TRAF6

Summary

Gene Symbol: TRAF6
Description: TNF receptor associated factor 6
Alias: MGC:3310, RNF85, TNF receptor-associated factor 6, E3 ubiquitin-protein ligase TRAF6, RING finger protein 85, RING-type E3 ubiquitin transferase TRAF6, TNF receptor-associated factor 6, E3 ubiquitin protein ligase, interleukin-1 signal transducer
Species: human
Products:     TRAF6

Top Publications

  1. Walsh M, Kim G, Maurizio P, Molnar E, Choi Y. TRAF6 autoubiquitination-independent activation of the NFkappaB and MAPK pathways in response to IL-1 and RANKL. PLoS ONE. 2008;3:e4064 pubmed publisher
    The adapter protein TRAF6 is critical for mediating signal transduction from members of the IL-1R/TLR and TNFR superfamilies...
  2. Deng L, Wang C, Spencer E, Yang L, Braun A, You J, et al. Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell. 2000;103:351-61 pubmed
    b>TRAF6 is a signal transducer in the NF-kappaB pathway that activates IkappaB kinase (IKK) in response to proinflammatory cytokines. We have purified a heterodimeric protein complex that links TRAF6 to IKK activation...
  3. Kanayama A, Seth R, Sun L, Ea C, Hong M, Shaito A, et al. TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains. Mol Cell. 2004;15:535-48 pubmed
    ..TAK1 is in turn activated by TRAF6, a RING domain ubiquitin ligase that facilitates the synthesis of lysine 63-linked polyubiquitin chains...
  4. Sun L, Deng L, Ea C, Xia Z, Chen Z. The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. Mol Cell. 2004;14:289-301 pubmed
    ..Here we present evidence that TRAF6 ubiquitin ligase and TAK1 protein kinase mediate IKK activation by BCL10 and MALT1...
  5. Yoshida H, Jono H, Kai H, Li J. The tumor suppressor cylindromatosis (CYLD) acts as a negative regulator for toll-like receptor 2 signaling via negative cross-talk with TRAF6 AND TRAF7. J Biol Chem. 2005;280:41111-21 pubmed
    ..PGN), MALP-2, and Pam3CSK4 induces activation of IKKs-IkappaBalpha and MKK3/6-p38 pathways not only by TRAF6 but also by TRAF7, a recently identified TRAF family member...
  6. Li S, Strelow A, Fontana E, Wesche H. IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase. Proc Natl Acad Sci U S A. 2002;99:5567-72 pubmed
    ..IRAK-4 is the closest human homolog to Pelle. Endogenous IRAK-4 interacts with IRAK-1 and TRAF6 in an IL-1-dependent manner, and overexpression of IRAK-4 can activate NF-kappa B as well as mitogen-activated ..
  7. Wang Y, Li L, Han K, Zhai Z, Shu H. A20 is a potent inhibitor of TLR3- and Sendai virus-induced activation of NF-kappaB and ISRE and IFN-beta promoter. FEBS Lett. 2004;576:86-90 pubmed
    ..These data suggest that A20 targets TRIF to inhibit TLR3-mediated induction of IFN-beta transcription and functions as a feedback negative regulator for TLR3 signaling and cellular anti-viral response. ..
  8. Mercier P, Lewis M, Hau D, Saltibus L, Xiao W, Spyracopoulos L. Structure, interactions, and dynamics of the RING domain from human TRAF6. Protein Sci. 2007;16:602-14 pubmed
    ..responsible for activation of the transcription factor NF-kappaB involves Lys63-linked polyubiquitination of TRAF6. Covalent attachment of ubiquitin (Ub) to TRAF6, and subsequent poly(Ub) chain synthesis, is catalyzed by the ..
  9. Kim J, Ozato K. The sequestosome 1/p62 attenuates cytokine gene expression in activated macrophages by inhibiting IFN regulatory factor 8 and TNF receptor-associated factor 6/NF-kappaB activity. J Immunol. 2009;182:2131-40 pubmed publisher
    ..Together, p62 may provide a mechanism by which to control excessive inflammatory responses after macrophage activation. ..

More Information

Publications103 found, 100 shown here

  1. Liu C, Qian W, Qian Y, Giltiay N, Lu Y, Swaidani S, et al. Act1, a U-box E3 ubiquitin ligase for IL-17 signaling. Sci Signal. 2009;2:ra63 pubmed publisher
    ..complex, Act1 mediated the lysine-63-linked ubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6), a component of IL-17-mediated signaling...
