SIMILARITY Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily. UniProt Q5ZJB4 1 EQUAL 759 EQUAL Reactome Database ID Release 82 434005 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434005 Reactome R-GGA-434005 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-GGA-434005.2 Reactome DB_ID: 113592 2 Reactome DB_ID: 433938 1 activated IKKs complex [cytosol] activated IKKs complex Reactome DB_ID: 434000 1 O-phospho-L-serine at 190 190 EQUAL O-phospho-L-serine at 194 194 EQUAL 1 EQUAL 759 EQUAL Reactome DB_ID: 433953 1 O-phospho-L-serine at unknown position O-phospho-L-serine at unknown position 1 EQUAL 739 EQUAL Reactome Database ID Release 82 433938 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433938 Reactome R-GGA-433938 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-433938.1 Reactome DB_ID: 29370 2 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 975491 Activated chicken TAK1 complexes [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 82 434076 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434076 Reactome Database ID Release 82 433955 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433955 Reactome R-GGA-433955 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-433955.1 17047224 Pubmed 2006 Regulation and function of IKK and IKK-related kinases Hacker, H Karin, M Sci STKE 2006:re13 17332413 Pubmed 2007 Multiple functions of the IKK-related kinase IKKepsilon in interferon-mediated antiviral immunity Tenoever, BR Ng, SL Chua, MA McWhirter, SM Garcia-Sastre, A Maniatis, T Science 315:1274-8 2.7.11.1 activated IKKs phosphorylates IkB alpha causing the NFkB complex to dissociate from the phospho-IkB activated IKKs phosphorylates IkB alpha causing the NFkB complex to dissociate from the phospho-IkB The phosphorylation and ubiquitination of IkB kinase complex is mediated by two distinct pathways, either the classical or alternative pathway. In the classical NF-kB signaling pathway, the activated IKK complex, predominantly acting through IKK beta in an IKK gamma-dependent manner, catalyzes the phosphorylation of IkBs (at sites corresponding to Ser32 and Ser36 of human IkB-alpha or Ser19 and Ser22 of human IkB-beta), polyubiquitination (at sites corresponding to Lys21 and Lys22 of human IkB-alpha) and subsequent degradation by the 26S proteasome. The K-48 ubiquitination is mediated by the E2 ubiquitin ligases (or SCFs) formed by three subunits: Skp1, Cul A (Cdc53), and one of many F-box proteins.<p>Chicken IkB-alpha shows 71% identity to the human IkB alpha kinase. Multiple sequence alignment of the human and chicken IKB-alpha showed that chicken Ser36 and Ser40 correspond to human Ser32 and Ser 36 mentioned above.<p>There is insufficient data for chicken IkB beta to make a comparison with other species. Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 434019 1 IkB alpha : NFkB complex [cytosol] IkB alpha : NFkB complex Reactome DB_ID: 433980 1 UniProt:P98152 RELA RELA RELA FUNCTION NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. RELA shows a weak DNA-binding site which could contribute directly to DNA binding in the NF-kappa-B complex.SUBUNIT Component of the NF-kappa-B p65-p50 complex. Component of the NF-kappa-B p65-c-Rel complex. Component of the NF-kappa-B p65-p105 complex.TISSUE SPECIFICITY Spleen; lower level in brain.DOMAIN The transcriptional activation domain 1/TA1 and the transcriptional activation domain 2/TA2 have direct transcriptional activation properties (By similarity). The 9aaTAD motif found within the transcriptional activation domain 2 is a conserved motif present in a large number of transcription factors that is required for their transcriptional transactivation activity (By similarity). UniProt P98152 1 EQUAL 558 EQUAL Reactome DB_ID: 433811 1 UniProt:Q91974 NFKBIA NFKBIA NFKBIA IKBA FUNCTION Inhibits NF-kappa-B by complexing with and trapping it in the cytoplasm. May be involved in regulation of transcriptional responses to NF-kappa-B, including cell adhesion, immune and pro-inflammatory responses, apoptosis, differentiation and growth. Controlled by sequential serine-phosphorylation, ubiquitination and degradation. Tyrosine-phosphorylation could only lead to dissociation from NF-kappa-B (By similarity).SUBUNIT Interacts with RELA.TISSUE SPECIFICITY Highly expressed in lymph node, thymus followed by liver, brain, muscle, kidney, gastrointestinal and reproductive tract.PTM Ubiquitinated; subsequent to stimulus-dependent phosphorylation on serines, polyubiquitination targets the protein for rapid degradation via the ubiquitin system.SIMILARITY Belongs to the NF-kappa-B inhibitor family. UniProt Q91974 1 EQUAL 318 EQUAL Reactome DB_ID: 433962 1 UniProt:Q04861 