BioPAX pathway converted from "TICAM1,TRAF6-dependent induction of TAK1 complex" in the Reactome database. TICAM1,TRAF6-dependent induction of TAK1 complex TICAM1,TRAF6-dependent induction of TAK1 complex In human, together with ubiquitin-conjugating E2-type enzymes UBC13 and UEV1A (also known as UBE2V1), TRAF6 catalyses Lys63-linked ubiquitination. It is believed that auto polyubiquitination and oligomerization of TRAF6 is followed by binding the ubiquitin receptors of TAB2 or TAB3 (TAK1 binding protein 2 and 3), which stimulates phosphorylation and activation of TGF beta-activated kinase 1(TAK1).<p>TAK1 phosphorylates IKK alpha and IKK beta, which in turn phosphorylate NF-kB inhibitors - IkB and eventually results in IkB degradation and NF-kB translocation to the nucleus. Also TAK1 mediates JNK and p38 MAP kinases activation by phosphorylating MKK4/7 and MKK3/6 respectivly resulting in the activation of many transcription factors. <p>The role of TRAF6 is somewhat controversial and probably cell type specific. TRAF6 autoubiquitination was found to be dispensable for TRAF6 function to activate TAK1 pathway. These findings are consistent with the new mechanism of TRAF6-mediated NF-kB activation that was suggested by Xia et al. (2009). TRAF6 generates unanchored Lys63-linked polyubiquitin chains that bind to the regulatory subunits of TAK1 (TAB2 or TAB3) and IKK(NEMO), leading to the activation of the kinases.<p> Xia et al. (2009) demonstrated in vitro that unlike polyubiquitin chains covalently attached to TRAF6 or IRAK, TAB2 and NEMO-associated ubiquitin chains were found to be unanchored and susceptible to N-terminal ubiquitin cleavage. Only K63-linked polyubiquitin chains, but not monomeric ubiquitin, activated TAK1 in a dose-dependent manner. Optimal activation of the IKK complex was achieved using ubiquitin polymers containing both K48 and K63 linkages.<p>Furthermore, the authors proposed that the TAK1 complexes might be brougt in close proximity by binding several TAB2/3 to a single polyubiquitin chain to facilitate TAK1 kinase trans-phosphorylation. Alternativly, the possibility that polyUb binding promotes allosteric activation of TAK1 complex should be considered (Walsh et al 2008). Authored: Shamovsky, V, 2010-06-01 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Edited: Shamovsky, V, 2010-11-15 Viral dsRNA:TLR3:TICAM1 complex recruits TRAF6 Viral dsRNA:TLR3:TICAM1 complex recruits TRAF6 TRAF6 is recruited to the N-terminal domain of TICAM1 and this event is followed by auto polyubiquitination and oligomerization of TRAF6. Authored: Shamovsky, V, 2009-12-16 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Edited: Shamovsky, V, 2009-12-16 Reactome DB_ID: 166366 1 cytosol GO 0005829 UniProt:Q9Y4K3 TRAF6 TRAF6 TRAF6 RNF85 FUNCTION E3 ubiquitin ligase that, together with UBE2N and UBE2V1, mediates the synthesis of 'Lys-63'-linked-polyubiquitin chains conjugated to proteins, such as IKBKG, IRAK1, AKT1 and AKT2 (PubMed:11057907, PubMed:18347055, PubMed:19713527, PubMed:19465916). Also mediates ubiquitination of free/unanchored polyubiquitin chain that leads to MAP3K7 activation (PubMed:19675569). Leads to the activation of NF-kappa-B and JUN (PubMed:16378096, PubMed:17135271). Seems to also play a role in dendritic cells (DCs) maturation and/or activation (By similarity). Represses c-Myb-mediated transactivation, in B-lymphocytes (PubMed:18093978, PubMed:18758450). Adapter protein that seems to play a role in signal transduction initiated via TNF receptor, IL-1 receptor and IL-17 receptor (PubMed:8837778, PubMed:19825828, PubMed:12140561). Regulates osteoclast differentiation by mediating the activation of adapter protein complex 1 (AP-1) and NF-kappa-B, in response to RANK-L stimulation (By similarity). Together with MAP3K8, mediates CD40 signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production (By similarity).