Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Reshma Sundar
  • Maréne LandströmEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_635


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...
This is a preview of subscription content, log in to check access.


  1. Adhikari A, Xu M, Chen ZJ. Ubiquitin-mediated activation of TAK1 and IKK. Oncogene. 2007;26(22):3214–26.  https://doi.org/10.1038/sj.onc.1210413. [pii] 1210413.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Bhoj VG, Chen ZJ. Ubiquitylation in innate and adaptive immunity. Nature. 2009;458(7237):430–7.  https://doi.org/10.1038/nature07959. [pii] doi:nature07959.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 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.  https://doi.org/10.1038/ncb1086. [pii] ncb1086.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Bradley JR, Pober JS. Tumor necrosis factor receptor-associated factors (TRAFs). Oncogene. 2001;20(44):6482–91.  https://doi.org/10.1038/sj.onc.1204788.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Cao Z, Xiong J, Takeuchi M, Kurama T, Goeddel DV. TRAF6 is a signal transducer for interleukin-1. Nature. 1996;383(6599):443–6.  https://doi.org/10.1038/383443a0.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 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.  https://doi.org/10.1042/BJ20130760.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Dadgostar H, Cheng G. Membrane localization of TRAF 3 enables JNK activation. J Biol Chem. 2000;275(4):2539–44.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Darnay BG, Besse A, Poblenz AT, Lamothe B, Jacoby JJ. TRAFs in RANK signaling. Adv Exp Med Biol. 2007;597:152–9.  https://doi.org/10.1007/978-0-387-70630-6_12.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature. 2003;425(6958):577–84.  https://doi.org/10.1038/nature02006.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 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.  https://doi.org/10.1016/j.molcel.2007.11.039. [pii] S1097-2765(08)00016-6.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 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.  https://doi.org/10.1126/scisignal.2004207.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Gudey SK, Wallenius A, Landstrom M. Regulated intramembrane proteolysis of the TGFbeta type I receptor conveys oncogenic signals. Future oncology. 2014b.  https://doi.org/10.2217/fon.14.45.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Heldin CH, Moustakas A. Role of Smads in TGFbeta signaling. Cell Tissue Res. 2011.  https://doi.org/10.1007/s00441-011-1190-x.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 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.  https://doi.org/10.1016/j.ceb.2009.01.021.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 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.  https://doi.org/10.1006/excr.1999.4733. [pii] S001448279994733X.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 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.  https://doi.org/10.1038/ncomms11267.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 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.  https://doi.org/10.1038/ncomms3562.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 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.  https://doi.org/10.1074/jbc.M109.007146. [pii] M109.007146.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 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.  https://doi.org/10.1074/jbc.M609503200. [pii] M609503200.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Landstrom M. The TAK1-TRAF6 signalling pathway. Int J Biochem Cell Biol. 2010;42(5):585–9.  https://doi.org/10.1016/j.biocel.2009.12.023. [pii] S1357-2725(10)00005-1.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 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.  https://doi.org/10.1016/j.molcel.2009.06.018. [pii] S1097-2765(09)00431-6.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 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.  https://doi.org/10.18632/oncotarget.4895.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 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.  https://doi.org/10.3727/096504016X14749340314441.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  33. Massague J. TGFbeta in Cancer. Cell. 2008;134(2):215–30.  https://doi.org/10.1016/j.cell.2008.07.001. [pii] S0092-8674(08)00878-7.CrossRefPubMedPubMedCentralGoogle Scholar
  34. Mu Y, Gudey SK, Landstrom M. Non-Smad signaling pathways. Cell Tissue Res. 2011a.  https://doi.org/10.1007/s00441-011-1201-y.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 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.  https://doi.org/10.1038/ncomms1332.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  40. Shaw RJ. Tumor suppression by LKB1: SIK-ness prevents metastasis. Sci Signal. 2009;2(86):pe55.  https://doi.org/10.1126/scisignal.286pe55. [pii] scisignal.286pe55.CrossRefPubMedPubMedCentralGoogle Scholar
  41. Sitaram RT, Mallikarjuna P, Landstrom M, Ljungberg B. Transforming growth factor-beta promotes aggressiveness and invasion of clear cell renal cell carcinoma. Oncotarget. 2016.  https://doi.org/10.18632/oncotarget.9177.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 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.  https://doi.org/10.18632/oncotarget.6346.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 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.  https://doi.org/10.1038/ncb1780.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 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.  https://doi.org/10.4161/15384101.2014.990302.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 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.  https://doi.org/10.1038/nature736. [pii] nature736.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 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.  https://doi.org/10.2217/14796694.5.1.1.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 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.  https://doi.org/10.1038/35085597. [pii] 35085597.CrossRefPubMedGoogle Scholar
  49. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  50. Wrana JL, Attisano L, Wieser R, Ventura F, Massague J. Mechanism of activation of the TGF-beta receptor. Nature. 1994;370(6488):341–7.  https://doi.org/10.1038/370341a0.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 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.  https://doi.org/10.1074/jbc.C400063200. [pii] C400063200.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 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.  https://doi.org/10.1083/jcb.201411025.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 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.PubMedPubMedCentralGoogle Scholar
  55. 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.  https://doi.org/10.1016/j.molcel.2008.09.002.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 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.  https://doi.org/10.1016/j.cellsig.2013.09.019.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Medical Biosciences and Department of PathologyUmeå UniversityUmeåSweden
  2. 2.Uppsala UniversityUppsalaSweden