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Encyclopedia of Signaling Molecules pp 1–8Cite as

TRAF6

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Synonyms

E3 ubiquitin-protein ligase, tumor necrosis factor receptor-associated factor 6 (TRAF6); Interleukin-1 signal transducer; Location chromosome 11p12; MGC:3310; RING finger protein 85 (RNF85)

Historical Background

Tumor necrosis factor receptor-associated factors 1 and 2 (TRAFs) were initially identified as adaptor proteins that associate with the type-2 tumor necrosis factor (TNF) receptor (TNF-R2) (Cao et al. 1996; Ishida et al. 1996; Rothe et al. 1994). The TRAF family members play important roles in the signal transduction cascades that regulate inflammatory responses via nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinases (MAPKs) that are initiated by activated cell surface receptors, such as TNF-R, interleukin 1 receptor (IL-1R), and Toll-like receptors (TLRs). The TRAFs have different cellular and physiological functions despite of their conserved C-terminal domain found in TRAF1-6 (Fig. 1). Unlike the other TRAFs,...

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References

  • Adhikari A, Xu M, Chen ZJ. Ubiquitin-mediated activation of TAK1 and IKK. Oncogene. 2007;26(22):3214–26. doi:10.1038/sj.onc.1210413. [pii] 1210413.

    Article  CAS  PubMed  Google Scholar 

  • 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):2821–30.

    Article  CAS  PubMed  Google Scholar 

  • Bhoj VG, Chen ZJ. Ubiquitylation in innate and adaptive immunity. Nature. 2009;458(7237):430–7. doi:10.1038/nature07959. [pii] doi:nature07959.

    Article  CAS  PubMed  Google Scholar 

  • Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer G, Rick J, Kuster B, Superti-Furga G. A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. Nat Cell Biol. 2004;6(2):97–105. doi:10.1038/ncb1086. [pii] ncb1086.

    Article  CAS  PubMed  Google Scholar 

  • Bradley JR, Pober JS. Tumor necrosis factor receptor-associated factors (TRAFs). Oncogene. 2001;20(44):6482–91. doi:10.1038/sj.onc.1204788.

    Article  CAS  PubMed  Google Scholar 

  • Cao Z, Xiong J, Takeuchi M, Kurama T, Goeddel DV. TRAF6 is a signal transducer for interleukin-1. Nature. 1996;383(6599):443–6. doi:10.1038/383443a0.

    Article  CAS  PubMed  Google Scholar 

  • Cheng G, Cleary AM, Ye ZS, Hong DI, Lederman S, Baltimore D. Involvement of CRAF1, a relative of TRAF, in CD40 signaling. Science. 1995;267(5203):1494–8.

    Article  CAS  PubMed  Google Scholar 

  • Cheng KK, Lam KS, Wang Y, Wu D, Zhang M, Wang B, Li X, Hoo RL, Huang Z, Sweeney G, Xu A. TRAF6-mediated ubiquitination of APPL1 enhances hepatic actions of insulin by promoting the membrane translocation of Akt. Biochem J. 2013;455(2):207–16. doi:10.1042/BJ20130760.

    Article  CAS  PubMed  Google Scholar 

  • Dadgostar H, Cheng G. Membrane localization of TRAF 3 enables JNK activation. J Biol Chem. 2000;275(4):2539–44.

    Article  CAS  PubMed  Google Scholar 

  • Darnay BG, Besse A, Poblenz AT, Lamothe B, Jacoby JJ. TRAFs in RANK signaling. Adv Exp Med Biol. 2007;597:152–9. doi:10.1007/978-0-387-70630-6_12.

    Article  PubMed  Google Scholar 

  • Deng L, Wang C, Spencer E, Yang L, Braun A, You J, Slaughter C, Pickart C, Chen ZJ. Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell. 2000;103(2):351–61. [pii] S0092-8674(00)00126-4.

    Google Scholar 

  • Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature. 2003;425(6958):577–84. doi:10.1038/nature02006.

    Article  CAS  PubMed  Google Scholar 

  • Groppe J, Hinck CS, Samavarchi-Tehrani P, Zubieta C, Schuermann JP, Taylor AB, Schwarz PM, Wrana JL, Hinck AP. Cooperative assembly of TGF-beta superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding. Mol Cell. 2008;29(2):157–68. doi:10.1016/j.molcel.2007.11.039. [pii] S1097-2765(08)00016-6.

    Article  CAS  PubMed  Google Scholar 

  • Gudey SK, Sundar R, Mu Y, Wallenius A, Zang G, Bergh A, Heldin CH, Landstrom M. TRAF6 stimulates the tumor-promoting effects of TGFbeta type I receptor through polyubiquitination and activation of presenilin 1. Sci Signal. 2014a;7(307):ra2. doi:10.1126/scisignal.2004207.