NFKB1 NFKB1 NFKB1 FUNCTION P105 is the precursor of the p50 subunit of the nuclear factor NF-kappa-B, which binds to the kappa-B consensus sequence 5'-GGRNNYYCC-3', located in the enhancer region of genes involved in immune response and acute phase reactions. The precursor protein itself does not bind to DNA.SUBUNIT Active NF-kappa-B is a heterodimer of an about 50 kDa DNA-binding subunit and the weak DNA-binding subunit p65. Two heterodimers might form a labile tetramer.DOMAIN The C-terminus of p105 might be involved in cytoplasmic retention, inhibition of DNA-binding by p50 homodimers, and/or transcription activation.PTM While translation occurs, the particular unfolded structure after the GRR repeat promotes the generation of p50 making it an acceptable substrate for the proteasome. This process is known as cotranslational processing. The processed form is active and the unprocessed form acts as an inhibitor (I kappa B-like), being able to form cytosolic complexes with NF-kappa B, trapping it in the cytoplasm. Complete folding of the region downstream of the GRR repeat precludes processing (By similarity).PTM S-nitrosylation of Cys-66 affects DNA binding. UniProt Q04861 1 EQUAL 984 EQUAL Reactome Database ID Release 82 434019 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434019 Reactome R-GGA-434019 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-434019.1 Reactome DB_ID: 113592 2 Reactome DB_ID: 434125 1 NFkB complex(p50/p65) [cytosol] NFkB complex(p50/p65) Reactome DB_ID: 433980 1 1 EQUAL 558 EQUAL Reactome DB_ID: 433962 1 1 EQUAL 984 EQUAL Reactome Database ID Release 82 434125 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434125 Reactome R-GGA-434125 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-434125.1 Reactome DB_ID: 29370 2 Reactome DB_ID: 433842 1 O-phospho-L-serine at 36 36 EQUAL O-phospho-L-serine at 40 40 EQUAL 1 EQUAL 318 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 433938 Reactome Database ID Release 82 434081 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434081 Reactome Database ID Release 82 433986 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433986 Reactome R-GGA-433986 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-433986.1 Released NFkB complex migrates to the nucleus and turns on transcription Released NFkB complex migrates to the nucleus and turns on transcription 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> Chicken NFkB p105 (precursor of p50) subunit and NFkB p65 subunit showed 71% and 51% identity to the corresponding human NFkB subunits (UniProtKB sequence data using NCBI BLASTP 2.2.20). Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 434125 1 Reactome DB_ID: 433908 1 nucleoplasm GO 0005654 NFkB complex(p50/p65) [nucleoplasm] NFkB complex(p50/p65) Reactome DB_ID: 433824 1 1 EQUAL 558 EQUAL Reactome DB_ID: 434062 1 1 EQUAL 984 EQUAL Reactome Database ID Release 82 433908 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433908 Reactome R-GGA-433908 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-433908.1 Reactome Database ID Release 82 433823 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433823 Reactome R-GGA-433823 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-433823.1 16056267 Pubmed 2005 Ubiquitin signalling in the NF-kappaB pathway Chen, ZJ Nat Cell Biol 7:758-65 15371334 Pubmed 2004 Signaling to NF-kappaB Hayden, MS Ghosh, S Genes Dev 18:2195-224 Reactome Database ID Release 82 434001 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434001 Reactome R-GGA-434001 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-434001.1 1533881 Pubmed 1992 p105, the NF-kappa B p50 precursor protein, is one of the cellular proteins complexed with the v-Rel oncoprotein in transformed chicken spleen cells Capobianco, AJ Chang, D Mosialos, G Gilmore, TD J Virol 66:3758-67 GO 0007250 GO biological process MAPK activation in TLR cascade MAPK activation in TLR cascade 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. Authored: Shamovsky, V, 2010-01-05 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2011-02-17 Activated TAK1 mediates Jun kinases (JNK) phosphorylation and activation Activated TAK1 mediates Jun kinases (JNK) phosphorylation and activation C-Jun NH2 terminal kinases are stress activated MAPKs, also known as SAPKs. The JNK pathway is activated by heat shock, or inflammatory cytokines, or UV radiation. The JNKs are encoded by at least three genes: JNK1/SAPK-gamma, JNK2/SAPK-alpha and JNK3/ SAPK-beta.<p>Activation of JNKs is mediated by activated TAK1 which phosphorylates two dual specificity enzymes MKK4 (MAPK kinase 4) and MKK7(MAPK kinase 7). Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2011-02-17 2.7.11.1 Phosphorylation of MKK4 by activated TAK1 Phosphorylation of MKK4 by activated TAK1 Phosphorylation of MKK4 and MKK7 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 the deletion of the mkk4 gene.<p>Chicken MKK4 protein as confirmed by mRNA sequence shows 96% identity to human MKK4 (UniProtKB sequence data using NCBI BLASTP 2.2.20). Multiple sequence alignment of the proteins by ClustalW demonstrated that chicken MKK4 serine residue 224 and threonine 228 correspond to human Ser257 and Thr261, that are required for the activation.<p> Since no MKK7 ortholog was identified in the chicken genome, only chicken MKK4 protein is annotated in the chicken JNK pathway as a homolog of the well characterized human MKK4 / MKK7 proteins. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 437642 1 ENSEMBL:ENSGALP00000001475 MKK4 MKK4 MAP2K4 ENSEMBL ENSGALP00000001475 Reactome DB_ID: 113592 2 Reactome DB_ID: 437975 1 O-phospho-L-serine at unknown position O-phospho-L-threonine at unknown position Reactome DB_ID: 29370 2 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 975491 Reactome Database ID Release 82 437999 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437999 Reactome R-GGA-437999 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-437999.1 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 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 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 2.7.12.1 MKK4 phosphorylates JNK MKK4 phosphorylates JNK Activated JNK kinases (MKK4 and MKK7) phosphorylate threonine and tyrosine residues in the characteristic Thr-Pro-Tyr phosphoacceptor loop of each JNK isoform.<p>Chicken JNK2(MAPK9) shows 98% identity with human JNK2 (UniProtKB sequence data using NCBI BLASTP 2.2.20). Multiple sequence alignment of the human, mouse and chicken JNK2 proteins by ClustalW showed that Thr183 and Tyr185 residues, that are responsible for the JNK activation in human, are identical for all three orthologs.<p>Other chicken JNK isoforms JNK1(MAPK8) and JNK3(MAPK10), whose existence is confirmed at the transcript level, share 99% and 95% amino-acid sequence identity with their human counterparts respectively. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2011-02-17 Converted from EntitySet in Reactome Reactome DB_ID: 433872 1 JNK homologs [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MAPK9_(JNK2) [cytosol] UniProt P79996 Reactome DB_ID: 113592 2 Converted from EntitySet in Reactome Reactome DB_ID: 437957 1 phosphorylated JNK homologs [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phosphorylated MAPK9_(JNK2) [cytosol] Reactome DB_ID: 29370 2 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 437975 O-phospho-L-serine at unknown position O-phospho-L-threonine at unknown position GO 0004712 GO molecular function Reactome Database ID Release 82 438025 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=438025 Reactome Database ID Release 82 438005 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=438005 Reactome R-GGA-438005 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-438005.1 Activated JNK migrates to the nucleoplasm Activated JNK migrates to the nucleoplasm Shortly after phosphorylation JNKs are translocated to nucleus where they associate and activate their target transcription factors. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Converted from EntitySet in Reactome Reactome DB_ID: 437957 1 Converted from EntitySet in Reactome Reactome DB_ID: 438012 1 phosphorylated JNK homologs [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phosphorylated MAPK9_(JNK2) [nucleoplasm] Reactome Database ID Release 82 437995 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437995 Reactome R-GGA-437995 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-437995.1 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 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 2.7.11 Activation and dimerization of c-JUN in the nucleus Activation and dimerization of c-JUN in the nucleus Shortly after phosphorylation JNKs are translocated to nucleus where they associate and activate their target transcription factors. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 29358 4 Reactome DB_ID: 438016 2 UniProt:P18870 JUN JUN JUN FUNCTION Transcription factor that recognizes and binds to the enhancer heptamer motif 5'-TGA[CG]TCA-3'. May be involved in activated KRAS-mediated transcriptional activation of USP28. May bind to the USP28 promoter.SUBUNIT Interacts with FOS to form a dimer. Interacts with Gallid herpesvirus 2 MEQ protein.SIMILARITY Belongs to the bZIP family. Jun subfamily. UniProt P18870 1 EQUAL 314 EQUAL Reactome DB_ID: 113582 4 Reactome DB_ID: 437991 1 activated c-JUN dimer [nucleoplasm] activated c-JUN dimer Reactome DB_ID: 438013 2 O-phospho-L-serine at 63 63 EQUAL O-phospho-L-serine at 73 73 EQUAL 1 EQUAL 314 EQUAL Reactome Database ID Release 82 437991 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437991 Reactome R-GGA-437991 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-437991.