Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


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 TRAFs, TRAF7 possesses several WD40 repeats in its C-terminal domain (Bouwmeester et al. 2004; Xu et al. 2004; Bradley and Pober 2001; Darnay et al. 2007). The TRAFs are genetically conserved in mammals (Arch et al. 1998), Dictyostelium discoideum (Regnier et al. 1995), Caenorhabditis elegans (Wajant et al. 1998), and Drosophila (Liu et al. 1999; Zapata et al. 2000).
TRAF6, Fig. 1

Domain structures found in members of the tumor necrosis factor receptor-associated factor (TRAF) family. TRAF1 lacks the Really Interesting New Gene (RING) domain which possesses ubiquitin ligase activity, while other domains found in TRAF1-TRAF7 are conserved with the exception of the C-terminal TRAF domain. In contrast TRAF7 harbors seven WD40 domains in its C-terminal part

TRAF Family

In addition to inflammatory responses, TRAF proteins regulate cell proliferation and survival. TRAF family members share a stretch of conserved sequence at their C-terminal domains known as the TRAF domain (Rothe et al. 1994). The TRAF domain is divided into a highly conserved carboxyl terminal region (C-domain), the TRAF-C sub-domain, and the coiled-coil amino terminal region and the TRAF-N sub-domain (Inoue et al. 2000). The TRAF domain mediates homo- and hetero-dimerization of TRAF family members, although TRAF4 shows a poor ability to associate with the other family members. The TRAF domain confers also direct or indirect interaction with the intracellular domain of cell surface receptors and signal transducers (Kaufman and Choi 1999; Cheng et al. 1995).

All TRAFs, except TRAF1, contain an amino terminal RING finger motif, in addition to the TRAF domain (Hsu et al. 1996). TRAF4 contains seven zinc finger domains, while TRAF2, TRAF3, TRAF5, and TRAF6 have fewer zinc finger domains.


TRAF6 (gene accession number of TRAF6 NM_004620, http://www.ncbi.nlm.nih.gov/gene/7189) was first identified independently as an adaptor protein, important for NF-κB activation, initiated by IL-1 and CD40. It was initially isolated using yeast two hybrid systems using an EST expression library (Cao et al. 1996; Ishida et al. 1996). TRAF6 is a cytosolic protein although it is predominantly present in membrane-bound cellular compartments (Dadgostar and Cheng 2000). TRAF6 contains a C3HC3D-type Really Interesting New Gene (RING) finger followed by five zinc finger regions in its N-terminus (Inoue et al. 2000). TRAF6 plays a specific role in innate and adaptive immune response apart from another diverse range of physiological processes (Naito et al. 1999; Lomaga et al. 1999). TRAF6 exists in a trimeric form at very high concentrations. TRAF6 null mice have an abnormal phenotype of defective bone formation and die at early age (Naito et al. 1999; Lomaga et al. 1999).

TRAF6 functions as an E3 ubiquitin ligase that interacts with the E2-conjugating enzyme Msm2, which consists of Ubc13 and Uev1A to synthesize lysine-63-linked polyubiquitin (Deng et al. 2000; Wang et al. 2001). The enzymatic activity of TRAF6 is promoted by its oligomerization and autoubiquitination on Lys124, which has been reported to be the key ubiquitin lysine acceptor site on TRAF6 (Lamothe et al. 2007; Bhoj and Chen 2009). Previously it has been reported that TRAF6 interacts with tumor members of the TNFR family such as CD40 and RANK, IL-1R/Toll-like receptor (TLR) family members (Muzio et al. 1997; Wesche et al. 1999; Suzuki et al. 2002). Recent studies have demonstrated that TRAF6 also binds to the type I transforming growth factor β (TGFβ) receptor (TβRI) (Sorrentino et al. 2008).

Role of TRAF6 for Smad-Independent TGFβ Signaling

TGFβ is a multifunctional cytokine involved in many critical cellular functions, such as growth arrest, differentiation, and apoptosis, which is a crucial event during embryogenesis, angiogenesis, and epithelial-mesenchymal transition (EMT) (Massague 2008; Heldin et al. 2009; Heldin and Moustakas 2011). TGFβ receptors are transmembrane serine/threonine kinase cell surface glycoproteins, which are expressed ubiquitously. TβRI is a 53 kDa protein and has a high specificity to bind to the TβRII to form a hetero-tetrameric complex. The TGFβ ligand initially binds to the TβRII; this enhances the affinity between TβRII and TβRI and thereby TβRII phosphorylates TβRI at the unique GS domain, which is located in the start of its kinase domain (Wrana et al. 1994; Yamashita et al. 1994; Groppe et al. 2008). When the receptor complex is activated, Smad-dependent and Smad-independent pathways are activated (Mu et al. 2011b; Heldin and Moustakas 2011) (Fig. 2).
TRAF6, Fig. 2

