TRAF6

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TNF receptor-associated factor 6, E3 ubiquitin protein ligase
Protein TRAF6 PDB 1lb4.png
PDB rendering based on 1lb4.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols TRAF6 ; MGC:3310; RNF85
External IDs OMIM602355 MGI108072 HomoloGene3395 GeneCards: TRAF6 Gene
RNA expression pattern
PBB GE TRAF6 205558 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 7189 22034
Ensembl ENSG00000175104 ENSMUSG00000027164
UniProt Q9Y4K3 P70196
RefSeq (mRNA) NM_004620 NM_009424
RefSeq (protein) NP_004611 NP_033450
Location (UCSC) Chr 11:
36.51 – 36.53 Mb
Chr 2:
101.68 – 101.7 Mb
PubMed search [1] [2]

TRAF6 is a TRAF human protein.

Function[edit]

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.[1]

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

Interactions[edit]

TRAF6 has been shown to interact with:

References[edit]

  1. ^ "Entrez Gene: TRAF6 TNF receptor-associated factor 6". 
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  3. ^ 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. 
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  6. ^ 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. 
  7. ^ 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. 
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  13. ^ a b 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. doi:10.1126/science.278.5343.1612. PMID 9374458. 
  14. ^ 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. 
  15. ^ 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. 
  16. ^ Takatsuna H, Kato H, Gohda J, Akiyama T, Moriya A, Okamoto Y et al. (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. 
  17. ^ 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. 
  18. ^ a b 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. 
  19. ^ a b c 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. 
  20. ^ a b c Takaesu G, Kishida S, Hiyama A, Yamaguchi K, Shibuya H, Irie K et al. (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. 
  21. ^ a b c Walsh MC, Kim GK, Maurizio PL, Molnar EE, Choi Y. 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. 
  22. ^ a b 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. doi:10.1038/18465. PMID 10094049. 
  23. ^ a b 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. 
  24. ^ a b 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. 
  25. ^ Sorrentino A, Thakur N, Grimsby S, Marcusson A, von Bulow V, Schuster N et al. (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. 
  26. ^ a b Chen L, Dong W, Zou T, Ouyang L, He G, Liu Y et al. (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. 
  27. ^ Mizukami J, Takaesu G, Akatsuka H, Sakurai H, Ninomiya-Tsuji J, Matsumoto K et al. (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. 
  28. ^ 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. 
  29. ^ 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. 
  30. ^ 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. 
  31. ^ Kim HH, Lee DE, Shin JN, Lee YS, Jeon YM, Chung CH et al. (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. 
  32. ^ Wald D, Qin J, Zhao Z, Qian Y, Naramura M, Tian L et al. (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. 
  33. ^ 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. 
  34. ^ 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. doi:10.1016/s0014-5793(98)01645-7. PMID 9928991. 
  35. ^ 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. 
  36. ^ Xia XZ, Treanor J, Senaldi G, Khare SD, Boone T, Kelley M et al. (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. 
  37. ^ Deng L, Wang C, Spencer E, Yang L, Braun A, You J et al. (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. 
  38. ^ Newton K, Matsumoto ML, Wertz IE, Kirkpatrick DS, Lill JR, Tan J et al. (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. 
  39. ^ 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[edit]

  • 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. 
  • 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[edit]