ID:TRAF6_HUMAN DESCRIPTION: RecName: Full=TNF receptor-associated factor 6; EC=6.3.2.-; AltName: Full=E3 ubiquitin-protein ligase TRAF6; AltName: Full=Interleukin-1 signal transducer; AltName: Full=RING finger protein 85; 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, AKT1 and AKT2. Also mediates ubiquitination of free/unanchored polyubiquitin chain that leads to MAP3K7 activation. Leads to the activation of NF- kappa-B and JUN. May be essential for the formation of functional osteoclasts. Seems to also play a role in dendritic cells (DCs) maturation and/or activation. Represses c-Myb-mediated transactivation, in B-lymphocytes. Adapter protein that seems to play a role in signal transduction initiated via TNF receptor, IL- 1 receptor and IL-17 receptor. Regulates osteoclast differentiation by mediating the activation of adapter protein complex 1 (AP-1) and NF-kappa-B, in response to RANK-L stimulation. 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. Binds to TNFRSF5/CD40 and TNFRSF11A/RANK. Associates with NGFR, TNFRSF17, IRAK1, IRAK2, IRAK3, IRAK4, 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 PELI1, PELI2 and PELI3. Binds UBE2V1. Interacts with MAVS/IPS1. Interacts with TAX1BP1. Interacts with IL1RL1. Interacts with TRAFD1. Interacts with ZNF675. Interacts with AJUBA. Interacts with TICAM1 and TICAM2. Interacts with ZFAND5. 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 (via TRAF domains) with WDR34 (via WD domains). Interacts with RBCK1. Interacts with TRAF3IP2. Interacts with LIMD1 (via LIM domains) (By similarity). Interacts with RSAD2/viperin (By similarity). Interacts with IFIT3 (via N-terminus). INTERACTION: P25942:CD40; NbExp=2; IntAct=EBI-359276, EBI-525714; Q9QZH6:Ecsit (xeno); NbExp=2; IntAct=EBI-359276, EBI-527020; P14778:IL1R1; NbExp=2; IntAct=EBI-359276, EBI-525905; P51617:IRAK1; NbExp=3; IntAct=EBI-359276, EBI-358664; O43187:IRAK2; NbExp=3; IntAct=EBI-359276, EBI-447733; P07174:Ngfr (xeno); NbExp=2; IntAct=EBI-359276, EBI-1038810; Q9BVN2-2:RUSC1; NbExp=2; IntAct=EBI-359276, EBI-6257338; Q86VP1:TAX1BP1; NbExp=3; IntAct=EBI-359276, EBI-529518; P51668:UBE2D1; NbExp=2; IntAct=EBI-359276, EBI-743540; P62837:UBE2D2; NbExp=2; IntAct=EBI-359276, EBI-347677; P61077:UBE2D3; NbExp=2; IntAct=EBI-359276, EBI-348268; P61088:UBE2N; NbExp=3; IntAct=EBI-359276, EBI-1052908; Q01220:VACWR178 (xeno); NbExp=2; IntAct=EBI-359276, EBI-3863691; Q8TD23:ZNF675; NbExp=4; IntAct=EBI-359276, EBI-528190; SUBCELLULAR LOCATION: Cytoplasm. Cytoplasm, cell cortex. Nucleus. Lipid droplet (By similarity). Note=Found in the nuclei of some agressive B-cell lymphoma cell lines as well as in the nuclei of both resting and activated T- and B-lymphocytes. Found in punctate nuclear body protein complexes. Ubiquitination may occur in the cytoplasm and sumoylation in the nucleus. RSAD2/viperin recruits it to the lipid droplet (By similarity). 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; after cell stimulation with IL- 1-beta or TGF-beta. 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. SIMILARITY: Belongs to the TNF receptor-associated factor family. A subfamily. SIMILARITY: Contains 1 MATH domain. SIMILARITY: Contains 1 RING-type zinc finger. SIMILARITY: Contains 2 TRAF-type zinc fingers. WEB RESOURCE: Name=SeattleSNPs; URL="http://pga.gs.washington.edu/data/traf6/";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on Q9Y4K3
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Gene Ontology (GO) Annotations with Structured Vocabulary