TGFβ-induced Lys63-linked polyubiquitination and subsequent activation of the ubiquitin ligase TRAF6 causes PKCζ-dependent activation of TNF-alpha converting enzyme (TACE) and Lys63-linked polyubiquitination of PS1, which results in generation of an intracellular fragment of the type I TGFβ receptor (TβRI-ICD) which enters the nucleus where it associates with components of the transcriptional complex, such as p300, and promotes expression of the pro-invasive genes TβRI, Snail, and MMP2. TRAF6 associates via a conserved consensus site in the TβRI to promote non-canonical and Smad-independent pathways to cause Lys63-linked polyubiquitination and activation of the TAK1-MKK3/6-p38 MAPK pathway. In contrast, TRAF6 is not required for canonical TGFβ-induced activation of the Smad-signaling pathway, where the activated Smad complex binds to Smad-binding elements (SBE) in their specific target genes, such as Smad7. Epithelial to mesenchymal transition (EMT) is regulated by the canonical TGFβ-induced Smad pathway

TGFβ is known to transduce signals through Smad proteins as well as non-Smad mediators, like extracellular signal-regulated kinases (ERKs), the small GTPases Rho, Rac, Cdc42, c-Jun N-terminal kinases (JNKs), and mitogen-activated protein kinase (MAPK) (Derynck and Zhang 2003; Landstrom 2010; Mu et al. 2011a). Yamaguchi et al. (1995) originally showed that transforming growth factor-β-activated kinase-1 (TAK1), a member of mitogen-activated protein kinase kinase kinase (MAPKKK) family, functions as a mediator in a signaling pathway of TGFβ superfamily members. TAK1 regulates various cellular responses like cell survival through activation of JNK, p38 MAPK, and inflammatory responses via IκB kinase (IKK) and NfKappaB pathways (Adhikari et al. 2007; Thakur et al. 2009; Landstrom 2010 plus Hamidi et al. 2012). TAK1 is also crucial for the activation of LKB1 serine/threonine kinase which in turn controls cell metabolism, growth, and polarity (Adhikari et al. 2007; Shaw 2009; Thakur et al. 2009; Landstrom 2010; Mu et al. 2011a).

Later, Sorrentino et al. (2008) and Yamashita et al. (2008) reported that TRAF6 is crucial for the activation of downstream targets p38 MAPK pathway in TGFβ signaling cascade, through its enzymatic activity as an E3 ligase. Sorrentino et al. showed that TRAF6 constitutively binds to TGFbeta type I receptor conserved consensus motif (basic residue-X-P-X-E-X-X-aromatic/acidic acid) TGF-β type 1 receptor (TβR1), and this interaction leads to the autoubiquitination of TRAF6, in response to TGFβ stimulation of cells which in turn causes Lys63-linked polyubiquitination of TAK1 at Lys34 (Sorrentino et al. 2008). The kinase activity of TAK1 might be inhibited by N-terminal part of TAK1 itself (Yamaguchi et al. 1995); therefore, it is possible that this cascade of events then leads to the activation of TAK1 either due to a conformational change to open up its structure or recruitment of the TAK1-binding proteins 2 and 3 (TAB2 and TAB3) (Sorrentino et al. 2008; Landstrom 2010). Kim et al. (2009) reported that TGFβ-induced autoubiquitination of TAK1 recruits the adaptor molecule TAB1.

Recently, Mu et al. (2011b) showed a novel TRAF6-dependent pathway by which TGFβ mediates its oncogenic effects. TRAF6 binds to TβRI via conserved consensus site and upon TGFβ-induced autoubiquitination and activation causes Lys63-linked polyubiquitination of TβRI. In cancer cells, TβRI undergoes cleavage by TNF-alpha converting enzyme (TACE) in a PKCζ-dependent manner, and the intracellular domain (ICD) of cleaved TβRI translocates to the nucleus where it associates with the transcriptional regulator p300 and the snail promoter (Fig. 2). The association of TβRI-ICD to p300 and the snail promoter enhances tumor invasion by induction of pro-invasive genes such as snail and MMP2. The negative regulation of TGFβ signaling due to the ectodomain shedding of TβRI by TACE was previously reported (Liu et al. 2009). Their report suggests that the TACE-mediated ectodomain shedding of TβRI also results in reduced TGFβ-mediated growth inhibition and EMT.