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Homotrimer. Homooligomer. N-terminal region is dimeric while C-terminal region is trimeric; maybe providing a mode of oligomerization. Upon IL1B treatment, forms a complex with PELI1, IRAK1, IRAK4 and MYD88; this complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation. Direct binding of SMAD6 to PELI1 prevents the complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression. Binds to TNFRSF5/CD40 and TNFRSF11A/RANK. Associates with NGFR, TNFRSF17, IRAK2, IRAK3, RIPK2, MAP3K1, MAP3K5, MAP3K14, CSK, TRAF, TRAF-interacting protein TRIP and TNF receptor associated protein TDP2. Interacts with IL17R. Interacts with SQSTM1 bridging NTRK1 and NGFR. Forms a ternary complex with SQSTM1 and PRKCZ (By similarity). Interacts with PELI2 and PELI3. Binds UBE2V1. Interacts with TAX1BP1. Interacts with ZNF675. Interacts with ARRB1 and ARRB2. Interacts with MAP3K7 and TAB1/MAP3K7IP1; during IL-1 signaling. Interacts with UBE2N. Interacts with TGFBR1, HDAC1 and RANGAP1. Interacts with AKT1, AKT2 and AKT3. Interacts (via TRAF domains) with NUMBL (via C-terminal). Interacts with RBCK1. Interacts with LIMD1 (via LIM domains) (By similarity). Interacts with RSAD2/viperin (By similarity). Interacts (via C-terminus) with EIF2AK2/PKR (via the kinase catalytic domain) (By similarity). Interacts with ZFAND5. Interacts with IL1RL1. Interacts with TRAFD1. Interacts with AJUBA. Interacts with MAVS/IPS1. Interacts (via TRAF domains) with DYNC2I2 (via WD domains). Interacts with IFIT3 (via N-terminus). Interacts with TICAM2. Interacts with CARD14. Interacts with CD40 and MAP3K8; the interaction is required for ERK activation (By similarity). Interacts with TICAM1 and this interaction is enhanced in the presence of WDFY1 (PubMed:25736436). Interacts with TANK; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with USP10; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with ZC3H12A; this interaction increases in response to DNA damage and is stimulated by TANK (PubMed:25861989). Interacts with WDFY3 (By similarity). Interacts with TRIM13 (PubMed:28087809). Interacts with GPS2 (By similarity). Interacts (via C-terminus) with SASH1 (PubMed:23776175). Interacts with LRRC19 (PubMed:25026888). Interacts with IL17RA AND TRAF3IP2. Interacts with TOMM70 (PubMed:20628368). Interacts with AMBRA1; interaction is required to mediate 'Lys-63'-linked ubiquitination of ULK1 (PubMed:23524951).TISSUE SPECIFICITY Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.DOMAIN The coiled coil domain mediates homo- and hetero-oligomerization.DOMAIN The MATH/TRAF domain binds to receptor cytoplasmic domains.PTM Sumoylated on Lys-124, Lys-142 and Lys-453 with SUMO1.PTM Polyubiquitinated on Lys-124 by TRAF3IP2; after cell stimulation with IL17A (PubMed:19825828). Polyubiquitinated on Lys-124; after cell stimulation with IL1B or TGFB. This ligand-induced cell stimulation leads to dimerization/oligomerization of TRAF6 molecules, followed by auto-ubiquitination which involves UBE2N and UBE2V1 and leads to TRAF6 activation. This 'Lys-63' site-specific poly-ubiquitination appears to be associated with the activation of signaling molecules. Endogenous autoubiquitination occurs only for the cytoplasmic form. Deubiquitinated by USP10 in a TANK-dependent manner, leading to the negative regulation of NF-kappaB signaling upon DNA damage (PubMed:25861989). LRRC19 induces 'Lys-63' ubiquitination (PubMed:25026888).SIMILARITY Belongs to the TNF receptor-associated factor family. A subfamily. Reactome http://www.reactome.org Homo sapiens NCBI Taxonomy 9606 UniProt Q9Y4K3 Chain Coordinates 1 EQUAL 522 EQUAL Reactome DB_ID: 168907 1 endosome membrane GO 0010008 viral dsRNA:TLR3:TICAM1 [endosome membrane] viral dsRNA:TLR3:TICAM1 viral dsRNA:TLR3:TRIF Reactome DB_ID: 450316 2 UniProt:Q8IUC6 TICAM1 TICAM1 PRVTIRB TICAM1 TRIF FUNCTION Involved in innate immunity against invading pathogens. Adapter used by TLR3, TLR4 (through TICAM2) and TLR5 to mediate NF-kappa-B and interferon-regulatory factor (IRF) activation, and to induce apoptosis (PubMed:12471095, PubMed:12539043, PubMed:14739303, PubMed:28747347). Ligand binding to these receptors results in TRIF recruitment through its TIR domain (PubMed:12471095, PubMed:12539043, PubMed:14739303). Distinct protein-interaction motifs allow recruitment of the effector proteins TBK1, TRAF6 and RIPK1, which in turn, lead to the activation of transcription factors IRF3 and