TRAF6

TRAF6
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1LB4, 1LB5, 1LB6, 2ECI, 2JMD, 3HCS, 3HCT, 3HCU, 4Z8M
Identifiers
Aliases	TRAF6, MGC:3310, RNF85, TNF receptor associated factor 6
External IDs	OMIM: 602355 MGI: 108072 HomoloGene: 3395 GeneCards: TRAF6
Gene location (Human) Chr. Chromosome 11 (human)[1] Band 11p12 Start 36,483,769 bp[1] End 36,510,272 bp[1]
Gene location (Mouse) Chr. Chromosome 2 (mouse)[2] Band 2|2 E2 Start 101,678,429 bp[2] End 101,701,669 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • protein N-terminus binding • histone deacetylase binding • GO:1904264, GO:1904822, GO:0090622, GO:0090302 ubiquitin protein ligase activity • metal ion binding • mitogen-activated protein kinase kinase kinase binding • zinc ion binding • GO:0001948 protein binding • thioesterase binding • ubiquitin conjugating enzyme binding • protein kinase binding • protein kinase B binding • ubiquitin-protein transferase activity • identical protein binding • ubiquitin protein ligase binding • transferase activity • tumor necrosis factor receptor binding Cellular component • cytoplasm • cytosol • lipid droplet • perinuclear region of cytoplasm • cytoplasmic side of plasma membrane • cell nucleus • cell membrane • cell cortex • endosome membrane • CD40 receptor complex • macromolecular complex Biological process • positive regulation of transcription regulatory region DNA binding • response to interleukin-1 • toll-like receptor signaling pathway • Fc-epsilon receptor signaling pathway • odontogenesis of dentin-containing tooth • positive regulation of interleukin-12 biosynthetic process • animal organ morphogenesis • T-helper 1 type immune response • toll-like receptor 9 signaling pathway • regulation of apoptotic process • ossification • regulation of immunoglobulin secretion • cytokine-mediated signaling pathway • osteoclast differentiation • positive regulation of osteoclast differentiation • stimulatory C-type lectin receptor signaling pathway • activation of NF-kappaB-inducing kinase activity • bone resorption • JNK cascade • membrane protein intracellular domain proteolysis • protein ubiquitination • positive regulation of T cell proliferation • I-kappaB kinase/NF-kappaB signaling • protein autoubiquitination • immune system process • positive regulation of JUN kinase activity • positive regulation of sequence-specific DNA binding transcription factor activity • protein polyubiquitination • negative regulation of apoptotic process • negative regulation of transcription from RNA polymerase II promoter • positive regulation of interleukin-6 biosynthetic process • positive regulation of lipopolysaccharide-mediated signaling pathway • activation of MAPK activity • positive regulation of NF-kappaB transcription factor activity • positive regulation of interleukin-2 production • positive regulation of T cell cytokine production • immune response • negative regulation of transcription, DNA-templated • nucleotide-binding oligomerization domain containing signaling pathway • positive regulation of protein ubiquitination • positive regulation of smooth muscle cell proliferation • antigen processing and presentation of exogenous peptide antigen via MHC class II • cell development • protein K63-linked ubiquitination • myeloid dendritic cell differentiation • MyD88-dependent toll-like receptor signaling pathway • neural tube closure • bone remodeling • positive regulation of apoptotic process • positive regulation of I-kappaB kinase/NF-kappaB signaling • cellular response to lipopolysaccharide • T cell receptor signaling pathway • activation of protein kinase activity • positive regulation of transcription from RNA polymerase II promoter • signal transduction • cellular response to DNA damage stimulus • protein deubiquitination • regulation of I-kappaB kinase/NF-kappaB signaling • interleukin-1-mediated signaling pathway • cellular response to cytokine stimulus • positive regulation of NIK/NF-kappaB signaling • positive regulation of leukocyte adhesion to vascular endothelial cell Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	7189	22034
Ensembl	ENSG00000175104	ENSMUSG00000027164
UniProt	Q9Y4K3	P70196
RefSeq (mRNA)	NM_145803 NM_004620	NM_009424 NM_001303273
RefSeq (protein)	NP_004611 NP_665802	NP_001290202 NP_033450
Location (UCSC)	Chr 11: 36.48 – 36.51 Mb	Chr 2: 101.68 – 101.7 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

TRAF6 is a TRAF human protein.