    Google Scholar 

  • Gudey SK, Wallenius A, Landstrom M. Regulated intramembrane proteolysis of the TGFbeta type I receptor conveys oncogenic signals. Future oncology. 2014b. doi:10.2217/fon.14.45.

    PubMed  Google Scholar 

  • Hamidi A, von Bulow V, Hamidi R, Winssinger N, Barluenga S, Heldin CH, Landström M. Polyubiquitination of transforming growth factor β (TGFβ)-associated kinase 1 mediates nuclear factor-κB activation in response to different inflammatory stimuli. J Biol Chem. 2012;287(1):123–33.

    Article  CAS  PubMed  Google Scholar 

  • Heldin CH, Moustakas A. Role of Smads in TGFbeta signaling. Cell Tissue Res. 2011. doi:10.1007/s00441-011-1190-x.

    PubMed  Google Scholar 

  • Heldin CH, Landstrom M, Moustakas A. Mechanism of TGF-beta signaling to growth arrest, apoptosis, and epithelial-mesenchymal transition. Curr Opin Cell Biol. 2009;21(2):166–76. doi:10.1016/j.ceb.2009.01.021.

    Article  CAS  PubMed  Google Scholar 

  • Hsu H, Shu HB, Pan MG, Goeddel DV. TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell. 1996;84(2):299–308. [pii] S0092-8674(00)80984-8.

    Google Scholar 

  • Inoue J, Ishida T, Tsukamoto N, Kobayashi N, Naito A, Azuma S, Yamamoto T. Tumor necrosis factor receptor-associated factor (TRAF) family: adapter proteins that mediate cytokine signaling. Exp Cell Res. 2000;254(1):14–24. doi:10.1006/excr.1999.4733. [pii] S001448279994733X.

    Article  CAS  PubMed  Google Scholar 

  • Ishida T, Mizushima S, Azuma S, Kobayashi N, Tojo T, Suzuki K, Aizawa S, Watanabe T, Mosialos G, Kieff E, Yamamoto T, Inoue J. 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):28745–8.

    Article  CAS  PubMed  Google Scholar 

  • Ji YX, Zhang P, Zhang XJ, Zhao YC, Deng KQ, Jiang X, Wang PX, Huang Z, Li H. The ubiquitin E3 ligase TRAF6 exacerbates pathological cardiac hypertrophy via TAK1-dependent signalling. Nat Commun. 2016;7:11267. doi:10.1038/ncomms11267.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jung SM, Lee JH, Park J, Oh YS, Lee SK, Park JS, Lee YS, Kim JH, Lee JY, Bae YS, Koo SH, Kim SJ, Park SH. Smad6 inhibits non-canonical TGF-beta1 signalling by recruiting the deubiquitinase A20 to TRAF6. Nat Commun. 2013;4:2562. doi:10.1038/ncomms3562.

    PubMed  Google Scholar 

  • Kaufman DR, Choi Y. Signaling by tumor necrosis factor receptors: pathways, paradigms and targets for therapeutic modulation. Int Rev Immunol. 1999;18(4):405–27.

    Article  CAS  PubMed  Google Scholar 

  • Kim SI, Kwak JH, Na HJ, Kim JK, Ding Y, Choi ME. Transforming growth factor-beta (TGF-beta1) activates TAK1 via TAB1-mediated autophosphorylation, independent of TGF-beta receptor kinase activity in mesangial cells. J Biol Chem. 2009;284(33):22285–96. doi:10.1074/jbc.M109.007146. [pii] M109.007146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lamothe B, Besse A, Campos AD, Webster WK, Wu H, Darnay BG. Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation. J Biol Chem. 2007;282(6):4102–12. doi:10.1074/jbc.M609503200. [pii] M609503200.

    Article  CAS  PubMed  Google Scholar 

  • Landstrom M. The TAK1-TRAF6 signalling pathway. Int J Biochem Cell Biol. 2010;42(5):585–9. doi:10.1016/j.biocel.2009.12.023. [pii] S1357-2725(10)00005-1.

    Article  PubMed  Google Scholar 

  • Liu H, Su YC, Becker E, Treisman J, Skolnik EY. A Drosophila TNF-receptor-associated factor (TRAF) binds the ste20 kinase Misshapen and activates Jun kinase. Curr Biol. 1999;9(2):101–4. [pii] S0960-9822(99)80023-2.