IRF7, NF-kappa-B and FADD respectively (PubMed:12471095, PubMed:12539043, PubMed:14739303). Phosphorylation by TBK1 on the pLxIS motif leads to recruitment and subsequent activation of the transcription factor IRF3 to induce expression of type I interferon and exert a potent immunity against invading pathogens (PubMed:25636800). Component of a multi-helicase-TICAM1 complex that acts as a cytoplasmic sensor of viral double-stranded RNA (dsRNA) and plays a role in the activation of a cascade of antiviral responses including the induction of proinflammatory cytokines (By similarity).SUBUNIT Homodimer (PubMed:12539043). Found in a multi-helicase-TICAM1 complex at least composed of DHX36, DDX1, DDX21 and TICAM1; this complex exists in resting cells with or without poly(I:C) RNA ligand stimulation. Interacts (via TIR domain) with DDX21 (via C-terminus). Interacts (via TIR domain) with DHX36 (via C-terminus) (By similarity). Interacts with AZI2 and IRF7 (PubMed:12471095, PubMed:15611223). Interacts with TICAM2 in TLR4 recruitment (PubMed:12721283, PubMed:25736436). Interaction with PIAS4 inhibits the TICAM1-induced NF-kappa-B, IRF and IFNB1 activation (PubMed:15251447). Interacts with IKBKB and IKBKE. Interaction with SARM1 blocks TICAM1-dependent transcription factor activation (PubMed:16964262). Interacts with TRAF3 (By similarity). Interacts (when phosphorylated) with IRF3; following activation and phosphorylation on the pLxIS motif by TBK1, recruits IRF3 (PubMed:12471095, PubMed:14739303, PubMed:25636800, PubMed:27302953). Interacts with TBK1, TRAF6 and RIPK1 and these interactions are enhanced in the presence of WDFY1 (PubMed:14982987, PubMed:25736436). Interacts with TRAFD1 (By similarity). Interacts with UBQLN1 (via UBA domain) (PubMed:21695056). Interacts with TLR4 in response to LPS in a WDFY1-dependent manner (By similarity). Interacts with WDFY1 in response to poly(I:C) (By similarity). Interacts (via the TIR domain) with TLR3 in response to poly(I:C) and this interaction is enhanced in the presence of WDFY1 (PubMed:25736436). Interacts with TRIM56 (PubMed:22948160). Component of a multi-helicase-TICAM1 complex that acts as a cytoplasmic sensor of viral double-stranded RNA (dsRNA) and plays a role in the activation of a cascade of antiviral responses including the induction of proinflammatory cytokines (By similarity). Interacts (via the TIR domain) with TLR5 (PubMed:20855887). Interacts with TRIM8 (PubMed:28747347).SUBUNIT (Microbial infection) Interacts with hepatitis C virus (HCV) NS3/4A protease; this interaction leads to TICAM1 cleavage, thereby disrupting TLR3 signaling and preventing the establishment of an antiviral state.SUBUNIT (Microbial infection) Interacts with Seneca Valley virus protease 3C; this interaction allows the cleavage of TICAM1/TRIF and subsequent suppression of host innate immunity.SUBUNIT (Microbial infection) Interacts (via C-terminus) with coxsackievirus B3 (CVB3) protease 3C.TISSUE SPECIFICITY Ubiquitously expressed but with higher levels in liver.DOMAIN The pLxIS motif constitutes an IRF3-binding motif: following phosphorylation by TBK1, the phosphorylated pLxIS motif of TICAM1 recruits IRF3 (PubMed:25636800). IRF3 is then phosphorylated and activated by TBK1 to induce type-I interferons and other cytokines (PubMed:25636800).DOMAIN The N-terminal region is essential for activation of the IFNB promoter activity.DOMAIN The N-terminal domain (TRIF-NTD) is globular and consists of two alpha-helical subdomains connected by a 14-residue linker. It shares structural similarity with IFIT family members N-terminal regions.PTM Phosphorylated by TBK1 (PubMed:14530355, PubMed:25636800). Following activation, phosphorylated by TBK1 at Ser-210 in the pLxIS motif (PubMed:25636800). The phosphorylated pLxIS motif constitutes an IRF3-binding motif, leading to recruitment of the transcription factor IRF3 to induce type-I interferons and other cytokines (PubMed:25636800, PubMed:27302953).PTM Polyubiquitinated at Lys-229 by TRIM38 with 'Lys-48'-linked chains, leading to proteasomal degradation (PubMed:23056470). Polyubiquitinated with 'Lys-6'- and 'Lys-33'-linked chains in a TRIM8-dependent manner; ubiquitination