  2. Shembade N, Harhaj N, Liebl D, Harhaj E. Essential role for TAX1BP1 in the termination of TNF-alpha-, IL-1- and LPS-mediated NF-kappaB and JNK signaling. EMBO J. 2007;26:3910-22 pubmed
    ..and LPS-mediated IKK and JNK activation is elevated and persistent owing to enhanced ubiquitination of RIP1 and TRAF6. Furthermore, in the absence of TAX1BP1, A20 is impaired in RIP1 binding, deubiquitination of TRAF6 and inhibition ..
  3. Sasai M, Tatematsu M, Oshiumi H, Funami K, Matsumoto M, Hatakeyama S, et al. Direct binding of TRAF2 and TRAF6 to TICAM-1/TRIF adaptor participates in activation of the Toll-like receptor 3/4 pathway. Mol Immunol. 2010;47:1283-91 pubmed publisher
    ..By mutation of the two distinct binding sites for TRAF2 and TRAF6 in N+TIR TICAM-1, the induction of IFN-beta was completely abrogated...
  4. Lee H, Jang S, Kim H, Yoon J, Chung K. PINK1 stimulates interleukin-1?-mediated inflammatory signaling via the positive regulation of TRAF6 and TAK1. Cell Mol Life Sci. 2012;69:3301-15 pubmed publisher
    ..We show that PINK1 specifically binds to TRAF6 and TAK1, and facilitates the autodimerization and autoubiquitination of TRAF6...
  5. Kanamori M, Kai C, Hayashizaki Y, Suzuki H. NF-kappaB activator Act1 associates with IL-1/Toll pathway adaptor molecule TRAF6. FEBS Lett. 2002;532:241-6 pubmed
    ..We identified and confirmed that Act1 interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6); notably, Act1 binds to TRAF6 only among TRAF family proteins...
  6. Ma Q, Zhou L, Shi H, Huo K. NUMBL interacts with TAB2 and inhibits TNFalpha and IL-1beta-induced NF-kappaB activation. Cell Signal. 2008;20:1044-51 pubmed publisher
    ..NUMBL also inhibited TAB2, TAK1, TRAF6 and RIP-induced activation of NF-kappaB in a dose-dependent manner...
  7. Zucchelli S, Codrich M, Marcuzzi F, Pinto M, Vilotti S, Biagioli M, et al. TRAF6 promotes atypical ubiquitination of mutant DJ-1 and alpha-synuclein and is localized to Lewy bodies in sporadic Parkinson's disease brains. Hum Mol Genet. 2010;19:3759-70 pubmed publisher
    ..In this study, we identify the E3 ubiquitin ligase tumor necrosis factor-receptor associated factor 6 (TRAF6) as a common player in genetic and sporadic cases. TRAF6 binds misfolded mutant DJ-1 and aSYN...
  8. Yuk J, Shin D, Lee H, Kim J, Kim S, Jin H, et al. The orphan nuclear receptor SHP acts as a negative regulator in inflammatory signaling triggered by Toll-like receptors. Nat Immunol. 2011;12:742-51 pubmed publisher
    ..both a repressor of transactivation of the NF-?B subunit p65 and an inhibitor of polyubiquitination of the adaptor TRAF6. SHP-mediated inhibition of signaling via the TLR was mimicked by macrophage-stimulating protein (MSP), a strong ..
  9. Sun H, Li X, Meng Y, Fan L, Li M, Fang J. TRAF6 upregulates expression of HIF-1? and promotes tumor angiogenesis. Cancer Res. 2013;73:4950-9 pubmed publisher
    TNF receptor (TNFR)-associated factor TRAF6 is a key activator of NF-?B, playing a critical role in the regulation of innate immune responses and their connection to adaptive immune responses...
  10. Heyninck K, Beyaert R. The cytokine-inducible zinc finger protein A20 inhibits IL-1-induced NF-kappaB activation at the level of TRAF6. FEBS Lett. 1999;442:147-50 pubmed
    ..by IL-1 is mediated by activation of the transcription factor NF-kappaB, and requires the signal adapter protein TRAF6. The latter interacts with the NF-kappaB-inducing kinase NIK, which is believed to be part of the IkappaB kinase ..
  11. Davies C, Mak T, Young L, Eliopoulos A. TRAF6 is required for TRAF2-dependent CD40 signal transduction in nonhemopoietic cells. Mol Cell Biol. 2005;25:9806-19 pubmed
    ..In this study we present evidence that the CD40-interacting proteins TRAF2 and TRAF6 play an important physiological role in CD40 signaling in nonhemopoietic cells...
