Abstract
Tumor necrosis factor (TNF) receptor (TNFR) associated factor 6 (TRAF6) is a unique member of the TRAF family of adaptor proteins that is involved in both the TNF receptor superfamily and the interleukin-1 receptor (IL-1R)/Toll-like receptor (TLR) superfamily signal transduction pathways. The ability to mediate signals from both families of receptors implicates TRAF6 as an important regulator of a diverse range of physiological processes such as innate and adaptive immunity, bone metabolism, and the development of lymph nodes, mammary glands, skin, and the central nervous system. This chapter will highlight the structural and biochemical studies of TRAF6 in receptor interactions and discuss the potential for peptidomimetic drug application based on TRAF6 receptor binding motif.
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References
Ishida T, Mizushima S, Azuma S et al. Identification of TRAF6, a novel tumor necrosis factor receptor-associated factor protein that mediates signaling from an amino-terminal domain of the CD40 cytoplasmic region. J Biol Chem 1996; 271(46):28745–28748.
Cao Z, Xiong J, Takeuchi M et al. TRAF6 is a signal transducer for interleukin-1. Nature 1996; 383(6599):443–446.
Naito A, Azuma S, Tanaka S et al. Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells 1999; 4(6):353–362.
Lomaga MA, Yeh WC, Sarosi I et al. TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev 1999; 13(8):1015–1024.
Lomaga MA, Henderson JT, Elia AJ et al. Tumor necrosis factor receptor-associated factor 6 (TRAF6) deficiency results in exencephaly and is required for apoptosis within the developing CNS. J Neurosci 2000; 20(19):7384–7393.
Naito A, Yoshida H, Nishioka E et al. TRAF6-deficient mice display hypohidrotic ectodermal dysplasia. Proc Natl Acad Sci USA 2002; 99(13):8766–8771.
Kong YY, Yoshida H, Sarosi I et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 1999; 397(6717):315–323.
Darnay BG, Ni J, Moore PA et al. 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 1999; 274(12):7724–7731 (%19).
Pullen SS, Miller HG, Everdeen DS et al. CD40-tumor necrosis factor receptor-associated factor (TRAF) interactions: Regulation of CD40 signaling through multiple TRAF binding sites and TRAF hetero-oligomerization. Biochemistry 1998; 37(34):11836–11845.
Muzio M, Ni J, Feng P et al. IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science 1997; 278(5343):1612–1615.
Wesche H, Gao X, Li X et al. IRAK-M is a novel member of the Pelle/interleukin-1 receptor-associated kinase (IRAK) family. J Biol Chem 1999; 274(27):19403–19410.
Suzuki N, Suzuki S, Duncan GS et al. Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Nature 2002; 416(6882):750–756.
Burns K, Clatworthy J, Martin L et al. Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor. Nat Cell Biol 2000; 2(6):346–351.
O’Neill LA, Fitzgerald KA, Bowie AG. The Toll-IL-1 receptor adaptor family grows to five members. Trends Immunol 2003; 24(6):286–290.
Ghosh S, Karin M. Missing pieces in the NF-kappaB puzzle. Cell 2002; 109(Suppl):S81–S96.
Shaulian E, Karin M. AP-1 as a regulator of cell life and death. Nat Cell Biol 2002; 4(5):E131–E136.
Deng L, Wang C, Spencer E et al. Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 2000; 103(2):351–361.
Wang C, Deng L, Hong M et al. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 2001; 412(6844):346–351, (%19).
Trompouki E, Hatzivassiliou E, Tsichritzis T et al. CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members. Nature 2003; 424(6950):793–796.
Brummelkamp TR, Nijman SM, Dirac AM et al. Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB. Nature 2003; 424(6950):797–801.
Kovalenko A, Chable-Bessia C, Cantarella G et al. The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. Nature 2003; 424(6950):801–805.
Wertz I, O’Rourke K, Zhon H et al. De-ubiquitin and ubiquitin ligase domains of A20 downregulate NF-κB signalling. Nature 2004; 430(7000):694–699.
Arch RH, Gedrich RW, Thompson CB. Tumor necrosis factor receptor-associated factors (TRAFs)—a family of adapter proteins that regulates life and death. Genes Dev 1998; 12(18):2821–2830.
Rothe M, Wong SC, Henzel WJ et al. A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor. Cell 1994; 78(4):681–692.
Ye H, Cirilli M, Wu H. The use of construct variation and diffraction data analysis in the crystallization of the TRAF domain of human tumor necrosis factor receptor associated factor 6. Acta Crystallogr D Biol Crystallogr 2002; 58(Pt 10 Pt 2):1886–1888.
Takeuchi M, Rothe M, Goeddel DV. Anatomy of TRAF2. Distinct domains for nuclear factor-kappaB activation and association with tumor necrosis factor signaling proteins. J Biol Chem 1996; 271(33):19935–19942.
Park YC, Burkitt V, Villa AR et al. Structural basis for self-association and receptor recognition of human TRAF2. Nature 1999; 398(6727):533–538.
Ye H, Arron JR, Lamothe B et al. Distinct molecular mechanism for initiating TRAF6 signalling. Nature 2002; 418(6896):443–447.
Wu H. Assembly of post-receptor signaling complexes for the tumor necrosis factor receptor superfamily. Adv Protein Chem 2004; 68:225–279.
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© 2007 Landes Bioscience and Springer Science+Business Media
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Chung, J.Y., Lu, M., Yin, Q., Lin, SC., Wu, H. (2007). Molecular Basis for the Unique Specificity of TRAF6. In: Wu, H. (eds) TNF Receptor Associated Factors (TRAFs). Advances in Experimental Medicine and Biology, vol 597. Springer, New York, NY. https://doi.org/10.1007/978-0-387-70630-6_10
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DOI: https://doi.org/10.1007/978-0-387-70630-6_10
Publisher Name: Springer, New York, NY
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