disrupts the interaction with TBK1 and subsequent interferon production (PubMed:28747347).PTM (Microbial infection) Cleaved and degraded by hepatitis A virus (HAV) protein 3CD allowing the virus to disrupt host TLR3 signaling.PTM (Microbial infection) Cleaved by CVB3 protease 3C allowing the virus to disrupt host TLR3 signaling.PTM (Microbial infection) Cleaved by Seneca Valley virus protease 3C allowing the virus to disrupt host TLR3 signaling.PTM (Microbial infection) Cleaved by protease 3C of human enterovirus D68 (EV68) allowing the virus to disrupt host TLR3 signaling.PTM (Microbial infection) Cleaved by HCV protease NS3/4A, thereby disrupting TLR3 signaling and preventing the establishment of an antiviral state. UniProt Q8IUC6 1 EQUAL 712 EQUAL Reactome DB_ID: 167985 1 viral dsRNA :TLR3 [endosome membrane] viral dsRNA :TLR3 Reactome DB_ID: 2000341 2 UniProt:O15455 TLR3 TLR3 TLR3 FUNCTION Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR3 is a nucleotide-sensing TLR which is activated by double-stranded RNA, a sign of viral infection. Acts via the adapter TRIF/TICAM1, leading to NF-kappa-B activation, IRF3 nuclear translocation, cytokine secretion and the inflammatory response.SUBUNIT Monomer and homodimer; dimerization is triggered by ligand-binding, the signaling unit is composed of one ds-RNA of around 40 bp and two TLR3 molecules, and lateral clustering of signaling units along the length of the ds-RNA ligand is required for TLR3 signal transduction. Interacts (via transmembrane domain) with UNC93B1; the interaction is required for transport from the ER to the endosomes (PubMed:33432245). Interacts with SRC; upon binding of double-stranded RNA. Interacts with TICAM1 (via the TIR domain) in response to poly(I:C) and this interaction is enhanced in the presence of WDFY1 (PubMed:25736436). The tyrosine-phosphorylated form (via TIR domain) interacts with WDFY1 (via WD repeat 2) in response to poly(I:C) (PubMed:25736436).TISSUE SPECIFICITY Expressed at high level in placenta and pancreas. Also detected in CD11c+ immature dendritic cells. Only expressed in dendritic cells and not in other leukocytes, including monocyte precursors. TLR3 is the TLR that is expressed most strongly in the brain, especially in astrocytes, glia, and neurons.DOMAIN ds-RNA binding is mediated by LRR 1 to 3, and LRR 17 to 18.PTM Heavily N-glycosylated, except on that part of the surface of the ectodomain that is involved in ligand binding.PTM TLR3 signaling requires a proteolytic cleavage mediated by cathepsins CTSB and CTSH, the cleavage occurs between amino acids 252 and 346. The cleaved form of TLR3 is the predominant form found in endosomes.POLYMORPHISM The Phe-412 allele (dbSNP:rs3775291) occurs with a frequency of 30% in populations with European and Asian ancestry, and confers some natural resistance to HIV-1 infection.SIMILARITY Belongs to the Toll-like receptor family. UniProt O15455 24 EQUAL 904 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9038432 1 endosome lumen GO 0031904 TLR3 ligand [endosome lumen] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 81 167985 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=167985 Reactome R-HSA-167985 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-167985.4 Reactome Database ID Release 81 168907 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168907 Reactome R-HSA-168907 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-HSA-168907.3 Reactome DB_ID: 177693 1 viral dsRNA:TLR3:TRIF:TRAF6 [endosome membrane] viral dsRNA:TLR3:TRIF:TRAF6 Reactome DB_ID: 168907 1 Reactome DB_ID: 450272 1 1 EQUAL 522 EQUAL Reactome Database ID Release 81 177693 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=177693 Reactome R-HSA-177693 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-HSA-177693.2 Reactome Database ID Release 81 177694 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=177694 Reactome R-HSA-177694 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-HSA-177694.2 19112497 Pubmed 2008 TRAF6 autoubiquitination-independent activation of the NFkappaB and MAPK pathways in response to IL-1 and RANKL Walsh, MC Kim, GK Maurizio, PL Molnar, EE Choi, Y PLoS One 3:e4064 