  12. Shi M, Deng W, Bi E, Mao K, Ji Y, Lin G, et al. TRIM30 alpha negatively regulates TLR-mediated NF-kappa B activation by targeting TAB2 and TAB3 for degradation. Nat Immunol. 2008;9:369-77 pubmed publisher
    ..Our results collectively indicate that TRIM30alpha negatively regulates TLR-mediated NF-kappaB activation by targeting degradation of TAB2 and TAB3 by a 'feedback' mechanism. ..
  13. Murata H, Sakaguchi M, Kataoka K, Huh N. SARM1 and TRAF6 bind to and stabilize PINK1 on depolarized mitochondria. Mol Biol Cell. 2013;24:2772-84 pubmed publisher
    ..complex with sterile ? and TIR motif containing 1 (SARM1) and tumor necrosis factor receptor-associated factor 6 (TRAF6), which is important for import of PINK1 in the outer membrane and stabilization of PINK1 on depolarized ..
  14. Li X, Commane M, Jiang Z, Stark G. IL-1-induced NFkappa B and c-Jun N-terminal kinase (JNK) activation diverge at IL-1 receptor-associated kinase (IRAK). Proc Natl Acad Sci U S A. 2001;98:4461-5 pubmed
    ..These studies reveal that the IL-1-induced signaling pathways leading to NFkappaB and JNK activation diverge either at IRAK or at a point nearer to the receptor. ..
  15. Jiang Z, Mak T, Sen G, Li X. Toll-like receptor 3-mediated activation of NF-kappaB and IRF3 diverges at Toll-IL-1 receptor domain-containing adapter inducing IFN-beta. Proc Natl Acad Sci U S A. 2004;101:3533-8 pubmed
    ..Instead, TRAF6, TAK1, and TAB2 are recruited to TLR3 on poly(I.C) stimulation...
  16. Uemura N, Kajino T, Sanjo H, Sato S, Akira S, Matsumoto K, et al. TAK1 is a component of the Epstein-Barr virus LMP1 complex and is essential for activation of JNK but not of NF-kappaB. J Biol Chem. 2006;281:7863-72 pubmed
    ..Genetic analysis has revealed that tumor necrosis factor receptor-associated factor 6 (TRAF6) is an indispensable intermediate of LMP1 signaling leading to activation of both NF-kappaB and JNK...
  17. Bai S, Zha J, Zhao H, Ross F, Teitelbaum S. Tumor necrosis factor receptor-associated factor 6 is an intranuclear transcriptional coactivator in osteoclasts. J Biol Chem. 2008;283:30861-7 pubmed publisher
    Tumor necrosis factor receptor-associated factor 6 (TRAF6) associates with the cytoplasmic domain of receptor activator of NF-kappaB (RANK) and is an essential component of the signaling complex mediating osteoclastogenesis...
  18. Yin Q, Lin S, Lamothe B, Lu M, Lo Y, Hura G, et al. E2 interaction and dimerization in the crystal structure of TRAF6. Nat Struct Mol Biol. 2009;16:658-66 pubmed publisher
    ..Here we report the crystal structures of TRAF6 and its complex with the ubiquitin-conjugating enzyme (E2) Ubc13...
  19. Marinis J, Homer C, McDonald C, Abbott D. A novel motif in the Crohn's disease susceptibility protein, NOD2, allows TRAF4 to down-regulate innate immune responses. J Biol Chem. 2011;286:1938-50 pubmed publisher
    ..This work identifies a novel negative regulator of NOD2 signaling. Additionally, it defines a TRAF4 binding motif within NOD2 involved in termination of innate immune signaling responses. ..
  20. Bruneau S, Datta D, Flaxenburg J, Pal S, Briscoe D. TRAF6 inhibits proangiogenic signals in endothelial cells and regulates the expression of vascular endothelial growth factor. Biochem Biophys Res Commun. 2012;419:66-71 pubmed publisher
    ..Paradoxically, rather than inhibiting VEGF expression, we found that knockdown of TRAF6 resulted in a 4-6-fold increase in basal VEGF promoter activity compared to control siRNA-transfected EC (P<0...
  21. Wooten M, Seibenhener M, Mamidipudi V, Diaz Meco M, Barker P, Moscat J. The atypical protein kinase C-interacting protein p62 is a scaffold for NF-kappaB activation by nerve growth factor. J Biol Chem. 2001;276:7709-12 pubmed
    ..Here we show that the atypical protein kinase C-interacting protein, p62, which binds TRAF6, selectively interacts with TrkA but not p75. In contrast, TRAF6 interacts with p75 but not TrkA...