Molecular Function: GO:0004842 ubiquitin-protein transferase activity GO:0005164 tumor necrosis factor receptor binding GO:0005515 protein binding GO:0008270 zinc ion binding GO:0016740 transferase activity GO:0019901 protein kinase binding GO:0031435 mitogen-activated protein kinase kinase kinase binding GO:0031624 ubiquitin conjugating enzyme binding GO:0031625 ubiquitin protein ligase binding GO:0031996 thioesterase binding GO:0042802 identical protein binding GO:0042826 histone deacetylase binding GO:0043422 protein kinase B binding GO:0046872 metal ion binding GO:0047485 protein N-terminus binding GO:0061630 ubiquitin protein ligase activity
Biological Process: GO:0000122 negative regulation of transcription from RNA polymerase II promoter GO:0000187 activation of MAPK activity GO:0000209 protein polyubiquitination GO:0001503 ossification GO:0001843 neural tube closure GO:0002223 stimulatory C-type lectin receptor signaling pathway GO:0002224 toll-like receptor signaling pathway GO:0002376 immune system process GO:0002726 positive regulation of T cell cytokine production GO:0002755 MyD88-dependent toll-like receptor signaling pathway GO:0006955 immune response GO:0006974 cellular response to DNA damage stimulus GO:0007165 signal transduction GO:0007249 I-kappaB kinase/NF-kappaB signaling GO:0007250 activation of NF-kappaB-inducing kinase activity GO:0007254 JNK cascade GO:0009887 animal organ morphogenesis GO:0016567 protein ubiquitination GO:0016579 protein deubiquitination GO:0019221 cytokine-mediated signaling pathway GO:0019886 antigen processing and presentation of exogenous peptide antigen via MHC class II GO:0030316 osteoclast differentiation GO:0031293 membrane protein intracellular domain proteolysis GO:0031398 positive regulation of protein ubiquitination GO:0031666 positive regulation of lipopolysaccharide-mediated signaling pathway GO:0032147 activation of protein kinase activity GO:0032743 positive regulation of interleukin-2 production GO:0034162 toll-like receptor 9 signaling pathway GO:0038095 Fc-epsilon receptor signaling pathway GO:0042088 T-helper 1 type immune response GO:0042102 positive regulation of T cell proliferation GO:0042475 odontogenesis of dentin-containing tooth GO:0042981 regulation of apoptotic process GO:0043011 myeloid dendritic cell differentiation GO:0043065 positive regulation of apoptotic process GO:0043066 negative regulation of apoptotic process GO:0043122 regulation of I-kappaB kinase/NF-kappaB signaling GO:0043123 positive regulation of I-kappaB kinase/NF-kappaB signaling GO:0043507 positive regulation of JUN kinase activity GO:0045084 positive regulation of interleukin-12 biosynthetic process GO:0045410 positive regulation of interleukin-6 biosynthetic process GO:0045453 bone resorption GO:0045672 positive regulation of osteoclast differentiation GO:0045892 negative regulation of transcription, DNA-templated GO:0045944 positive regulation of transcription from RNA polymerase II promoter GO:0046849 bone remodeling GO:0048468 cell development GO:0048661 positive regulation of smooth muscle cell proliferation GO:0050852 T cell receptor signaling pathway GO:0051023 regulation of immunoglobulin secretion GO:0051091 positive regulation of sequence-specific DNA binding transcription factor activity GO:0051092 positive regulation of NF-kappaB transcription factor activity GO:0051865 protein autoubiquitination GO:0070423 nucleotide-binding oligomerization domain containing signaling pathway GO:0070498 interleukin-1-mediated signaling pathway GO:0070534 protein K63-linked ubiquitination GO:0070555 response to interleukin-1 GO:0071222 cellular response to lipopolysaccharide GO:2000679 positive regulation of transcription regulatory region DNA binding