20047764 Pubmed 2010 Direct binding of TRAF2 and TRAF6 to TICAM-1/TRIF adaptor participates in activation of the Toll-like receptor 3/4 pathway Sasai, M Tatematsu, M Oshiumi, H Funami, K Matsumoto, M Hatakeyama, S Seya, T Mol Immunol 11057907 Pubmed 2000 Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain Deng, L Wang, C Spencer, E Yang, L Braun, A You, J Slaughter, C Pickart, C Chen, ZJ Cell 103:351-61 Auto ubiqitination of TRAF6 bound to viral dsRNS:TLR3:TICAM1 complex Auto ubiqitination of TRAF6 bound to viral dsRNS:TLR3:TICAM1 complex TRAF6 possesses ubiquitin ligase activity and undergoes K-63-linked auto-ubiquitination. 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, 2009-12-16 Reviewed: Gillespie, ME, 2010-03-02 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Edited: Shamovsky, V, 2010-02-27 Reactome DB_ID: 177693 1 Converted from EntitySet in Reactome Reactome DB_ID: 113595 3 Ub [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity UBB(153-228) [cytosol] RPS27A(1-76) [cytosol] UBB(1-76) [cytosol] UBC(457-532) [cytosol] UBC(153-228) [cytosol] UBC(77-152) [cytosol] UBC(305-380) [cytosol] UBC(1-76) [cytosol] UBC(229-304) [cytosol] UBB(77-152) [cytosol] UBA52(1-76) [cytosol] UBC(533-608) [cytosol] UBC(381-456) [cytosol] UBC(609-684) [cytosol] UniProt P0CG47 UniProt P62979 UniProt P0CG48 UniProt P62987 Reactome DB_ID: 450309 1 viral dsRNA:TLR3:TICAM1:K63pUb-TRAF6 [endosome membrane] viral dsRNA:TLR3:TICAM1:K63pUb-TRAF6 Reactome DB_ID: 450227 1 ubiquitinylated lysine (K63polyUb [endosome membrane]) at 124 124 EQUAL ubiquitinylated lysine [MOD:01148] 1 EQUAL 522 EQUAL Reactome DB_ID: 168907 1 Reactome Database ID Release 81 450309 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450309 Reactome R-HSA-450309 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-HSA-450309.2 Reactome Database ID Release 81 450259 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450259 Reactome R-HSA-450259 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-HSA-450259.2 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 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 6.3.2.19 Activated TRAF6 synthesizes unanchored polyubiquitin chains upon TLR3 stimulation Activated TRAF6 synthesizes unanchored polyubiquitin chains upon TLR3 stimulation E3 ubiquitin ligase TRAF6 generates free K63 -linked polyubiquitin chains that non-covalently associate with ubiquitin receptors of TAB2/TAB3 regulatory proteins of the TAK1 complex, leading to the activation of the TAK1 kinase. Authored: Shamovsky, V, 2009-12-16 Reviewed: Gillespie, ME, 2010-03-02 Edited: Shamovsky, V, 2010-02-27 Converted from EntitySet in Reactome Reactome DB_ID: 113595 1 Reactome DB_ID: 450152 1 K63polyUb [cytosol] K63polyUb K63-polyubiquitin Lys-63 polyubiquitin PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 450309 GO 0004842 GO molecular function Reactome Database ID Release 81 1986608 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1986608 Reactome Database ID Release 81 9628444 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9628444 Reactome R-HSA-9628444 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9628444.1 Activated TLR3:TRIF:K63pUb-TRAF6 recruits TAK1complex Activated TLR3:TRIF:K63pUb-TRAF6 recruits TAK1complex TAK1-binding protein 2 (TAB2) and/or TAB3, as part of a complex that also contains TAK1 and TAB1, binds polyubiquitinated TRAF6. The TAB2 and TAB3 regulatory subunits of the TAK1 complex contain C-terminal Npl4 zinc finger (NZF) motifs that recognize with Lys63-pUb chains (Kanayama et al. 2004). The recognition mechanism is specific for Lys63-linked ubiquitin chains [Kulathu Y et al 2009]. TAK1 can be activated by unattached Lys63-polyubiquitinated chains when TRAF6 has no detectable polyubiquitination (Xia et al. 2009) and thus the synthesis of these chains by TRAF6 may be the signal transduction mechanism.This binding leads to autophosphorylation and activation of TAK1. Authored: Shamovsky, V, 2009-12-16 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Edited: Shamovsky, V, 2009-12-16 Reactome DB_ID: 450152 2 Reactome DB_ID: 450309 1 Reactome DB_ID: 450277 2 TAB1:TAB2,TAB3:TAK1 [cytosol] TAB1:TAB2,TAB3:TAK1 