  22. Huang Q, Yang J, Lin Y, Walker C, Cheng J, Liu Z, et al. Differential regulation of interleukin 1 receptor and Toll-like receptor signaling by MEKK3. Nat Immunol. 2004;5:98-103 pubmed
    ..complex of MyD88, IL-1R-associated protein kinase (IRAK) and tumor necrosis factor receptor-associated factor 6 (TRAF6), which is believed to function 'upstream' of the cascades of IkappaB kinase (IKK) and nuclear factor-kappaB (NF-..
  23. Verstak B, Nagpal K, Bottomley S, Golenbock D, Hertzog P, Mansell A. MyD88 adapter-like (Mal)/TIRAP interaction with TRAF6 is critical for TLR2- and TLR4-mediated NF-kappaB proinflammatory responses. J Biol Chem. 2009;284:24192-203 pubmed publisher
    ..We have previously reported an interaction between Mal and tumor necrosis factor receptor-associated factor 6 (TRAF6) via a TRAF6-binding motif, the disruption of which inhibited TLR-mediated NF-kappaB-luciferase reporter activity...
  24. Zhang X, Zhang J, Zhang L, van Dam H, Ten Dijke P. UBE2O negatively regulates TRAF6-mediated NF-?B activation by inhibiting TRAF6 polyubiquitination. Cell Res. 2013;23:366-77 pubmed publisher
    Tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) is a key regulator of the activation of transcription factor NF-?B by the interleukin-1 receptor (IL-1R)/Toll-like receptor (TLR) superfamily...
  25. Bremm A, Freund S, Komander D. Lys11-linked ubiquitin chains adopt compact conformations and are preferentially hydrolyzed by the deubiquitinase Cezanne. Nat Struct Mol Biol. 2010;17:939-47 pubmed publisher
    ..Our data highlight the intrinsic specificity of the ubiquitin system that extends to Lys11-linked chains and emphasize that differentially linked polyubiquitin chains must be regarded as independent post-translational modifications. ..
  26. Windheim M, Stafford M, Peggie M, Cohen P. Interleukin-1 (IL-1) induces the Lys63-linked polyubiquitination of IL-1 receptor-associated kinase 1 to facilitate NEMO binding and the activation of IkappaBalpha kinase. Mol Cell Biol. 2008;28:1783-91 pubmed publisher
    ..Our data suggest a model in which the recruitment of the NEMO-IKK complex to K63-pUb-IRAK1 and the recruitment of the TAK1 complex to TRAF6 facilitate the TAK1-catalyzed activation of IKK by the TRAF6-IRAK1 complex.
  27. Paul P, Kumar A. TRAF6 coordinates the activation of autophagy and ubiquitin-proteasome systems in atrophying skeletal muscle. Autophagy. 2011;7:555-6 pubmed
    ..Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) is an important adaptor protein involved in receptor-mediated activation of various signaling pathways in ..
  28. Yasunaga J, Lin F, Lu X, Jeang K. Ubiquitin-specific peptidase 20 targets TRAF6 and human T cell leukemia virus type 1 tax to negatively regulate NF-kappaB signaling. J Virol. 2011;85:6212-9 pubmed publisher
    ..Here, we report that ubiquitin-specific peptidase USP20 deubiquitinates TRAF6 and Tax and suppresses interleukin 1? (IL-1?)- and Tax-induced NF-?B activation...
  29. Baud V, Liu Z, Bennett B, Suzuki N, Xia Y, Karin M. Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain. Genes Dev. 1999;13:1297-308 pubmed
    ..The TNF-alpha and IL-1 signals are transduced through TRAF2 and TRAF6, respectively. Overexpressed TRAF2 or TRAF6 activate JNK, p38, or IKK in the absence of extracellular stimulation...
  30. Wajant H, Henkler F, Scheurich P. The TNF-receptor-associated factor family: scaffold molecules for cytokine receptors, kinases and their regulators. Cell Signal. 2001;13:389-400 pubmed
    ..In this review, we address the structural and molecular basis of TRAF protein functions and highlight their role in cytokine signalling. ..
  31. Boone D, Turer E, Lee E, Ahmad R, Wheeler M, Tsui C, et al. The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat Immunol. 2004;5:1052-60 pubmed
    ..A20 accomplished this biochemically by directly removing ubiquitin moieties from the signaling molecule TRAF6. The critical function of this deubiquitinating enzyme in the restriction of TLR signals emphasizes the importance ..