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 438012 GO 0004705 GO molecular function Reactome Database ID Release 82 438001 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=438001 Reactome Database ID Release 82 438026 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=438026 Reactome R-GGA-438026 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-GGA-438026.2 18793328 Pubmed 2008 c-Jun expression, activation and function in neural cell death, inflammation and repair Raivich, G J Neurochem 107:898-906 INHIBITION Reactome Database ID Release 82 442857 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442857 Reactome R-GGA-442857 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442857.1 Converted from EntitySet in Reactome Reactome DB_ID: 442886 MAPK phosphatases [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MKP2 [nucleoplasm] MKP5 [nucleoplasm] MKP1 [nucleoplasm] MKP3 [nucleoplasm] UniProt Q9PW71 UniProt Q5ZJF8 UniProt O42253 UniProt Q7T2L9 Reactome Database ID Release 82 437986 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437986 Reactome R-GGA-437986 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-GGA-437986.2 7839144 Pubmed 1995 Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms Derijard, B Raingeaud, J Barrett, T Wu, IH Han, J Ulevitch, RJ Davis, RJ Science 267:682-5 11057897 Pubmed 2000 Signal transduction by the JNK group of MAP kinases Davis, RJ Cell 103:239-52 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 12471242 Pubmed 2002 Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases Johnson, GL Lapadat, R Science 298:1911-2 GO 0007254 GO biological process Activated TAK1 mediates p38 MAP kinase phosphorylation Activated TAK1 mediates p38 MAP kinase phosphorylation 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. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2011-02-17 2.7.11.1 Phosphorylation of MKK3/MKK6 by activated TAK1 Phosphorylation of MKK3/MKK6 by activated TAK1 MKK3 and MKK6 are two closely related dual-specificity protein kinases that activate p38 MAP kinase. MKK3 and MKK6 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. MKK3 and MKK6 are both activated by different forms of cellular stress and inflammatory cytokines. 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 in activation of these protein kinases correspond to human sites Ser189 and Thr193 for MKK3 and Ser207 and Thr211 for MKK6.<p>Since there is no data for chicken MKK6, this hypothetical chicken protein is annotated in the chicken p38 pathway as homolog of well characterized human MKK6. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 113592 2 Converted from EntitySet in Reactome Reactome DB_ID: 437632 1 MKK3/MKK6 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MKK3 [cytosol] UniProt Q5ZL06 Reactome DB_ID: 29370 2 Converted from EntitySet in Reactome Reactome DB_ID: 437977 1 phospho MKK3/ phospho MKK6 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phosphorylated MKK3 [cytosol] PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 975491 Reactome Database ID Release 82 437984 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437984 Reactome R-GGA-437984 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-437984.1 activated MAPK3/MAPK6 migrates to nucleus activated MAPK3/MAPK6 migrates to nucleus 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. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Converted from EntitySet in Reactome Reactome DB_ID: 437977 1 Converted from EntitySet in Reactome Reactome DB_ID: 442940 1 phospho MKK3/ phospho MKK6 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phosphorylated MKK3 [nucleoplasm] Reactome Database ID Release 82 442938 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442938 Reactome R-GGA-442938 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442938.1 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 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 2.7.12.1 activated chicken MKK3/MKK6 phosphorylates p38 MAPK complexed with MAPKAPK2 or MAPKAPK3 activated chicken MKK3/MKK6 phosphorylates p38 MAPK complexed with MAPKAPK2 or MAPKAPK3 The MAPK level components of this cascade are p38MAPK-alpha, -beta, -gamma and -sigma. All of those isoforms are activated by phosphorylation of the Thr and Tyr in the Thr-Gly-Tyr motif in their activation loops. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 29358 2 Reactome DB_ID: 442951 1 p38 MAPK : MAPKAPK 2 or MAPKAPK3 [nucleoplasm] p38 MAPK : MAPKAPK 2 or MAPKAPK3 Converted from EntitySet in Reactome Reactome DB_ID: 442936 1 MAPKAPK2 and/or MAPKAPK3 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MAPKAPK2 [nucleoplasm] MAPKAPK3 [nucleoplasm] ENSEMBL ENSGALP00000001295 ENSEMBL ENSGALP00000003578 Converted from EntitySet in Reactome Reactome DB_ID: 442963 1 p38 MAP kinase [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MAPK13 [nucleoplasm] MAPK14 [nucleoplasm] MAPK11 [nucleoplasm] MAPK12 [nucleoplasm] ENSEMBL ENSGALP00000001204 ENSEMBL ENSGALP00000001201 UniProt Q5ZIK8 ENSEMBL ENSGALP00000014011 Reactome Database ID Release 82 442951 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442951 Reactome R-GGA-442951 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442951.1 Reactome DB_ID: 113582 2 Reactome DB_ID: 442905 1 phospho -p38 MAPK : MAPKAPK 2 or MAPKAPK3 [nucleoplasm] phospho -p38 MAPK : MAPKAPK 2 or MAPKAPK3 Converted from EntitySet in Reactome Reactome DB_ID: 442936 1 Converted from EntitySet in Reactome Reactome DB_ID: 442851 1 phospho_p38 MAP kinase [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phosphorylated MAPK14 [nucleoplasm] phosphorylated MAPK12 [nucleoplasm] phosphorylated MAPK13 [nucleoplasm] phosphorylated MAPK11 [nucleoplasm] Reactome Database ID Release 82 442905 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442905 Reactome R-GGA-442905 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442905.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 442940 Reactome Database ID Release 82 437955 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437955 Reactome Database ID Release 82 438019 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=438019 Reactome R-GGA-438019 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-438019.1 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 2.7.12.1 Active p38 MAPK phosphorylates MAPKAPK2 or 3 Active p38 MAPK phosphorylates MAPKAPK2 or 3 Human p38 MAPK alpha forms a complex with MK2 even when the signaling pathway is not activated. This heterodimer is found mainly in the nucleus. The crystal structure of the unphosphorylated p38alpha-MK2 heterodimer was determined. The C-terminal regulatory domain of MK2 binds in the docking groove of p38 MAPK alpha, and the ATP-binding sites of both kinases are at the heterodimer interface (ter Haar et al. 2007).<p>Upon activation, p38 MAPK alpha activates MK2 by phosphorylating Thr-222, Ser-272, and Thr-334 (Ben-Levy et al. 1995). <p>The phosphorylation of MK2 at Thr-334 attenuates the affinity of the binary complex MK2:p38 alpha by an order of magnitude and leads to a large conformational change of an autoinhibitory domain in MK2. This conformational change unmasks not only the MK2 substrate-binding site but also the MK2 nuclear export signal (NES) thus leading to the MK2:p38 alpha translocation from the nucleus to the cytoplasm. Cytoplasmic active MK2 then phosphorylates downstream targets such as the heat-shock protein HSP27 and tristetraprolin (TTP) (Meng et al. 2002, Lukas et al. 2004, White et al. 2007).<p>MAPKAPK (MAPK-activated protein) kinase 3 (MK3, also known as 3pK) has been identified as the second p38 MAPK-activated kinase that is stimulated by different stresses (McLaughlin et al. 1996; Sithanandam et al. 1996; reviewed in Gaestel 2006). MK3 shows 75% sequence identity to MK2 and, like MK2, is activated by p38 MAPK alpha and p38 MAPK beta. MK3 phosphorylates peptide substrates with kinetic constants similar to MK2 and phosphorylates the same serine residues in HSP27 at the same relative rates as MK2 (Clifton et al. 1996) indicating an identical phosphorylation-site consensus sequence. Hence, it is assumed that its substrate spectrum is either identical to or at least overlapping with MK2. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 29358 3 Reactome DB_ID: 442905 1 Reactome DB_ID: 113582 3 Reactome DB_ID: 442915 1 phospho -p38 MAPK : phospho- MAPKAPK 2 or phospho MAPKAPK3 [nucleoplasm] phospho -p38 MAPK : phospho- MAPKAPK 2 or phospho MAPKAPK3 Converted from EntitySet in Reactome Reactome DB_ID: 442851 1 Converted from EntitySet in Reactome Reactome DB_ID: 442949 1 phospho MAPKAPK2 and/or phospho MAPKAPK3 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phosphorylated MAPKAPK3 [nucleoplasm] phosphorylated MAPKAPK2 [nucleoplasm] Reactome Database ID Release 82 442915 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442915 Reactome R-GGA-442915 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442915.