TRIKA2 Reactome DB_ID: 167923 1 UniProt:Q15750 TAB1 TAB1 MAP3K7IP1 TAB1 FUNCTION May be an important signaling intermediate between TGFB receptors and MAP3K7/TAK1. May play an important role in mammalian embryogenesis.SUBUNIT Interacts with XIAP and BIRC7 (PubMed:17560374, PubMed:11865055). Interacts with TRAF6 and MAP3K7; during IL-1 signaling (PubMed:8638164, PubMed:10094049, PubMed:11323434). Identified in the TRIKA2 complex composed of MAP3K7, TAB1 and TAB2 (PubMed:11460167).TISSUE SPECIFICITY Ubiquitous.PTM Monoubiquitinated. Deubiquitinated by Y.enterocolitica YopP.CAUTION Lacks several key residues involved in metal-binding and catalytic activity, therefore has lost phosphatase activity. UniProt Q15750 1 EQUAL 504 EQUAL Reactome DB_ID: 168156 1 UniProt:O43318 MAP3K7 MAP3K7 TAK1 MAP3K7 FUNCTION Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signal transduction of TRAF6, various cytokines including interleukin-1 (IL-1), transforming growth factor-beta (TGFB), TGFB-related factors like BMP2 and BMP4, toll-like receptors (TLR), tumor necrosis factor receptor CD40 and B-cell receptor (BCR). Ceramides are also able to activate MAP3K7/TAK1. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K1/MEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs, c-jun N-terminal kinases (JNKs) and I-kappa-B kinase complex (IKK). Both p38 MAPK and JNK pathways control the transcription factors activator protein-1 (AP-1), while nuclear factor-kappa B is activated by IKK. MAP3K7 activates also IKBKB and MAPK8/JNK1 in response to TRAF6 signaling and mediates BMP2-induced apoptosis. In osmotic stress signaling, plays a major role in the activation of MAPK8/JNK1, but not that of NF-kappa-B. Promotes TRIM5 capsid-specific restriction activity. Phosphorylates RIPK1 at 'Ser-321' which positively regulates RIPK1 interaction with RIPK3 to promote necroptosis but negatively regulates RIPK1 kinase activity and its interaction with FADD to mediate apoptosis (By similarity).ACTIVITY REGULATION Activated by proinflammatory cytokines and in response to physical and chemical stresses, including osmotic stress, oxidative stress, arsenic and ultraviolet light irradiation. Activated by 'Lys-63'-linked polyubiquitination and by autophosphorylation. Association with TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2 promotes activation through autophosphorylation, whereas PPM1B/PP2CB, PP2A and PPP6C dephosphorylation leads to inactivation.SUBUNIT Can form homodimer (PubMed:27426733). Binds both upstream activators and downstream substrates in multimolecular complexes. Interacts with TAB1/MAP3K7IP1, TAB2/MAP3K7IP2 and TAB3/MAP3K7IP3 (PubMed:10838074, PubMed:11460167, PubMed:12242293, PubMed:14670075, PubMed:16289117, PubMed:19675569, PubMed:8638164). Identified in the TRIKA2 complex composed of MAP3K7/TAK1, TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2 (PubMed:11460167). Interacts with PPM1L and PPM1B/PP2CB (PubMed:11104763). Interaction with PP2A and PPP6C leads to its repressed activity (PubMed:17079228). Interacts with TRAF6 and TAB1/MAP3K7IP1; during IL-1 signaling (PubMed:10094049, PubMed:12242293). Interacts with TAOK1 and TAOK2; interaction with TAOK2 interferes with MAP3K7 interaction with IKKA, thus preventing NF-kappa-B activation (PubMed:16893890). Interacts with DYNC2I2 (via WD domains) (PubMed:19521662). Interacts with CYLD and RBCK1 (PubMed:17449468, PubMed:17548520). Interacts with TGFBR1; induces MAP3K7/TAK1 activation by TRAF6 (PubMed:18758450). Interacts with MAPK8IP1 and SMAD6 (By similarity). Interacts with isoform 1 of VRK2 (PubMed:18286207). Interacts with DAB2; the interaction is induced by TGF-beta stimulation and may mediate TGF-beta stimulated JNK activation (PubMed:15894542). Interacts with TRIM5 (PubMed:21512573). Part of a complex containing ITCH, NDFIP1 and MAP3K7 (By similarity). Interacts with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation (PubMed:26334375). Interacts with PLEKHM1 (via N- and C-terminus) (By similarity). Interacts with TRIM8 (PubMed:22084099). Found in a complex with SH3RF1, RAC2, MAP2K7/MKK7, MAPK8IP1/JIP1, MAPK8/JNK1 and MAPK9/JNK2 (By similarity). Interacts with SASH1 (PubMed:23776175). Interacts with RIPK1 (By similarity).SUBUNIT (Microbial infection) Interacts with herpes simplex virus 2 protein US2; this interaction induces MAP3K7 phosphorylation and subsequent activation.TISSUE SPECIFICITY Isoform 1A is the most abundant in ovary, skeletal muscle, spleen and blood mononuclear cells. Isoform 1B is highly expressed in brain, kidney and small intestine. Isoform 1C is the major form in prostate. Isoform 1D is the less abundant form.PTM Association with TAB1/MAP3K7IP1 promotes autophosphorylation at Ser-192 and subsequent activation. Association with TAB2/MAP3K7IP2, itself associated with free unanchored Lys-63 polyubiquitin chain, promotes autophosphorylation and subsequent activation of MAP3K7. Dephosphorylation at Ser-192 by PPM1B/PP2CB and at Thr-187 by PP2A and PPP6C leads to inactivation.PTM 'Lys-48'-linked polyubiquitination at Lys-72 is induced by TNFalpha, and leads to proteasomal degradation. Undergoes 'Lys-48'-linked polyubiquitination catalyzed by ITCH (By similarity). Requires 'Lys-63'-linked polyubiquitination for autophosphorylation and subsequent activation. 'Lys-63'-linked ubiquitination does not lead to proteasomal degradation. Deubiquitinated by CYLD, a protease that selectively cleaves 'Lys-63'-linked ubiquitin chains. Deubiquitinated by Y.enterocolitica YopP.PTM (Microbial infection) Cleaved and inactivated by the proteases 3C of coxsackievirus A16 and human enterovirus D68, allowing the virus to disrupt TRAF6-triggered NF-kappa-B induction.PTM (Microbial infection) Acetylation of Thr-184 and Thr-187 by Yersinia YopJ prevents phosphorylation and activation, thus blocking the MAPK signaling pathway.SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily. UniProt O43318 1 EQUAL 606 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 446874 1 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] UniProt Q9NYJ8 UniProt Q8N5C8 Reactome Database ID Release 81 450277 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450277 Reactome R-HSA-450277 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-HSA-450277.2 Reactome DB_ID: 177689 1 viral dsRNA:TLR3:TRIF:polyUb-TRAF6:TAK1:TAB1:TAB2/TAB3: free polyUb chain [endosome membrane] viral dsRNA:TLR3:TRIF:polyUb-TRAF6:TAK1:TAB1:TAB2/TAB3: free polyUb chain Reactome DB_ID: 450271 2 K63polyUb [endosome membrane] K63polyUb K63-polyubiquitin K63 Ligated polyubiquitin Chain Converted from EntitySet in Reactome Reactome DB_ID: 975101 2 TAB2/3 [endosome membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity TAB2 [endosome membrane] TAB3 [endosome membrane] Reactome DB_ID: 450315 2 1 EQUAL 606 EQUAL Reactome DB_ID: 450309 1 Reactome DB_ID: 450238 2 1 EQUAL 504 EQUAL Reactome Database ID Release 81 177689 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=177689 Reactome R-HSA-177689 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-HSA-177689.2 Reactome Database ID Release 81 177690 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=177690 Reactome R-HSA-177690 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-HSA-177690.3 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 15327770 Pubmed 2004 TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains Kanayama, A Seth, RB Sun, L Ea, CK Hong, M Shaito, A Chiu, YH Deng, L Chen, ZJ Mol Cell 15:535-48 17496917 Pubmed 2007 Ubiquitin-mediated activation of TAK1 and IKK Adhikari, A Xu, M Chen, ZJ Oncogene 26:3214-26 2.7.11 Activation of recruited TAK1 within the activated TLR3 complex Activation of recruited TAK1 within the activated TLR3 complex TAK1 complex consists of transforming growth factor-beta (TGFB)-activated kinase (TAK1) and TAK1-binding protein 1 (TAB1), TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Shibuya et al. 1996, Sakurai et al. 2000). TAB1 promotes TAK1 autophosphorylation at the kinase activation lobe, probably through an allosteric mechanism (Brown et al. 2005, Ono et al. 2001). The TAK1 complex is regulated by polyubiquitination. Binding of TAB2 and TAB3 to Lys63-linked polyubiquitin chains leads to the activation of TAK1 by an uncertain mechanism. Binding of multiple TAK1 complexes to the same polyubiquitin chain may promote