  32. Lamothe B, Campos A, Webster W, Gopinathan A, Hur L, Darnay B. The RING domain and first zinc finger of TRAF6 coordinate signaling by interleukin-1, lipopolysaccharide, and RANKL. J Biol Chem. 2008;283:24871-80 pubmed publisher
    b>TRAF6, a crucial adaptor molecule in innate and adaptive immunity, contains three distinct functional domains...
  33. Ning S, Campos A, Darnay B, Bentz G, Pagano J. TRAF6 and the three C-terminal lysine sites on IRF7 are required for its ubiquitination-mediated activation by the tumor necrosis factor receptor family member latent membrane protein 1. Mol Cell Biol. 2008;28:6536-46 pubmed publisher
    ..Biol. 27:2910-2918, 2007). In this study, with the use of small interfering RNA and TNFR-associated factor 6 (TRAF6) knockout cells, we first show that TRAF6 and its E3 ligase activity are required for LMP1-stimulated IRF7 ..
  34. Ninomiya Tsuji J, Kishimoto K, Hiyama A, Inoue J, Cao Z, Matsumoto K. The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway. Nature. 1999;398:252-6 pubmed
    ..cascade that leads to activation of the transcription factor NF-kappaB and is relayed through the protein TRAF6 and a succession of kinase enzymes, including NF-kappaB-inducing kinase (NIK) and I kappaB kinases (IKKs)...
  35. Takaesu G, Kishida S, Hiyama A, Yamaguchi K, Shibuya H, Irie K, et al. TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway. Mol Cell. 2000;5:649-58 pubmed
    ..we report the identification of TAB2, a novel intermediate in the IL-1 pathway that functionally links TAK1 to TRAF6. Expression of TAB2 induces JNK and NF-kappaB activation, whereas a dominant-negative mutant TAB2 impairs their ..
  36. Seibenhener M, Babu J, Geetha T, Wong H, Krishna N, Wooten M. Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in ubiquitin proteasome degradation. Mol Cell Biol. 2004;24:8055-68 pubmed
    ..Altogether, our results support the hypothesis that p62 may act as a critical ubiquitin chain-targeting factor that shuttles substrates for proteasomal degradation. ..
  37. Kishida S, Sanjo H, Akira S, Matsumoto K, Ninomiya Tsuji J. TAK1-binding protein 2 facilitates ubiquitination of TRAF6 and assembly of TRAF6 with IKK in the IL-1 signaling pathway. Genes Cells. 2005;10:447-54 pubmed
    ..adaptor that links TAK1 to an upstream signaling intermediate, tumor necrosis factor receptor-associated factor 6 (TRAF6). Recently, ubiquitination of TRAF6 was shown to play an essential role in the activation of TAK1...
  38. Martin P, Diaz Meco M, Moscat J. The signaling adapter p62 is an important mediator of T helper 2 cell function and allergic airway inflammation. EMBO J. 2006;25:3524-33 pubmed
  39. Muroi M, Tanamoto K. TRAF6 distinctively mediates MyD88- and IRAK-1-induced activation of NF-kappaB. J Leukoc Biol. 2008;83:702-7 pubmed
    ..it is known that expression of these proteins leads to the activation of NF-kappaB in a TNFR-associated factor 6 (TRAF6)-dependent manner...
  40. Tao M, Scacheri P, Marinis J, Harhaj E, Matesic L, Abbott D. ITCH K63-ubiquitinates the NOD2 binding protein, RIP2, to influence inflammatory signaling pathways. Curr Biol. 2009;19:1255-63 pubmed publisher
    ..These findings suggest that ITCH helps regulate NOD2-dependent signal transduction pathways and, as such, may be involved in the pathogenesis of NOD2-mediated inflammatory disease. ..
  41. Fitzgerald K, Palsson McDermott E, Bowie A, Jefferies C, Mansell A, Brady G, et al. Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature. 2001;413:78-83 pubmed
    ..Mal associates with TLR-4. Mal is therefore an adapter in TLR-4 signal transduction. ..
  42. Jiang Z, Ninomiya Tsuji J, Qian Y, Matsumoto K, Li X. Interleukin-1 (IL-1) receptor-associated kinase-dependent IL-1-induced signaling complexes phosphorylate TAK1 and TAB2 at the plasma membrane and activate TAK1 in the cytosol. Mol Cell Biol. 2002;22:7158-67 pubmed
    ..We now find that the phosphorylated IRAK in turn recruits TRAF6 to the receptor complex (complex I), which differs from the previous concept that IRAK interacts with TRAF6 after ..