Our group have also found that TβRI undergoes regulated intramembrane proteolysis in a manner dependent on TRAF6, resulting in the liberation of the intracellular domain (ICD) of TβRI in cancer cells (Gudey et al. 2014a). TRAF6 was found to recruit Presenilin1 (PS1), a key regulator protein in the γ-secretase complex to TβRI. TRAF6 activates PS1 by promoting Lys63-linked polyubiquitination of PS1. Activated PS1 cleaved TβRI in the transmembrane domain, and the generated TβRI-ICD enters the nucleus where it was found to bind to the promoter of TβRI encoding gene. The TRAF6- and PS1-induced cleavage and nuclear localization of TβRI promoted TGFβ-induced invasion in cancer cells (Gudey et al. 2014a, b). In the report from Sundar et al., we provided evidence for that TRAF6-promoted Lys63-linked polyubiquitination of Lys178 in TβRI (Sundar et al. 2015). TRAF6-mediated Lys63-linked polyubiquitination of TβRI at Lys178 was shown to promote regulation of genes controlling the cell cycle (CCND1), differentiation, and invasiveness of prostate cancer cells (Sundar et al. 2015).

Recently, Song et al. reported that the endocytic adaptor proteins APPL1 and APPL2 are required for TRAF6-mediated TGFβ-induced nuclear translocation of TβRI-ICD in human prostate and breast cancer cell lines. TRAF6 promoted TβRI-APPL1 complex formation and Lys63-linked polyubiquitination of APPL1 (Song et al. 2016). Moreover, APPL1-TβRI-ICD complexes were found at high levels in aggressive human prostate cancer tissue. Our group also reported that the adaptor protein CIN85 promoted recycling of TβRI to the cell surface by interaction of TβRI with the SH3 domain of CIN85 in response to TGFβ in a TRAF6-dependent manner (Yakymovych et al. 2015). Sitaram et al. reported that the generation of ALK5-ICD is positively associated with canonical TGFβ signaling and has a key role in promoting aggressiveness and invasion of clear cell renal cell carcinoma (ccRCC) (Sitaram et al. 2016).

RanBPM, a scaffold protein, was identified as a novel binding partner of TRAF6 and TBRI. Overexpression of RanBPM blocked TGFb-induced nuclear accumulation of TBRI-ICD (Zhang et al. 2014). Smad6 controls activation of the TβRI-TRAF6 pathway. Smad6 negatively regulates TGFβ-induced non-canonical TGFβ-TRAF6-TAK1-p38 MAPK pathway. Smad6 recruits deubiquitinating enzyme, A20, resulting in deubiquitination of TRAF6 in a TGFβ-dependent manner (Jung et al. 2013).

The role of TRAF6 in other signaling cascades besides TGFβ has recently been further explored. TRAF6 has been shown to promote Lys63-linked polyubiquitination of APPL1, in response to insulin hepatocytes, by causing membrane translocation of Akt (Cheng et al. 2013). TRAF6 is also reported to act as an essential molecular switch for the development of cardiac hypertrophy (Ji et al. 2016). This is dependent on TRAF6 autoubiquitination and its binding to TAK1, which in turn cause ubiquitination of TAK1 by TRAF6. High expression levels of TRAF6 were found in esophageal cancer tissues, and patients with high TRAF6 expression have significantly shorter survival time (Liu et al. 2016). Another study shows that miR-146b-5p inhibited the proliferation of glioma cells and promoted apoptosis by directly targeting TRAF6 (Liu et al. 2015). They found that TRAF6 overexpression was associated with miR-146b-5p downregulation and poor prognosis in human gliomas.


TRAF6 is an important enzyme causing Lys63-linked polyubiquitination of its substrates to promote pro-inflammatory responses downstream of members of the TNF-R, IL-1R, TLR, and TGFβ receptors. Recently, TRAF6 was also identified to be a crucial regulatory enzyme for Lys63-linked activations of TAK1 and for the proteolytic cleavage of TβRI by TACE and PS1. The TβRI-ICD enters the nucleus via its association with the endosomal adaptor protein APPL1. The nuclear TβRI-ICD promotes invasion of cancer cells. The identification of TRAF6 as a key regulator of TGFβ-induced tumor invasion will hopefully help to design novel inhibitors to prevent tumorigenic effects.