oligomerization of TAK1, facilitating TAK1 autophosphorylation and subsequent activation of its kinase activity (Kishimoto et al. 2000). The binding of TAB2/3 to polyubiquitinated TRAF6 may facilitate polyubiquitination of TAB2/3 by TRAF6 (Ishitani et al. 2003), which might result in conformational changes within the TAK1 complex that lead to TAK1 activation. Another possibility is that TAB2/3 may recruit the IKK complex by binding to ubiquitinated NEMO; polyubiquitin chains may function as a scaffold for higher order signaling complexes that allow interaction between TAK1 and IKK (Kanayama et al. 2004). Authored: Shamovsky, V, 2009-12-16 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Edited: Shamovsky, V, 2009-12-16 Reactome DB_ID: 177689 1 Reactome DB_ID: 113592 4 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 177691 1 viral dsRNA:TLR3:TRIF:pUb-TRAF6:TAB1:TAB2,TAB3:free polyUb: p-TAK1 [endosome membrane] viral dsRNA:TLR3:TRIF:pUb-TRAF6:TAB1:TAB2,TAB3:free polyUb: p-TAK1 Reactome DB_ID: 450271 2 Converted from EntitySet in Reactome Reactome DB_ID: 975101 2 Reactome DB_ID: 450309 1 Reactome DB_ID: 450332 2 O-phospho-L-threonine at 184 184 EQUAL O-phospho-L-threonine [MOD:00047] O-phospho-L-threonine at 187 187 EQUAL 1 EQUAL 606 EQUAL Reactome DB_ID: 450238 2 1 EQUAL 504 EQUAL Reactome Database ID Release 81 177691 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=177691 Reactome R-HSA-177691 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-HSA-177691.2 Reactome DB_ID: 29370 4 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: 177689 GO 0008349 GO molecular function Reactome Database ID Release 81 450212 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450212 Reactome Database ID Release 81 177692 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=177692 Reactome R-HSA-177692 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-HSA-177692.2 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 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 10702308 Pubmed 2000 TAK1 mitogen-activated protein kinase kinase kinase is activated by autophosphorylation within its activation loop Kishimoto, K Matsumoto, K Ninomiya-Tsuji, J J Biol Chem 275:7359-64 14633987 Pubmed 2003 Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling Ishitani, T Takaesu, G Ninomiya-Tsuji, J Shibuya, H Gaynor, RB Matsumoto, K EMBO J 22:6277-88 Phosphorylated TAK1 dissociates from the TLR3 receptor complex Phosphorylated TAK1 dissociates from the TLR3 receptor complex Phosphorylated TAK1 complexed with TRAF6-TAB1-TAB2/TAB3 leaves the activated TLR4 complex and translocates to the cytosol Authored: Shamovsky, V, 2010-05-21 Reviewed: Gillespie, ME, 2010-05-28 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Edited: Shamovsky, V, 2010-05-21 Reactome DB_ID: 177691 1 Reactome DB_ID: 847073 1 K63pUb-TRAF6:TAB1:TAB2,TAB3:free pUb:p-T-TAK1 [cytosol] K63pUb-TRAF6:TAB1:TAB2,TAB3:free pUb:p-T-TAK1 Reactome DB_ID: 2685681 1 ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 124 124 EQUAL 1 EQUAL 522 EQUAL Reactome DB_ID: 202527 2 O-phospho-L-threonine at 184 184 EQUAL O-phospho-L-threonine at 187 187 EQUAL 1 EQUAL 606 EQUAL Reactome DB_ID: 450152 2 Reactome DB_ID: 167923 2 1 EQUAL 504 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 446874 2 Reactome Database ID Release 81 847073 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=847073 Reactome R-HSA-847073 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-847073.4 Reactome DB_ID: 168907 1 Reactome Database ID Release 81 847070 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=847070 Reactome R-HSA-847070 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-HSA-847070.2 12242293 Pubmed 2002 Interleukin-1 (IL-1) receptor-associated kinase-dependent IL-1-induced signaling complexes phosphorylate TAK1 and TAB2 at the plasma membrane and activate TAK1 in the cytosol Jiang, Z Ninomiya-Tsuji, J Qian, Y Matsumoto, K Li, X Mol Cell Biol 22:7158-67 Reactome Database ID Release 81 9014325 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9014325 Reactome R-HSA-9014325 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-HSA-9014325.3 GO 0007249 GO biological process