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 442905 Reactome Database ID Release 82 442864 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442864 Reactome Database ID Release 82 442913 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442913 Reactome R-GGA-442913 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-GGA-442913.2 17255097 Pubmed 2007 Crystal structure of the p38 alpha-MAPKAP kinase 2 heterodimer Ter Haar, E Prabhakar, P Liu, X Lepre, C J Biol Chem 282:9733-9 15287722 Pubmed 2004 Catalysis and function of the p38 alpha.MK2a signaling complex Lukas, SM Kroe, RR Wildeson, J Peet, GW Frego, L Davidson, W Ingraham, RH Pargellis, CA Labadia, ME Werneburg, BG Biochemistry 43:9950-60 17395714 Pubmed 2007 Molecular basis of MAPK-activated protein kinase 2:p38 assembly White, A Pargellis, CA Studts, JM Werneburg, BG Farmer BT, 2nd Proc Natl Acad Sci U S A 104:6353-8 8846784 Pubmed 1995 Identification of novel phosphorylation sites required for activation of MAPKAP kinase-2 Ben-Levy, R Leighton, IA Doza, YN Attwood, P Morrice, N Marshall, CJ Cohen, P EMBO J 14:5920-30 12171911 Pubmed 2002 Structure of mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 suggests a bifunctional switch that couples kinase activation with nuclear export Meng, W Swenson, LL Fitzgibbon, MJ Hayakawa, K Ter Haar, E Behrens, AE Fulghum, JR Lippke, JA J Biol Chem 277:37401-5 INHIBITION Reactome Database ID Release 82 442897 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442897 Reactome R-GGA-442897 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442897.1 Converted from EntitySet in Reactome Reactome DB_ID: 442886 Nuclear export of p38 MAPK mediated by its substrate MAPKAPK2 or 3 Nuclear export of p38 MAPK mediated by its substrate MAPKAPK2 or 3 p38 MAPK alpha does not have a nuclear export signal (NES) and cannot leave the nucleus by itself, but rather needs to be associated with MAP kinase-activated protein kinase 2 (MAPKAPK2 or MK2). The NES of MAPKAPK2 facilitates the transport of both kinases from the nucleus to the cytoplasm but only after MK2 has been phosphorylated by p38alpha.<p>p38 MAPK alpha phosphorylates MK2 at Thr222, Ser272, and Thr334. The phosphorylation of Thr334 but not the kinase activity of MK2 has been demonstrated to be critical for the nuclear export of the p38 alpha - MK2 complex. Phosphorylation of Thr334 is believed to induce a conformational change in the complex exposing NES prior to interaction with the leptomycin B-sensitive nuclear export receptor. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 442915 1 Reactome DB_ID: 442925 1 phospho -p38 MAPK : phospho- MAPKAPK 2 or phospho-MAPKAPK3 [cytosol] phospho -p38 MAPK : phospho- MAPKAPK 2 or phospho-MAPKAPK3 Converted from EntitySet in Reactome Reactome DB_ID: 437968 1 phospho_p38 MAP kinase [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phosphorylated MAPK11 [cytosol] phosphorylated MAPK12 [cytosol] phosphorylated MAPK13 [cytosol] phosphorylated MAPK14 [cytosol] Converted from EntitySet in Reactome Reactome DB_ID: 442855 1 phospho MAPKAPK2 and/or phospho MAPKAPK3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phosphorylated MAPKAPK2 [cytosol] phosphorylated MAPKAPK3 [cytosol] Reactome Database ID Release 82 442925 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442925 Reactome R-GGA-442925 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442925.1 Reactome Database ID Release 82 442862 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442862 Reactome R-GGA-442862 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442862.1 Reactome Database ID Release 82 437980 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437980 Reactome R-GGA-437980 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-GGA-437980.2 15686620 Pubmed 2005 Activation and signaling of the p38 MAP kinase pathway Zarubin, T Han, J Cell Res 15:11-8 8761479 Pubmed 1996 Tyrosine phosphorylation and activation of a new mitogen-activated protein (MAP)-kinase cascade in human neutrophils stimulated with various agonists Nahas, N Molski, TF Fernandez, GA Sha'afi, RI Biochem J 318:247-53 GO 0038066 GO biological process ERK activation ERK activation Lipopolysaccharide and flagellin were shown to stimulate ERK activation in chicken heterophils.<p>Bioinformatic analysis reveals no evidence of ERK1 in the chicken genome, although chicken orthologs to other mediators of MEK-ERK signaling (MEK1, MEK2, ERK2 etc.) were identified. In this Reactome model we show ERK2 activation and assume that chicken MEK-ERK mediators behave like their human counterparts. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-11-05 activated MEK2 binds ERK2 activated MEK2 binds ERK2 Activated mammalian MEK1/2 is a serine/threonine kinase, which phosphorylates and activates ERK1/2. ERK1/2 is then translocates to the nucleus and activates transcription factors.