AK128396 - Homo sapiens cDNA FLJ46539 fis, clone THYMU3037836. JD100555 - Sequence 81579 from Patent EP1572962. JD452280 - Sequence 433304 from Patent EP1572962. JD378239 - Sequence 359263 from Patent EP1572962. JD455086 - Sequence 436110 from Patent EP1572962. JD229825 - Sequence 210849 from Patent EP1572962. JD221888 - Sequence 202912 from Patent EP1572962. JD135926 - Sequence 116950 from Patent EP1572962. JD194729 - Sequence 175753 from Patent EP1572962. JD430821 - Sequence 411845 from Patent EP1572962. JD558283 - Sequence 539307 from Patent EP1572962. BC031052 - Homo sapiens TNF receptor-associated factor 6, mRNA (cDNA clone MGC:33100 IMAGE:5272008), complete cds. FW573284 - JP 2010529847-A/5: Oligonucleotides for modulation of target RNA activity. U78798 - Human TNF receptor associated factor 6 (TRAF6) mRNA, complete cds. JD102375 - Sequence 83399 from Patent EP1572962. AK292978 - Homo sapiens cDNA FLJ75865 complete cds, highly similar to Homo sapiens TNF receptor-associated factor 6 (TRAF6), transcript variant 2, mRNA. JD112947 - Sequence 93971 from Patent EP1572962. JD051743 - Sequence 32767 from Patent EP1572962. JD131610 - Sequence 112634 from Patent EP1572962. JD059494 - Sequence 40518 from Patent EP1572962. DQ891209 - Synthetic construct clone IMAGE:100003839; FLH170176.01X; RZPDo839C0798D TNF receptor-associated factor 6 (TRAF6) gene, encodes complete protein. DQ894392 - Synthetic construct Homo sapiens clone IMAGE:100008852; FLH170172.01L; RZPDo839C0797D TNF receptor-associated factor 6 (TRAF6) gene, encodes complete protein. AB385137 - Synthetic construct DNA, clone: pF1KB5633, Homo sapiens TRAF6 gene for TNF receptor-associated factor 6, complete cds, without stop codon, in Flexi system. KJ901053 - Synthetic construct Homo sapiens clone ccsbBroadEn_10447 TRAF6 gene, encodes complete protein. JD244832 - Sequence 225856 from Patent EP1572962. JD544267 - Sequence 525291 from Patent EP1572962. JD190359 - Sequence 171383 from Patent EP1572962. JD195737 - Sequence 176761 from Patent EP1572962.
Biochemical and Signaling Pathways
BioCarta from NCI Cancer Genome Anatomy Project h_il1rPathway - Signal transduction through IL1R h_nfkbPathway - NF-kB Signaling Pathway h_ranklPathway - Bone Remodelling h_tall1Pathway - TACI and BCMA stimulation of B cell immune responses. h_tollPathway - Toll-Like Receptor Pathway h_RELAPathway - Acetylation and Deacetylation of RelA in The Nucleus h_cd40Pathway - CD40L Signaling Pathway
Reactome (by CSHL, EBI, and GO)
Protein Q9Y4K3 (Reactome details) participates in the following event(s):
R-HSA-166363 TRAF6 binds to hp- IRAK1 R-HSA-166869 TRAF6 binds MEKK1 R-HSA-177694 Viral dsRNA:TLR3:TICAM1 complex recruits TRAF6 R-HSA-193695 IRAK interacts with TRAF6 R-HSA-193700 p75NTR ICD signals to NF-kB R-HSA-202472 Translocation of TRAF6 to CBM complex R-HSA-446862 Hyperphosphorylated IRAK1 associates with TRAF6 R-HSA-450173 IRAK1 induces oligomerisation of TRAF6 R-HSA-507719 p62:MEKK3 binds to TRAF6 R-HSA-936963 IRAK2 induces TRAF6 oligomerization R-HSA-936985 Activated TLR4:TICAM1 recruits TRAF6 R-HSA-975111 TRAF6 binds to hp- IRAK1/or p-IRAK2:p-IRAK4:MyD88:activated TLR7/8 or 9 R-HSA-975185 IRAK2 induces TRAF6 oligomerization initiated from endosomal compartments R-HSA-975857 TRAF6 binds to hp- IRAK1 or p-IRAK2 R-HSA-2262777 TRAF6 binds to p-IRAK2 R-HSA-2730864 Recruitment of TRAF6 to CBM complex by binding to MALT1 R-HSA-5607747 TRAF6 binds MALT1 oligomers R-HSA-202453 Auto-ubiquitination of TRAF6 