    Google Scholar 

  • Liu C, Xu P, Lamouille S, Xu J, Derynck R. TACE-mediated ectodomain shedding of the type I TGF-beta receptor downregulates TGF-beta signaling. Mol Cell. 2009;35(1):26–36. doi:10.1016/j.molcel.2009.06.018. [pii] S1097-2765(09)00431-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu J, Xu J, Li H, Sun C, Yu L, Li Y, Shi C, Zhou X, Bian X, Ping Y, Wen Y, Zhao S, Xu H, Ren L, An T, Wang Q, Yu S. miR-146b-5p functions as a tumor suppressor by targeting TRAF6 and predicts the prognosis of human gliomas. Oncotarget. 2015;6(30):29129–42. doi:10.18632/oncotarget.4895.

    PubMed  PubMed Central  Google Scholar 

  • Liu X, Wang Z, Zhang G, Zhu Q, Zeng H, Wang T, Gao F, Qi Z, Zhang J, Wang R. High TRAF6 expression is associated with esophageal carcinoma recurrence and prompts cancer cell invasion. Oncol Res. 2016. doi:10.3727/096504016X14749340314441.

    Google Scholar 

  • Lomaga MA, Yeh WC, Sarosi I, Duncan GS, Furlonger C, Ho A, Morony S, Capparelli C, Van G, Kaufman S, van der Heiden A, Itie A, Wakeham A, Khoo W, Sasaki T, Cao Z, Penninger JM, Paige CJ, Lacey DL, Dunstan CR, Boyle WJ, Goeddel DV, Mak TW. TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev. 1999;13(8):1015–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Massague J. TGFbeta in Cancer. Cell. 2008;134(2):215–30. doi:10.1016/j.cell.2008.07.001. [pii] S0092-8674(08)00878-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mu Y, Gudey SK, Landstrom M. Non-Smad signaling pathways. Cell Tissue Res. 2011a. doi:10.1007/s00441-011-1201-y.

    PubMed Central  Google Scholar 

  • Mu Y, Sundar R, Thakur N, Ekman M, Gudey SK, Yakymovych M, Hermansson A, Dimitriou H, Bengoechea-Alonso MT, Ericsson J, Heldin CH, Landstrom M. TRAF6 ubiquitinates TGFbeta type I receptor to promote its cleavage and nuclear translocation in cancer. Nat Commun. 2011b;2:330. doi:10.1038/ncomms1332.

    Article  PubMed  PubMed Central  Google Scholar 

  • Muzio M, Ni J, Feng P, Dixit VM. IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science. 1997;278(5343):1612–5.

    Article  CAS  PubMed  Google Scholar 

  • Naito A, Azuma S, Tanaka S, Miyazaki T, Takaki S, Takatsu K, Nakao K, Nakamura K, Katsuki M, Yamamoto T, Inoue J. Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells. 1999;4(6):353–62. [pii] gtc265.

    Google Scholar 

  • Regnier CH, Tomasetto C, Moog-Lutz C, Chenard MP, Wendling C, Basset P, Rio MC. Presence of a new conserved domain in CART1, a novel member of the tumor necrosis factor receptor-associated protein family, which is expressed in breast carcinoma. J Biol Chem. 1995;270(43):25715–21.

    Article  CAS  PubMed  Google Scholar 

  • Rothe M, Wong SC, Henzel WJ, Goeddel DV. A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor. Cell. 1994;78 (4):681–92. [pii] 0092-8674(94)90532-0.

    Google Scholar 

  • Shaw RJ. Tumor suppression by LKB1: SIK-ness prevents metastasis. Sci Signal. 2009;2(86):pe55. doi:10.1126/scisignal.286pe55. [pii] scisignal.286pe55.

    Article  PubMed  Google Scholar 

  • Sitaram RT, Mallikarjuna P, Landstrom M, Ljungberg B. Transforming growth factor-beta promotes aggressiveness and invasion of clear cell renal cell carcinoma. Oncotarget. 2016. doi:10.18632/oncotarget.9177.

    PubMed  PubMed Central  Google Scholar 

  • Song J, Mu Y, Li C, Bergh A, Miaczynska M, Heldin CH, Landstrom M. APPL proteins promote TGFbeta-induced nuclear transport of the TGFbeta type I receptor intracellular domain. Oncotarget. 2016;7(1):279–92. doi:10.18632/oncotarget.6346.

    PubMed  Google Scholar 

  • Sorrentino A, Thakur N, Grimsby S, Marcusson A, von Bulow V, Schuster N, Zhang S, Heldin CH, Landstrom M. The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner. Nature Cell Biol. 2008;10(10):1199–207. doi:10.1038/ncb1780.

    Article  CAS  PubMed  Google Scholar 

  • Sundar R, Gudey SK, Heldin CH, Landstrom M. TRAF6 promotes TGFbeta-induced invasion and cell-cycle regulation via Lys63-linked polyubiquitination of Lys178 in TGFbeta type I receptor. Cell Cycle. 2015;14(4):554–65. doi:10.4161/15384101.2014.990302.