  43. Yoshida Y, Kumar A, Koyama Y, Peng H, Arman A, Boch J, et al. Interleukin 1 activates STAT3/nuclear factor-kappaB cross-talk via a unique TRAF6- and p65-dependent mechanism. J Biol Chem. 2004;279:1768-76 pubmed
    ..bind p65 homodimers, is shown to be uniquely dependent upon signal transduction through the carboxyl terminus of TRAF6. Furthermore, STAT3 and p65 are shown to physically interact, in vivo, and this interaction appears to inhibit the ..
  44. Wooten M, Geetha T, Seibenhener M, Babu J, Diaz Meco M, Moscat J. The p62 scaffold regulates nerve growth factor-induced NF-kappaB activation by influencing TRAF6 polyubiquitination. J Biol Chem. 2005;280:35625-9 pubmed
    ..1/p62 is a scaffolding protein with several interaction modules that include a PB1 dimerization domain, a TRAF6 (tumor necrosis factor receptor-associated factor 6) binding site, and a ubiquitin-associating (UBA) domain...
  45. Lappalainen M, Paavola Sakki P, Halme L, Turunen U, Helio T, Farkkila M, et al. Screening of tumor necrosis factor receptor-associated factor 6 as a candidate gene for inflammatory bowel disease. Scand J Gastroenterol. 2006;41:424-9 pubmed
    ..region contains a functional IBD candidate gene coding for tumor necrosis factor receptor-associated factor 6 (TRAF6), a signal transducer regulating innate and adaptive immunity as well as bone homeostasis...
  46. Lamothe B, Besse A, Campos A, Webster W, Wu H, Darnay B. 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;282:4102-12 pubmed
    Tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) is a key mediator in proximal signaling of the interleukin-1/Toll-like receptor and the TNF receptor superfamily...
  47. Yoshida R, Takaesu G, Yoshida H, Okamoto F, Yoshioka T, Choi Y, et al. TRAF6 and MEKK1 play a pivotal role in the RIG-I-like helicase antiviral pathway. J Biol Chem. 2008;283:36211-20 pubmed publisher
    ..b>TRAF6 and the downstream kinase TAK1 have been shown to be essential for the production of proinflammatory cytokines ..
  48. Wang K, Galson D, Auron P. TRAF6 is autoinhibited by an intramolecular interaction which is counteracted by trans-ubiquitination. J Cell Biochem. 2010;110:763-71 pubmed publisher
    ..Investigation of the mechanism by which TRAF6 is activated has demonstrated that two critical domains of the molecule required for activation and downstream ..
  49. Liu X, Wei B, Shi H, Shan Y, Wang C. Tom70 mediates activation of interferon regulatory factor 3 on mitochondria. Cell Res. 2010;20:994-1011 pubmed publisher
    ..Collectively, our study characterizes Tom70 as a critical adaptor linking MAVS to TBK1/IRF3, revealing that mitochondrion is evolutionarily integrated with innate immunity. ..
  50. Hinz M, Stilmann M, Arslan S, Khanna K, Dittmar G, Scheidereit C. A cytoplasmic ATM-TRAF6-cIAP1 module links nuclear DNA damage signaling to ubiquitin-mediated NF-?B activation. Mol Cell. 2010;40:63-74 pubmed publisher
    ..Through a TRAF-binding motif, ATM activates TRAF6, resulting in Ubc13-mediated K63-linked polyubiquitin synthesis and cIAP1 recruitment...
  51. Kobayashi N, Kadono Y, Naito A, Matsumoto K, Yamamoto T, Tanaka S, et al. Segregation of TRAF6-mediated signaling pathways clarifies its role in osteoclastogenesis. EMBO J. 2001;20:1271-80 pubmed
    ..These kinases are thought to be activated by tumor necrosis factor receptor-associated factor 6 (TRAF6). However, molecular mechanisms by which TRAF6 activates various downstream kinases remain to be elucidated...
  52. Evans P, Taylor E, Coadwell J, Heyninck K, Beyaert R, Kilshaw P. Isolation and characterization of two novel A20-like proteins. Biochem J. 2001;357:617-23 pubmed
    ..Co-immunoprecipitation studies indicated that TRAF6 was able to interact with both Cezanne and TRABID...
  53. Mansell A, Brint E, Gould J, O Neill L, Hertzog P. Mal interacts with tumor necrosis factor receptor-associated factor (TRAF)-6 to mediate NF-kappaB activation by toll-like receptor (TLR)-2 and TLR4. J Biol Chem. 2004;279:37227-30 pubmed
    ..In this study, we have identified a putative TRAF6 interaction site in Mal but not in MyD88 and we demonstrate that Mal can be co-immunoprecipitated with TRAF6...