  1. 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle Scholar
  3. Bhoj VG, Chen ZJ. Ubiquitylation in innate and adaptive immunity. Nature. 2009;458(7237):430–7. doi: 10.1038/nature07959. [pii] doi:nature07959.PubMedCrossRefGoogle 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. doi: 10.1038/ncb1086. [pii] ncb1086.PubMedCrossRefGoogle Scholar
  5. Bradley JR, Pober JS. Tumor necrosis factor receptor-associated factors (TRAFs). Oncogene. 2001;20(44):6482–91. doi: 10.1038/sj.onc.1204788.PubMedCrossRefGoogle 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. doi: 10.1038/383443a0.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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. doi: 10.1042/BJ20130760.PubMedCrossRefGoogle Scholar
  9. Dadgostar H, Cheng G. Membrane localization of TRAF 3 enables JNK activation. J Biol Chem. 2000;275(4):2539–44.PubMedCrossRefGoogle Scholar
  10. 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.PubMedCrossRefGoogle 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.Google Scholar
  12. 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.PubMedCrossRefGoogle 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. doi: 10.1016/j.molcel.2007.11.039. [pii] S1097-2765(08)00016-6.PubMedCrossRefGoogle 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. doi: 10.1126/scisignal.2004207.
  15. 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.PubMedGoogle 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.PubMedCrossRefGoogle Scholar
  17. Heldin CH, Moustakas A. Role of Smads in TGFbeta signaling. Cell Tissue Res. 2011. doi: 10.1007/s00441-011-1190-x.PubMedGoogle 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. doi: 10.1016/j.ceb.2009.01.021.PubMedCrossRefGoogle 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.Google 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. doi: 10.1006/excr.1999.4733. [pii] S001448279994733X.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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. doi: 10.1038/ncomms11267.PubMedPubMedCentralCrossRefGoogle 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. doi: 10.1038/ncomms3562.PubMedGoogle 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.PubMedCrossRefGoogle 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. doi: 10.1074/jbc.M109.007146. [pii] M109.007146.PubMedPubMedCentralCrossRefGoogle 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. doi: 10.1074/jbc.M609503200. [pii] M609503200.PubMedCrossRefGoogle Scholar
  27. 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.PubMedCrossRefGoogle 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.Google 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. doi: 10.1016/j.molcel.2009.06.018. [pii] S1097-2765(09)00431-6.PubMedPubMedCentralCrossRefGoogle 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. doi: 10.18632/oncotarget.4895.PubMedPubMedCentralCrossRefGoogle 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. doi: 10.3727/096504016X14749340314441.Google 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. doi: 10.1016/j.cell.2008.07.001. [pii] S0092-8674(08)00878-7.PubMedPubMedCentralCrossRefGoogle Scholar
  34. Mu Y, Gudey SK, Landstrom M. Non-Smad signaling pathways. Cell Tissue Res. 2011a. doi: 10.1007/s00441-011-1201-y.PubMedCentralGoogle 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. doi: 10.1038/ncomms1332.PubMedPubMedCentralCrossRefGoogle 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.PubMedCrossRefGoogle 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.Google 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.PubMedCrossRefGoogle 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.Google Scholar
  40. Shaw RJ. Tumor suppression by LKB1: SIK-ness prevents metastasis. Sci Signal. 2009;2(86):pe55. doi: 10.1126/scisignal.286pe55. [pii] scisignal.286pe55.PubMedCrossRefGoogle 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. doi: 10.18632/oncotarget.9177.PubMedPubMedCentralGoogle 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. doi: 10.18632/oncotarget.6346.PubMedCrossRefGoogle 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. doi: 10.1038/ncb1780.PubMedCrossRefGoogle 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. doi: 10.4161/15384101.2014.990302.PubMedPubMedCentralCrossRefGoogle 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. doi: 10.1038/nature736. [pii] nature736.PubMedCrossRefGoogle 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. doi: 10.2217/14796694.5.1.1.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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. doi: 10.1038/35085597. [pii] 35085597.PubMedCrossRefPubMedCentralGoogle 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.PubMedCrossRefGoogle 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. doi: 10.1038/370341a0.PubMedCrossRefGoogle 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. doi: 10.1074/jbc.C400063200. [pii] C400063200.PubMedCrossRefGoogle 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. doi: 10.1083/jcb.201411025.PubMedPubMedCentralCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedGoogle 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. doi: 10.1016/j.molcel.2008.09.002.PubMedPubMedCentralCrossRefGoogle 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.PubMedCrossRefGoogle 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. doi: 10.1016/j.cellsig.2013.09.019.PubMedCrossRefGoogle 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