R-HSA-193703 IKKbeta is activated R-HSA-193694 p62 is recruited and forms a complex with TRAF6 R-HSA-193665 MYD88 dissociates R-HSA-193669 TRAF6 binds to p75NTR:NRIF R-HSA-205112 gamma-secretase cleaves p75NTR, releasing NRIF and TRAF6 R-HSA-446894 TRAF6 binding leads to IRAK1:TRAF6 release R-HSA-8948015 hp-IRAK1:3xTRAF6 binds UBE2N:UBE2V1:K63-polyUb R-HSA-937032 NEMO subunit of IKK complex binds to activated IRAK1 R-HSA-937050 Pellino ubiquitinates hp-IRAK1 R-HSA-5690870 OTUD7B,TNFAIP3 deubiquitinate TRAF6 R-HSA-8869506 TNFAIP3 in OTUD7B:TNFAIP3:ZRANB1 deubiquitinates K63polyUb-TRAF6 R-HSA-918230 Recruitment of TRAF6/TRAF2 to IPS-1 R-HSA-8869456 USP4 deubiquitinate TRAF2,TRAF6 R-HSA-5690843 OTUB1, (OTUB2) binds RNF128, TRAF3, TRAF6, RHOA R-HSA-5696627 CYLD deubiquitinates K63polyUb-TRAF2,K63polyUb-TRAF6,K63polyUb-RIPK1,K63polyUb-IKBKG R-HSA-177690 Activated TLR3:TRIF:K63pUb-TRAF6 recruits TAK1complex R-HSA-975097 Activated TRAF6:p-IRAK2 interacts with TAK1 complex upon TLR7/8 or 9 stimulation R-HSA-975100 Dissociation of hp-IRAK1/or IRAK2:TRAF6-oligomer from the p-IRAK4 :oligo-Myd88:activated TLR7/8 or 9 complex R-HSA-975188 TRAF6 interacts with IRF7 upon TLR7/8 or 9 activation R-HSA-975106 Phosphorylation and release of IRF7 upon TLR7/8 or 9 activation R-HSA-975142 Pellino binds hp-IRAK1:TRAF6 upon TLR7/8 or 9 activation R-HSA-975119 NEMO subunit of IKK complex binds to activated IRAK1 upon stimulation of TLR7/8 or 9. R-HSA-975122 Pellino ubiquitinates hp-IRAK1 upon TLR7/8 or 9 activation
R-HSA-2262775 Dissociation of p-IRAK2:TRAF6 from the activated TLR:oligo-Myd88:Mal:p-IRAK4 complex R-HSA-937044 Pellino binds hp-IRAK1:TRAF6 R-HSA-166362 Dissociation of hp-IRAK1:TRAF6 from the activated TLR:oligo-Myd88:Mal:p-IRAK4 complex R-HSA-975879 Dissociation of hp-IRAK1:TRAF6 or IRAK2:TRAF6-oligomer from the activated TLR5 or 10:oligo-Myd88:p-IRAK4 complex R-HSA-936960 Activated TRAF6:p-IRAK2 interacts with TAK1 complex R-HSA-202510 Activation of TAK1-TAB2 complex R-HSA-446877 TRAF6 is K63 poly-ubiquitinated R-HSA-847070 Phosphorylated TAK1 dissociates from the TLR3 receptor complex R-HSA-937075 Phosphorylated TAK1 leaves activated TLR receptor complex R-HSA-936947 Activated TLR4:TICAM1:K63pUb-TRAF6 recruits TAK1complex R-HSA-446870 Polyubiquitinated TRAF6 binds the TAK1 complex R-HSA-193705 IKKbeta phosphorylates IkB causing NF-kB to dissociate R-HSA-193641 IKK-beta is recruited R-HSA-193684 p62 recruits an atypical PKC R-HSA-205118 TRAF6 polyubiquitinates NRIF R-HSA-741386 RIP2 induces K63-linked ubiquitination of NEMO R-HSA-177692 Activation of recruited TAK1 within the activated TLR3 complex R-HSA-975103 Auto phosphorylation of TAK1 bound to p-IRAK2:pUb oligo-TRAF6: free K63 pUb:TAB1:TAB2/TAB3 upon TLR7/8 or 9 activation R-HSA-975118 TRAF6 ubiquitinqtes IRF7 in a K63-dependent manner following TLR7/8 or 9 stimulation R-HSA-975139 IRAK1 phosphorylates Pellino upon TLR7/8 or 9 activation R-HSA-937034 IRAK1 phosphorylates Pellino R-HSA-936991 Auto phosphorylation of TAK1 bound to p-IRAK2:pUb oligo-TRAF6: free K63 pUb:TAB1:TAB2/TAB3 R-HSA-936951 Activation of TAK1 complex bound to activated TLR4 complex R-HSA-2730861 Recruitment of TAK1 kinase complex to oligo-K63-pUb-TRAF6 R-HSA-204949 NRIF and TRAF6 may activate JNK R-HSA-688137 RIP2 is K63 polyubiquitinated R-HSA-168915 K63-linked ubiquitination of RIP1 bound to the activated TLR complex R-HSA-9014342 K63-linked ubiquitination of RIP1 bound to the activated TLR complex R-HSA-933528 Interaction of MEKK1 with TRAF6 R-HSA-933537 Recruitment of TANK to TRAF6 R-HSA-202500 Activation of IKK