  54. Kawai T, Sato S, Ishii K, Coban C, Hemmi H, Yamamoto M, et al. Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat Immunol. 2004;5:1061-8 pubmed
    ..Furthermore, the adaptor molecule TRAF6 also bound and activated IRF7. Ubiquitin ligase activity of TRAF6 was required for IRF7 activation...
  55. Wan J, Zhang W, Wu L, Bai T, Zhang M, Lo K, et al. BS69, a specific adaptor in the latent membrane protein 1-mediated c-Jun N-terminal kinase pathway. Mol Cell Biol. 2006;26:448-56 pubmed
    ..potently activates the cellular c-Jun N-terminal kinase (JNK) pathway by sequentially engaging an unknown adaptor, TRAF6, TAB1/TAK1, and JNKKs...
  56. Lin S, Chung J, Lamothe B, Rajashankar K, Lu M, Lo Y, et al. Molecular basis for the unique deubiquitinating activity of the NF-kappaB inhibitor A20. J Mol Biol. 2008;376:526-40 pubmed publisher
    ..domain of A20 is a deubiquitinating enzyme (DUB) for Lys63-linked polyubiquitinated signaling mediators such as TRAF6 and RIP, its C-terminal domain is a ubiquitin ligase (E3) for Lys48-linked degradative polyubiquitination of the ..
  57. Conze D, Wu C, Thomas J, Landstrom A, Ashwell J. Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and toll-like receptor-mediated NF-kappaB activation. Mol Cell Biol. 2008;28:3538-47 pubmed publisher
    ..Stimulation through the interleukin-1 receptor (IL-1R) and some Toll-like receptors (TLRs) induces ubiquitination of TRAF6 and IRAK-1, signaling components required for NF-kappaB and mitogen-activated protein kinase activation...
  58. Sorrentino A, Thakur N, Grimsby S, Marcusson A, von Bulow V, Schuster N, et al. The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner. Nat Cell Biol. 2008;10:1199-207 pubmed publisher
    ..However, the molecular mechanisms for its activation are unknown. Here we report that the ubiquitin ligase (E3) TRAF6 interacts with a consensus motif present in TbetaRI...
  59. An J, Mo D, Liu H, Veena M, Srivatsan E, Massoumi R, et al. Inactivation of the CYLD deubiquitinase by HPV E6 mediates hypoxia-induced NF-kappaB activation. Cancer Cell. 2008;14:394-407 pubmed publisher
    ..Given the established role of NF-kappaB in human carcinogenesis, these findings provide a potential molecular/viral link between hypoxia and the adverse clinical outcomes observed in HPV-associated malignancies. ..
  60. Zhou L, Ma Q, Shi H, Huo K. NUMBL interacts with TRAF6 and promotes the degradation of TRAF6. Biochem Biophys Res Commun. 2010;392:409-14 pubmed publisher
    Tumor necrosis factor-associated factor 6 (TRAF6) is an essential adaptor protein for IL-1R or TLR-mediated NF-kappaB signaling pathway activation...
  61. Shi C, Kehrl J. TRAF6 and A20 regulate lysine 63-linked ubiquitination of Beclin-1 to control TLR4-induced autophagy. Sci Signal. 2010;3:ra42 pubmed publisher
    ..We found that tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6)-mediated, Lys(63) (K63)-linked ubiquitination of Beclin-1 is critical for TLR4-triggered autophagy in macrophages...
  62. Megas C, Hatzivassiliou E, Yin Q, Marinopoulou E, Hadweh P, Vignali D, et al. Mutational analysis of TRAF6 reveals a conserved functional role of the RING dimerization interface and a potentially necessary but insufficient role of RING-dependent TRAF6 polyubiquitination towards NF-?B activation. Cell Signal. 2011;23:772-7 pubmed publisher
    b>TRAF6 is an E3 ubiquitin ligase that plays a pivotal role in the activation of NF-?B by innate and adaptive immunity stimuli...
  63. Schwandner R, Yamaguchi K, Cao Z. Requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in interleukin 17 signal transduction. J Exp Med. 2000;191:1233-40 pubmed
    ..In embryonic fibroblasts (EFs) derived from TRAF6 knockout mice, IL-17 failed to activate the IkappaB kinases (IKKs) and JNK...