    Article  PubMed  PubMed Central  Google Scholar 

  • Suzuki N, Suzuki S, Duncan GS, Millar DG, Wada T, Mirtsos C, Takada H, Wakeham A, Itie A, Li S, Penninger JM, Wesche H, Ohashi PS, Mak TW, Yeh WC. Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Nature. 2002;416(6882):750–6. doi:10.1038/nature736. [pii] nature736.

    Article  CAS  PubMed  Google Scholar 

  • Thakur N, Sorrentino A, Heldin CH, Landstrom M. TGF-beta uses the E3-ligase TRAF6 to turn on the kinase TAK1 to kill prostate cancer cells. Future Oncol. 2009;5(1):1–3. doi:10.2217/14796694.5.1.1.

    Article  CAS  PubMed  Google Scholar 

  • Wajant H, Muhlenbeck F, Scheurich P. Identification of a TRAF (TNF receptor-associated factor) gene in Caenorhabditis elegans. J Mol Evol. 1998;47(6):656–62.

    Article  CAS  PubMed  Google Scholar 

  • Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature. 2001;412(6844):346–51. doi:10.1038/35085597. [pii] 35085597.

    Article  CAS  PubMed  Google Scholar 

  • Wesche H, Gao X, Li X, Kirschning CJ, Stark GR, Cao Z. IRAK-M is a novel member of the Pelle/interleukin-1 receptor-associated kinase (IRAK) family. J Biol Chem. 1999;274(27):19403–10.

    Article  CAS  PubMed  Google Scholar 

  • Wrana JL, Attisano L, Wieser R, Ventura F, Massague J. Mechanism of activation of the TGF-beta receptor. Nature. 1994;370(6488):341–7. doi:10.1038/370341a0.

    Article  CAS  PubMed  Google Scholar 

  • Xu LG, Li LY, Shu HB. TRAF7 potentiates MEKK3-induced AP1 and CHOP activation and induces apoptosis. J Biol Chem. 2004;279(17):17278–82. doi:10.1074/jbc.C400063200. [pii] C400063200.

    Article  CAS  PubMed  Google Scholar 

  • Yakymovych I, Yakymovych M, Zang G, Mu Y, Bergh A, Landstrom M, Heldin CH. CIN85 modulates TGFbeta signaling by promoting the presentation of TGFbeta receptors on the cell surface. J Cell Biol. 2015;210(2):319–32. doi:10.1083/jcb.201411025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamaguchi K, Shirakabe K, Shibuya H, Irie K, Oishi I, Ueno N, Taniguchi T, Nishida E, Matsumoto K. Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction. Science. 1995;270(5244):2008–11.

    Article  CAS  PubMed  Google Scholar 

  • Yamashita H, ten Dijke P, Franzen P, Miyazono K, Heldin CH. Formation of hetero-oligomeric complexes of type I and type II receptors for transforming growth factor-beta. J Biol Chem. 1994;269(31):20172–8.

    CAS  PubMed  Google Scholar 

  • Yamashita M, Fatyol K, Jin C, Wang X, Liu Z, Zhang YE. TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-beta. Mol cell. 2008;31(6):918–24. doi:10.1016/j.molcel.2008.09.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zapata JM, Matsuzawa S, Godzik A, Leo E, Wasserman SA, Reed JC. The Drosophila tumor necrosis factor receptor-associated factor-1 (DTRAF1) interacts with Pelle and regulates NFkappaB activity. J Biol Chem. 2000;275(16):12102–7.

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, Ma W, Tian S, Fan Z, Ma X, Yang X, Zhao Q, Tan K, Chen H, Chen D, Huang BR. RanBPM interacts with TbetaRI, TRAF6 and curbs TGF induced nuclear accumulation of TbetaRI. Cell Signal. 2014;26(1):162–72. doi:10.1016/j.cellsig.2013.09.019.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Medical Biosciences, Department of Pathology, Umeå University, Building 6M, Hospithal area, SE-901 85, Umeå, Sweden

    Reshma Sundar & Maréne Landström

  2. Uppsala University, SE-751 24, Uppsala, Sweden

    Maréne Landström

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  1. Reshma Sundar
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  2. Maréne Landström
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Correspondence to Maréne Landström .

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Editors and Affiliations

  1. Dept. Biological Science, Department of Molecular Science and Tech College of Natural Science, Suwon, Korea (Republic of)

    Sangdun Choi

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Sundar, R., Landström, M. (2016). TRAF6. In: Choi, S. (eds) Encyclopedia of Signaling Molecules. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6438-9_635-1

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  • DOI: https://doi.org/10.1007/978-1-4614-6438-9_635-1

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