Function

The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins are associated with, and mediate signal transduction from members of the TNF receptor superfamily. This protein mediates the signaling not only from the members of the TNF receptor superfamily, but also from the members of the Toll/IL-1 family. Signals from receptors such as CD40, TNFSF11/TRANCE/RANKL and IL-1 have been shown to be mediated by this protein. This protein also interacts with various protein kinases including IRAK1/IRAK, SRC and PKCzeta, which provides a link between distinct signaling pathways. This protein functions as a signal transducer in the NF-kappaB pathway that activates IkappaB kinase (IKK) in response to proinflammatory cytokines. The interaction of this protein with UBE2N/UBC13, and UBE2V1/UEV1A, which are ubiquitin conjugating enzymes catalyzing the formation of polyubiquitin chains, has been found to be required for IKK activation by this protein. Two alternatively spliced transcript variants encoding identical proteins have been reported.[5]

Signaling pathway of toll-like receptors. Dashed grey lines represent unknown associations

Interactions

TRAF6 has been shown to interact with:

• ASK1,[6][7][8]
• CD40,[9][10]
• FHL2,[11]
• HSPB2,[12]
• IKBKG,[13][14]
• IRAK1,[15][16][17][18][19][20][21][22][23]
• IRAK2,[16][17]
• MAP3K7IP1,[24][25][26]
• MAP3K7IP2,[13][23][24][25][27][28]
• MAP3K7[8][23][24][25][26][27][29]
• PPP4C,[30]
• RANK,[31][32][33][34][35]
• SDCBP,[15]
• SIGIRR,[36]
• Sequestosome 1,[37]
• TAX1BP1,[22]
• TNFAIP3,[38][39]
• TNFRSF13B,[40]
• UBE2N,[41] and
• Ubiquitin C.[14][28][30][42][43]

Model organisms

Model organisms have been used in the study of TRAF6 function. A conditional knockout mouse line called Traf6^{tm2a(EUCOMM)Wtsi} was generated at the Wellcome Trust Sanger Institute.[44] Male and female animals underwent a standardized phenotypic screen[45] to determine the effects of deletion.[46][47][48][49] Additional screens performed: - In-depth immunological phenotyping[50]

Traf6 knockout mouse phenotype

Characteristic	Phenotype
All data available at.[45][50]
Peripheral blood leukocytes 6 Weeks	Normal
Insulin	Normal
Haematology 6 Weeks	Normal
Homozygous viability at P14	Abnormal
Recessive lethal study	Abnormal
Body weight	Normal
Neurological assessment	Normal
Grip strength	Normal
Dysmorphology	Normal
Indirect calorimetry	Normal
Glucose tolerance test	Normal
Auditory brainstem response	Normal
DEXA	Normal
Radiography	Normal
Eye morphology	Normal
Clinical chemistry	Normal
Haematology 16 Weeks	Normal
Peripheral blood leukocytes 16 Weeks	Normal
Heart weight	Normal
Salmonella infection	Normal
Cytotoxic T Cell Function	Normal
Spleen Immunophenotyping	Normal
Mesenteric Lymph Node Immunophenotyping	Normal
Epidermal Immune Composition	Normal

