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; OMA:TRAF6 - orthologs
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 101,508,774 bp [2] End 101,532,014 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in secondary oocyte endothelial cell gonad islet of Langerhans Achilles tendon middle temporal gyrus testicle ascending aorta monocyte popliteal artery Top expressed in Ileal epithelium genital tubercle tail of embryo lumbar subsegment of spinal cord lumbar spinal ganglion granulocyte thymus ventricular zone condyle fossa More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein N-terminus binding histone deacetylase binding ubiquitin protein ligase activity metal ion binding mitogen-activated protein kinase kinase kinase binding zinc ion binding 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 nucleus plasma membrane cell cortex endosome membrane CD40 receptor complex protein-containing 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 animal organ morphogenesis T-helper 1 type immune response toll-like receptor 9 signaling pathway regulation of apoptotic process ossification 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 DNA-binding transcription factor activity protein polyubiquitination negative regulation of apoptotic process negative regulation of transcription by RNA polymerase II positive regulation of lipopolysaccharide-mediated signaling pathway 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 by RNA polymerase II 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: 101.51 – 101.53 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]}
• TAB1, ^{[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]}

References

1. GRCh38: Ensembl release 89: ENSG00000175104 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000027164 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: TRAF6 TNF receptor-associated factor 6".
6. Nishitoh H, Saitoh M, Mochida Y, Takeda K, Nakano H, Rothe M, Miyazono K, Ichijo H (September 1998). "ASK1 is essential for JNK/SAPK activation by TRAF2". Mol. Cell. 2 (3): 389–95. doi: 10.1016/s1097-2765(00)80283-x . PMID   9774977.
7. Hoeflich KP, Yeh WC, Yao Z, Mak TW, Woodgett JR (October 1999). "Mediation of TNF receptor-associated factor effector functions by apoptosis signal-regulating kinase-1 (ASK1)". Oncogene. 18 (42): 5814–20. doi:10.1038/sj.onc.1202975. PMID   10523862. S2CID   12132452.
8. Mochida Y, Takeda K, Saitoh M, Nishitoh H, Amagasa T, Ninomiya-Tsuji J, Matsumoto K, Ichijo H (October 2000). "ASK1 inhibits interleukin-1-induced NF-kappa B activity through disruption of TRAF6-TAK1 interaction". J. Biol. Chem. 275 (42): 32747–52. doi: 10.1074/jbc.M003042200 . PMID   10921914.
9. Tsukamoto N, Kobayashi N, Azuma S, Yamamoto T, Inoue J (February 1999). "Two differently regulated nuclear factor kappaB activation pathways triggered by the cytoplasmic tail of CD40". Proc. Natl. Acad. Sci. U.S.A. 96 (4): 1234–9. Bibcode:1999PNAS...96.1234T. doi: 10.1073/pnas.96.4.1234 . PMC   15446 . PMID   9990007.
10. Roy N, Deveraux QL, Takahashi R, Salvesen GS, Reed JC (Dec 1997). "The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases". EMBO J. 16 (23): 6914–25. doi:10.1093/emboj/16.23.6914. PMC   1170295 . PMID   9384571.
11. Bai S, Zha J, Zhao H, Ross FP, Teitelbaum SL (November 2008). "Tumor necrosis factor receptor-associated factor 6 is an intranuclear transcriptional coactivator in osteoclasts". J. Biol. Chem. 283 (45): 30861–7. doi: 10.1074/jbc.M802525200 . PMC   2662164 . PMID   18768464.
12. Wu Y, Liu J, Zhang Z, Huang H, Shen J, Zhang S, Jiang Y, Luo L, Yin Z (January 2009). "HSP27 regulates IL-1 stimulated IKK activation through interacting with TRAF6 and affecting its ubiquitination". Cell. Signal. 21 (1): 143–50. doi:10.1016/j.cellsig.2008.10.001. PMID   18950704.
13. Windheim M, Stafford M, Peggie M, Cohen P (March 2008). "Interleukin-1 (IL-1) induces the Lys63-linked polyubiquitination of IL-1 receptor-associated kinase 1 to facilitate NEMO binding and the activation of IkappaBalpha kinase". Mol. Cell. Biol. 28 (5): 1783–91. doi:10.1128/MCB.02380-06. PMC   2258775 . PMID   18180283.
14. Lamothe B, Campos AD, Webster WK, Gopinathan A, Hur L, Darnay BG (September 2008). "The RING domain and first zinc finger of TRAF6 coordinate signaling by interleukin-1, lipopolysaccharide, and RANKL". J. Biol. Chem. 283 (36): 24871–80. doi: 10.1074/jbc.M802749200 . PMC   2529010 . PMID   18617513.
15. Chen F, Du Y, Zhang Z, Chen G, Zhang M, Shu HB, Zhai Z, Chen D (April 2008). "Syntenin negatively regulates TRAF6-mediated IL-1R/TLR4 signaling". Cell. Signal. 20 (4): 666–74. doi:10.1016/j.cellsig.2007.12.002. PMID   18234474. S2CID   28812149.