complex R-HSA-168184 Activated TAK1 mediates phosphorylation of the IKK Complex R-HSA-450337 Activated TAK1 phosphorylates MKK4/MKK7 R-HSA-450346 activated human TAK1 phosphorylates MKK3/MKK6 R-HSA-933527 Recruitment of TBK1/IKK epsilon complex to TANK:TRAF6 R-HSA-2730876 Phosphorylation of IKK-beta by TAK1 R-HSA-933538 Recruitment of IRF7 to TRAF6 R-HSA-933525 Phosphorylation and release of IRF7 R-HSA-933530 Activation of IKK by MEKK1 R-HSA-166058 MyD88:Mal cascade initiated on plasma membrane R-HSA-975138 TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation R-HSA-975871 MyD88 cascade initiated on plasma membrane R-HSA-9014325 TICAM1,TRAF6-dependent induction of TAK1 complex R-HSA-209543 p75NTR recruits signalling complexes R-HSA-193692 Regulated proteolysis of p75NTR R-HSA-202424 Downstream TCR signaling R-HSA-9020702 Interleukin-1 signaling R-HSA-937042 IRAK2 mediated activation of TAK1 complex R-HSA-937072 TRAF6-mediated induction of TAK1 complex within TLR4 complex R-HSA-975155 MyD88 dependent cascade initiated on endosome R-HSA-975163 IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation R-HSA-2871837 FCERI mediated NF-kB activation R-HSA-5607764 CLEC7A (Dectin-1) signaling R-HSA-209560 NF-kB is activated and signals survival R-HSA-205043 NRIF signals cell death from the nucleus R-HSA-937039 IRAK1 recruits IKK complex R-HSA-5689896 Ovarian tumor domain proteases R-HSA-933541 TRAF6 mediated IRF7 activation R-HSA-5689880 Ub-specific processing proteases R-HSA-166016 Toll Like Receptor 4 (TLR4) Cascade R-HSA-168179 Toll Like Receptor TLR1:TLR2 Cascade R-HSA-168188 Toll Like Receptor TLR6:TLR2 Cascade R-HSA-168142 Toll Like Receptor 10 (TLR10) Cascade R-HSA-168176 Toll Like Receptor 5 (TLR5) Cascade R-HSA-168164 Toll Like Receptor 3 (TLR3) Cascade R-HSA-193639 p75NTR signals via NF-kB R-HSA-193704 p75 NTR receptor-mediated signalling R-HSA-202403 TCR signaling R-HSA-446652 Interleukin-1 family signaling R-HSA-937061 TRIF(TICAM1)-mediated TLR4 signaling R-HSA-168138 Toll Like Receptor 9 (TLR9) Cascade R-HSA-168181 Toll Like Receptor 7/8 (TLR7/8) Cascade R-HSA-2454202 Fc epsilon receptor (FCERI) signaling R-HSA-5621481 C-type lectin receptors (CLRs) R-HSA-975110 TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling R-HSA-975144 IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation R-HSA-204998 Cell death signalling via NRAGE, NRIF and NADE R-HSA-168638 NOD1/2 Signaling Pathway R-HSA-5688426 Deubiquitination R-HSA-168928 DDX58/IFIH1-mediated induction of interferon-alpha/beta R-HSA-168898 Toll-Like Receptors Cascades R-HSA-181438 Toll Like Receptor 2 (TLR2) Cascade R-HSA-73887 Death Receptor Signalling R-HSA-1280218 Adaptive Immune System R-HSA-449147 Signaling by Interleukins R-HSA-166166 MyD88-independent TLR4 cascade R-HSA-168249 Innate Immune System R-HSA-937041 IKK complex recruitment mediated by RIP1 R-HSA-168927 TICAM1, RIP1-mediated IKK complex recruitment R-HSA-168643 Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways R-HSA-597592 Post-translational protein modification R-HSA-933542 TRAF6 mediated NF-kB activation R-HSA-162582 Signal Transduction R-HSA-168256 Immune System R-HSA-1280215 Cytokine Signaling in Immune system R-HSA-445989 TAK1 activates NFkB by phosphorylation and activation of IKKs complex R-HSA-450321 JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 R-HSA-450302 activated TAK1 mediates p38 MAPK activation R-HSA-392499 Metabolism of proteins R-HSA-450294 MAP kinase activation R-HSA-448424 Interleukin-17 signaling
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