References

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2. GRCm38: Ensembl release 89: ENSMUSG00000027164 - Ensembl, May 2017
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4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: TRAF6 TNF receptor-associated factor 6".
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18. Qian Y, Commane M, Ninomiya-Tsuji J, Matsumoto K, Li X (November 2001). "IRAK-mediated translocation of TRAF6 and TAB2 in the interleukin-1-induced activation of NFkappa B". J. Biol. Chem. 276 (45): 41661–7. doi:10.1074/jbc.M102262200. PMID 11518704.
19. Cao Z, Xiong J, Takeuchi M, Kurama T, Goeddel DV (October 1996). "TRAF6 is a signal transducer for interleukin-1". Nature. 383 (6599): 443–6. doi:10.1038/383443a0. PMID 8837778.
20. Takatsuna H, Kato H, Gohda J, Akiyama T, Moriya A, Okamoto Y, Yamagata Y, Otsuka M, Umezawa K, Semba K, Inoue J (April 2003). "Identification of TIFA as an adapter protein that links tumor necrosis factor receptor-associated factor 6 (TRAF6) to interleukin-1 (IL-1) receptor-associated kinase-1 (IRAK-1) in IL-1 receptor signaling". J. Biol. Chem. 278 (14): 12144–50. doi:10.1074/jbc.M300720200. PMID 12566447.
21. Li S, Strelow A, Fontana EJ, Wesche H (April 2002). "IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase". Proc. Natl. Acad. Sci. U.S.A. 99 (8): 5567–72. doi:10.1073/pnas.082100399. PMC 122810. PMID 11960013.
22. Ling L, Goeddel DV (August 2000). "T6BP, a TRAF6-interacting protein involved in IL-1 signaling". Proc. Natl. Acad. Sci. U.S.A. 97 (17): 9567–72. doi:10.1073/pnas.170279097. PMC 16905. PMID 10920205.
23. Takaesu G, Ninomiya-Tsuji J, Kishida S, Li X, Stark GR, Matsumoto K (April 2001). "Interleukin-1 (IL-1) receptor-associated kinase leads to activation of TAK1 by inducing TAB2 translocation in the IL-1 signaling pathway". Mol. Cell. Biol. 21 (7): 2475–84. doi:10.1128/MCB.21.7.2475-2484.2001. PMC 86880. PMID 11259596.
24. Takaesu G, Kishida S, Hiyama A, Yamaguchi K, Shibuya H, Irie K, Ninomiya-Tsuji J, Matsumoto K (April 2000). "TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway". Mol. Cell. 5 (4): 649–58. doi:10.1016/s1097-2765(00)80244-0. PMID 10882101.
25. Walsh MC, Kim GK, Maurizio PL, Molnar EE, Choi Y (2008). Unutmaz D (ed.). "TRAF6 autoubiquitination-independent activation of the NFkappaB and MAPK pathways in response to IL-1 and RANKL". PLoS ONE. 3 (12): e4064. doi:10.1371/journal.pone.0004064. PMC 2603309. PMID 19112497.
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29. Sorrentino A, Thakur N, Grimsby S, Marcusson A, von Bulow V, Schuster N, Zhang S, Heldin CH, Landström M (October 2008). "The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner". Nat. Cell Biol. 10 (10): 1199–207. doi:10.1038/ncb1780. PMID 18758450.
30. Chen L, Dong W, Zou T, Ouyang L, He G, Liu Y, Qi Y (August 2008). "Protein phosphatase 4 negatively regulates LPS cascade by inhibiting ubiquitination of TRAF6". FEBS Lett. 582 (19): 2843–9. doi:10.1016/j.febslet.2008.07.014. PMID 18634786.
31. Mizukami J, Takaesu G, Akatsuka H, Sakurai H, Ninomiya-Tsuji J, Matsumoto K, Sakurai N (February 2002). "Receptor activator of NF-kappaB ligand (RANKL) activates TAK1 mitogen-activated protein kinase kinase kinase through a signaling complex containing RANK, TAB2, and TRAF6". Mol. Cell. Biol. 22 (4): 992–1000. doi:10.1128/mcb.22.4.992-1000.2002. PMC 134634. PMID 11809792.
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33. Darnay BG, Ni J, Moore PA, Aggarwal BB (March 1999). "Activation of NF-kappaB by RANK requires tumor necrosis factor receptor-associated factor (TRAF) 6 and NF-kappaB-inducing kinase. Identification of a novel TRAF6 interaction motif". J. Biol. Chem. 274 (12): 7724–31. doi:10.1074/jbc.274.12.7724. PMID 10075662.
34. Galibert L, Tometsko ME, Anderson DM, Cosman D, Dougall WC (Dec 1998). "The involvement of multiple tumor necrosis factor receptor (TNFR)-associated factors in the signaling mechanisms of receptor activator of NF-kappaB, a member of the TNFR superfamily". J. Biol. Chem. 273 (51): 34120–7. doi:10.1074/jbc.273.51.34120. PMID 9852070.
35. Kim HH, Lee DE, Shin JN, Lee YS, Jeon YM, Chung CH, Ni J, Kwon BS, Lee ZH (January 1999). "Receptor activator of NF-kappaB recruits multiple TRAF family adaptors and activates c-Jun N-terminal kinase". FEBS Lett. 443 (3): 297–302. doi:10.1016/s0014-5793(98)01731-1. PMID 10025951.
36. Wald D, Qin J, Zhao Z, Qian Y, Naramura M, Tian L, Towne J, Sims JE, Stark GR, Li X (September 2003). "SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling". Nat. Immunol. 4 (9): 920–7. doi:10.1038/ni968. PMID 12925853.
37. Sanz L, Diaz-Meco MT, Nakano H, Moscat J (April 2000). "The atypical PKC-interacting protein p62 channels NF-kappaB activation by the IL-1-TRAF6 pathway". EMBO J. 19 (7): 1576–86. doi:10.1093/emboj/19.7.1576. PMC 310227. PMID 10747026.
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Further reading

• Wajant H, Henkler F, Scheurich P (2001). "The TNF-receptor-associated factor family: scaffold molecules for cytokine receptors, kinases and their regulators". Cell. Signal. 13 (6): 389–400. doi:10.1016/S0898-6568(01)00160-7. PMID 11384837.
• Vlantis K, Polykratis A, Welz PS, van Loo G, Pasparakis M, Wullaert A (2016). "TLR-independent anti-inflammatory function of intestinal epithelial TRAF6 signalling prevents DSS-induced colitis in mice". Gut. 65 (6): 935–43. doi:10.1136/gutjnl-2014-308323. PMC 4893119. PMID 25761602.
• Bradley JR, Pober JS (2001). "Tumor necrosis factor receptor-associated factors (TRAFs)". Oncogene. 20 (44): 6482–91. doi:10.1038/sj.onc.1204788. PMID 11607847.
• Tanaka S, Nakamura K, Takahasi N, Suda T (2006). "Role of RANKL in physiological and pathological bone resorption and therapeutics targeting the RANKL-RANK signaling system". Immunol. Rev. 208: 30–49. doi:10.1111/j.0105-2896.2005.00327.x. PMID 16313339.

External links

• TRAF6 at the US National Library of Medicine Medical Subject Headings (MeSH)