16. Wesche H, Gao X, Li X, Kirschning CJ, Stark GR, Cao Z (July 1999). "IRAK-M is a novel member of the Pelle/interleukin-1 receptor-associated kinase (IRAK) family". J. Biol. Chem. 274 (27): 19403–10. doi: 10.1074/jbc.274.27.19403 . PMID   10383454.
17. Muzio M, Ni J, Feng P, Dixit VM (November 1997). "IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling". Science. 278 (5343): 1612–5. Bibcode:1997Sci...278.1612M. doi:10.1126/science.278.5343.1612. PMID   9374458.
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. Bibcode:1996Natur.383..443C. doi:10.1038/383443a0. PMID   8837778. S2CID   4269027.
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. Bibcode:2002PNAS...99.5567L. 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. Bibcode:2000PNAS...97.9567L. 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. Bibcode:2008PLoSO...3.4064W. doi: 10.1371/journal.pone.0004064 . PMC   2603309 . PMID   19112497.
26. Ninomiya-Tsuji J, Kishimoto K, Hiyama A, Inoue J, Cao Z, Matsumoto K (March 1999). "The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway". Nature. 398 (6724): 252–6. Bibcode:1999Natur.398..252N. doi:10.1038/18465. PMID   10094049. S2CID   4421236.
27. Ishitani T, Takaesu G, Ninomiya-Tsuji J, Shibuya H, Gaynor RB, Matsumoto K (Dec 2003). "Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling". EMBO J. 22 (23): 6277–88. doi:10.1093/emboj/cdg605. PMC   291846 . PMID   14633987.
28. Ma Q, Zhou L, Shi H, Huo K (June 2008). "NUMBL interacts with TAB2 and inhibits TNFalpha and IL-1beta-induced NF-kappaB activation". Cell. Signal. 20 (6): 1044–51. doi:10.1016/j.cellsig.2008.01.015. PMID   18299187.
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. S2CID   22984417.
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. Bibcode:2008FEBSL.582.2843C. doi: 10.1016/j.febslet.2008.07.014 . PMID   18634786. S2CID   27700566.
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.
32. Darnay BG, Haridas V, Ni J, Moore PA, Aggarwal BB (August 1998). "Characterization of the intracellular domain of receptor activator of NF-kappaB (RANK). Interaction with tumor necrosis factor receptor-associated factors and activation of NF-kappab and c-Jun N-terminal kinase". J. Biol. Chem. 273 (32): 20551–5. doi: 10.1074/jbc.273.32.20551 . PMID   9685412.
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. Bibcode:1999FEBSL.443..297K. doi: 10.1016/s0014-5793(98)01731-1 . PMID   10025951. S2CID   46210019.
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. S2CID   25246605.
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.
38. Heyninck K, Beyaert R (January 1999). "The cytokine-inducible zinc finger protein A20 inhibits IL-1-induced NF-kappaB activation at the level of TRAF6". FEBS Lett. 442 (2–3): 147–50. Bibcode:1999FEBSL.442..147H. doi: 10.1016/s0014-5793(98)01645-7 . PMID   9928991. S2CID   19072203.
39. Evans PC, Taylor ER, Coadwell J, Heyninck K, Beyaert R, Kilshaw PJ (August 2001). "Isolation and characterization of two novel A20-like proteins". Biochem. J. 357 (Pt 3): 617–23. doi:10.1042/0264-6021:3570617. PMC   1221992 . PMID   11463333.
40. Xia XZ, Treanor J, Senaldi G, Khare SD, Boone T, Kelley M, Theill LE, Colombero A, Solovyev I, Lee F, McCabe S, Elliott R, Miner K, Hawkins N, Guo J, Stolina M, Yu G, Wang J, Delaney J, Meng SY, Boyle WJ, Hsu H (July 2000). "TACI is a TRAF-interacting receptor for TALL-1, a tumor necrosis factor family member involved in B cell regulation". J. Exp. Med. 192 (1): 137–43. doi:10.1084/jem.192.1.137. PMC   1887716 . PMID   10880535.
41. Deng L, Wang C, Spencer E, Yang L, Braun A, You J, Slaughter C, Pickart C, Chen ZJ (October 2000). "Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain". Cell. 103 (2): 351–61. doi: 10.1016/s0092-8674(00)00126-4 . PMID   11057907. S2CID   18154645.
42. Newton K, Matsumoto ML, Wertz IE, Kirkpatrick DS, Lill JR, Tan J, Dugger D, Gordon N, Sidhu SS, Fellouse FA, Komuves L, French DM, Ferrando RE, Lam C, Compaan D, Yu C, Bosanac I, Hymowitz SG, Kelley RF, Dixit VM (August 2008). "Ubiquitin chain editing revealed by polyubiquitin linkage-specific antibodies". Cell. 134 (4): 668–78. doi: 10.1016/j.cell.2008.07.039 . PMID   18724939. S2CID   3955385.
43. Conze DB, Wu CJ, Thomas JA, Landstrom A, Ashwell JD (May 2008). "Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and toll-like receptor-mediated NF-kappaB activation". Mol. Cell. Biol. 28 (10): 3538–47. doi:10.1128/MCB.02098-07. PMC   2423148 . PMID   18347055.

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. S2CID   13811917.

External links

• TRAF6 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)