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.
^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)". Oncogene18 (42): 5814–20. doi:10.1038/sj.onc.1202975. PMID10523862.
^ abMochida Y, Takeda K, Saitoh M, Nishitoh H, Amagasa T, Ninomiya-Tsuji J et al. (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. PMID10921914.
^Wu Y, Liu J, Zhang Z, Huang H, Shen J, Zhang S et al. (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. PMID18950704.
^ abWesche 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. PMID10383454.
^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. PMID11518704.
^Cao Z, Xiong J, Takeuchi M, Kurama T, Goeddel DV (October 1996). "TRAF6 is a signal transducer for interleukin-1". Nature383 (6599): 443–6. doi:10.1038/383443a0. PMID8837778.
^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. PMID12566447.
^ abcTakaesu 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. Cell5 (4): 649–58. doi:10.1016/s1097-2765(00)80244-0. PMID10882101.
^ abNinomiya-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". Nature398 (6724): 252–6. doi:10.1038/18465. PMID10094049.
^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. PMID18758450.
^ abChen 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. PMID18634786.
^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. PMID9685412.
^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. PMID10075662.
^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. PMID9852070.
^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. PMID10025951.
^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. PMID12925853.
^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. PMID9928991.
^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". Cell103 (2): 351–61. doi:10.1016/s0092-8674(00)00126-4. PMID11057907.
^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". Cell134 (4): 668–78. doi:10.1016/j.cell.2008.07.039. PMID18724939.
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. PMID16313339.