<p> Chicken MEK2 showes 93% amino acid sequence identity to human MEK2. Multiple sequence alignment of human, mouse and chicken MEK2 by ClustalW allows to predict that the following chicken residues are involved in chicken MEK2 activation: Ser220 and Ser224 that are corresponding to human residues Ser222 and Ser226. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 451487 1 UniProt:Q90891 MAP2K2 MAP2K2 MKK2 PRKMK2 MAP2K2 MEK2 FUNCTION Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. Activates the ERK1 and ERK2 MAP kinases (By similarity).PTM Activated by phosphorylation on Ser/Thr catalyzed by MAP kinase kinase kinases (RAF).SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase subfamily. UniProt Q90891 O-phospho-L-serine at 220 220 EQUAL O-phospho-L-serine at 224 224 EQUAL 1 EQUAL 398 EQUAL Reactome DB_ID: 433942 1 UniProt:Q8UWG6 Extracellular signal-regulated kinase 2 Extracellular signal-regulated kinase 2 MAPK1 SIMILARITY Belongs to the protein kinase superfamily. UniProt Q8UWG6 1 EQUAL 368 EQUAL Reactome DB_ID: 451495 1 phospho MEK2 : ERK2 [cytosol] phospho MEK2 : ERK2 Reactome DB_ID: 451487 1 O-phospho-L-serine at 220 220 EQUAL O-phospho-L-serine at 224 224 EQUAL 1 EQUAL 398 EQUAL Reactome DB_ID: 433942 1 1 EQUAL 368 EQUAL Reactome Database ID Release 82 451495 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451495 Reactome R-GGA-451495 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-451495.1 Reactome Database ID Release 82 451482 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451482 Reactome R-GGA-451482 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-451482.1 18669607 Pubmed 2008 Flagellin and lipopolysaccharide up-regulation of IL-6 and CXCLi2 gene expression in chicken heterophils is mediated by ERK1/2-dependent activation of AP-1 and NF-kappaB signaling pathways Kogut, MH Genovese, KJ He, H Kaiser, P Innate Immun 14:213-22 17045653 Pubmed 2007 Flagellin and lipopolysaccharide stimulate the MEK-ERK signaling pathway in chicken heterophils through differential activation of the small GTPases, Ras and Rap1 Kogut, MH Genovese, KJ He, H Mol Immunol 44:1729-36 20163623 Pubmed 2009 Extracellular signal-regulated kinase (ERK) activation in chicken heterophils stimulated with phorbol 12-myristate 13-acetate (PMA), formyl-methionylleucyl-phenylalanine (fMLP) and lipopolysaccharide (LPS) Gerilechaogetu, - Hanieh, H Abe, A Kondo, Y Anim Sci J 80:577-84 2.7.11.1 activated MEK2 phosphorylates ERK2 activated MEK2 phosphorylates ERK2 Chicken ERK2 shares 99% of amino acid sequence identity with human and mouse ERK2. Multiple sequence alignment of human, mouse and chicken ERK2 by ClustalW allowed to predict that the following chicken residues are involved in chicken ERK2 activation: Thr193 and Tyr195 corresponding to mammalian Thr185 and Tyr187. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 451495 1 Reactome DB_ID: 113592 2 Reactome DB_ID: 451480 1 phospho ERK2 : phospho MEK2 [cytosol] phospho ERK2 : phospho MEK2 Reactome DB_ID: 451487 1 O-phospho-L-serine at 220 220 EQUAL O-phospho-L-serine at 224 224 EQUAL 1 EQUAL 398 EQUAL Reactome DB_ID: 451523 1 O-phospho-L-threonine at 193 193 EQUAL O4'-phospho-L-tyrosine at 195 195 EQUAL O4'-phospho-L-tyrosine [MOD:00048] 1 EQUAL 368 EQUAL Reactome Database ID Release 82 451480 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451480 Reactome R-GGA-451480 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-451480.1 Reactome DB_ID: 29370 2 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 451495 Reactome Database ID Release 82 451515 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451515 Reactome Database ID Release 82 451516 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451516 Reactome R-GGA-451516 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-451516.1 Dissociation of phospho ERK2 :phospho MEK2 complex Dissociation of phospho ERK2 :phospho MEK2 complex MEK-ERK pathways are considered to be highly conserved. Their involvement in up-regulation of the inflammatory response has been demonstrated in mammals and chicken (Johnson GL and Lapadat R 2002; Kogut M et al 2008). <p> In this model we assume that chicken MEK-ERK mediators behave like their human counterparts. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 451526 1 phospho ERK2 : phospho MEK2 [cytosol] phospho ERK2 : phospho MEK2 Reactome DB_ID: 451487 1 O-phospho-L-serine at 220 220 EQUAL O-phospho-L-serine at 224 224 EQUAL 1 EQUAL 398 EQUAL Reactome DB_ID: 451523 1 O-phospho-L-threonine at 193 193 EQUAL O4'-phospho-L-tyrosine at 195 195 EQUAL 1 EQUAL 368 EQUAL Reactome Database ID Release 82 451526 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451526 Reactome R-GGA-451526 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-451526.1 Reactome DB_ID: 451487 1 O-phospho-L-serine at 220 220 EQUAL O-phospho-L-serine at 224 224 EQUAL 1 EQUAL 398 EQUAL Reactome DB_ID: 451523 1 O-phospho-L-threonine at 193 193 EQUAL O4'-phospho-L-tyrosine at 195 195 EQUAL 1 EQUAL 368 EQUAL Reactome Database ID Release 82 451505 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451505 Reactome R-GGA-451505 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-451505.1 Dimerization of activated ERK2 Dimerization of activated ERK2 MEK-ERK pathways are considered to be highly conserved. Their involvement in up-regulation of the inflammatory response has been demonstrated in mammals and chicken (Johnson GL and Lapadat R 2002; Kogut M et al 2008). <p> In this model we assume that chicken MEK-ERK mediators behave like their human counterparts. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 451523 2 O-phospho-L-threonine at 193 193 EQUAL O4'-phospho-L-tyrosine at 195 195 EQUAL 1 EQUAL 368 EQUAL Reactome DB_ID: 451504 1 phospho ERK2 dimer [cytosol] phospho ERK2 dimer Reactome DB_ID: 451523 2 O-phospho-L-threonine at 193 193 EQUAL O4'-phospho-L-tyrosine at 195 195 EQUAL 1 EQUAL 368 EQUAL Reactome Database ID Release 82 451504 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451504 Reactome R-GGA-451504 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-451504.1 Reactome Database ID Release 82 451535 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451535 Reactome R-GGA-451535 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-GGA-451535.2 Nuclear translocation of phospho ERK2 dimer Nuclear translocation of phospho ERK2 dimer MEK-ERK pathways are considered to be highly conserved. Their involvement in up-regulation of the inflammatory response has been demonstrated in mammals and chicken (Johnson GL and Lapadat R 2002; Kogut M et al 2008). <p> In this model we assume that chicken MEK-ERK mediators behave like their human counterparts. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 451504 1 Reactome DB_ID: 451513 1 phospho ERK2 dimer [nucleoplasm] phospho ERK2 dimer Reactome DB_ID: 442961 2 O-phospho-L-threonine at 193 193 EQUAL O4'-phospho-L-tyrosine at 195 195 EQUAL 1 EQUAL 368 EQUAL Reactome Database ID Release 82 451513 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451513 Reactome R-GGA-451513 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-451513.1 Reactome Database ID Release 82 451508 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451508 Reactome R-GGA-451508 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-GGA-451508.2 Reactome Database ID Release 82 451478 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451478 Reactome R-GGA-451478 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-GGA-451478.2 20954007 Pubmed 2010 Advances in avian immunology--prospects for disease control: a review Kaiser, P Avian Pathol 39:309-24 GO 0070371 GO biological process Reactome Database ID Release 82 451524 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451524 Reactome R-GGA-451524 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-GGA-451524.2 19196711 Pubmed 2009 Selectivity of docking sites in MAPK kinases Bardwell, AJ Frankson, E Bardwell, L J Biol Chem 284:13165-73 GO 0000165 GO biological process Reactome Database ID Release 82 573298 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=573298 Reactome R-GGA-573298 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-GGA-573298.3 20498358 Pubmed 2010 Chicken TLR21 is an innate CpG DNA receptor distinct from mammalian TLR9 Keestra, AM de Zoete, MR Bouwman, LI van Putten, JP J Immunol 185:460-7 12873704 Pubmed 2003 CpG-ODN-induced nitric oxide production is mediated through clathrin-dependent endocytosis, endosomal maturation, and activation of PKC, MEK1/2 and p38 MAPK, and NF-kappaB pathways in avian macrophage cells (HD11) He, H Kogut, MH Cell Signal 15:911-7 GO 0038008 GO biological process Reactome Database ID Release 82 451477 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451477 Reactome R-GGA-451477 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-451477.1 15804288 Pubmed 2005 Identification and characterization of a functional, alternatively spliced Toll-like receptor 7 (TLR7) and genomic disruption of TLR8 in chickens Philbin, VJ Iqbal, M Boyd, Y Goodchild, MJ Beal, RK Bumstead, N Young, J Smith, AL Immunology 114:507-21 21095203 Pubmed 2011 Avian-specific TLRs and downstream effector responses to CpG-induction in chicken macrophages Ciraci, C Lamont, SJ Dev Comp Immunol 35:392-8 GO 0002755 GO biological process