  64. Trompouki E, Hatzivassiliou E, Tsichritzis T, Farmer H, Ashworth A, Mosialos G. CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members. Nature. 2003;424:793-6 pubmed
    ..in part, by the deubiquitination and inactivation of TNFR-associated factor 2 (TRAF2) and, to a lesser extent, TRAF6. These results indicate that CYLD is a negative regulator of the cytokine-mediated activation of NF-kappaB that is ..
  65. Kovalenko A, Chable Bessia C, Cantarella G, Israel A, Wallach D, Courtois G. The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. Nature. 2003;424:801-5 pubmed
    ..Truncations of CYLD found in cylindromatosis result in reduced enzymatic activity, indicating a link between impaired deubiquitination of CYLD substrates and human pathophysiology. ..
  66. Takaoka A, Yanai H, Kondo S, Duncan G, Negishi H, Mizutani T, et al. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature. 2005;434:243-9 pubmed
    ..We also provide evidence that IRF-5 interacts with and is activated by MyD88 and TRAF6, and that TLR activation results in the nuclear translocation of IRF-5 to activate cytokine gene transcription...
  67. Feng Y, Longmore G. The LIM protein Ajuba influences interleukin-1-induced NF-kappaB activation by affecting the assembly and activity of the protein kinase Czeta/p62/TRAF6 signaling complex. Mol Cell Biol. 2005;25:4010-22 pubmed
    ..in response to interleukin-1 (IL-1) and tumor necrosis factor signaling through the formation of an aPKC/p62/TRAF6 multiprotein signaling complex...
  68. Zhao J, Kong H, Li H, Huang B, Yang M, Zhu C, et al. IRF-8/interferon (IFN) consensus sequence-binding protein is involved in Toll-like receptor (TLR) signaling and contributes to the cross-talk between TLR and IFN-gamma signaling pathways. J Biol Chem. 2006;281:10073-80 pubmed
    ..Furthermore, co-immunoprecipitation experiments show that IRF-8 physically interacts with TRAF6 at a binding site between amino acid residues 356 and 305 of IRF-8...
  69. Shembade N, Harhaj N, Yamamoto M, Akira S, Harhaj E. The human T-cell leukemia virus type 1 Tax oncoprotein requires the ubiquitin-conjugating enzyme Ubc13 for NF-kappaB activation. J Virol. 2007;81:13735-42 pubmed
    ..Collectively, our results reveal that Ubc13 is essential for Tax ubiquitination, its interaction with NEMO, and Tax-mediated NF-kappaB activation...
  70. Xiao H, Qian W, Staschke K, Qian Y, Cui G, Deng L, et al. Pellino 3b negatively regulates interleukin-1-induced TAK1-dependent NF kappaB activation. J Biol Chem. 2008;283:14654-64 pubmed publisher
    ..Taken together, our results suggest that Pellino 3b acts as a negative regulator for IL-1 signaling by regulating IRAK degradation through its ubiquitin protein ligase activity. ..
  71. McCully R, Pomerantz J. The protein kinase C-responsive inhibitory domain of CARD11 functions in NF-kappaB activation to regulate the association of multiple signaling cofactors that differentially depend on Bcl10 and MALT1 for association. Mol Cell Biol. 2008;28:5668-86 pubmed publisher
    ..inhibitory domain (ID) that controls the association of CARD11 with multiple signaling cofactors, including Bcl10, TRAF6, TAK1, IKKgamma, and caspase-8, through an interaction that requires both the caspase recruitment domain (CARD) ..
  72. Ha U, Lim J, Kim H, Wu W, Jin S, Xu H, et al. MKP1 regulates the induction of MUC5AC mucin by Streptococcus pneumoniae pneumolysin by inhibiting the PAK4-JNK signaling pathway. J Biol Chem. 2008;283:30624-31 pubmed publisher
    ..Moreover pneumolysin also selectively induced expression of MKP1 via a TLR4-dependent MyD88-TRAF6-ERK signaling pathway, which inhibited the PAK4-JNK signaling pathway, thereby leading to up-regulation of MUC5AC ..
  73. Meng Q, Zheng M, Liu H, Song C, Zhang W, Yan J, et al. TRAF6 regulates proliferation, apoptosis, and invasion of osteosarcoma cell. Mol Cell Biochem. 2012;371:177-86 pubmed publisher
    b>TRAF6, a unique tumor necrosis factor receptor-associated factor (TRAF) family member, possesses a unique receptor-binding specificity that results in its crucial role as the signaling mediator for TNF receptor superfamily and ..
  74. Wong B, Besser D, Kim N, Arron J, Vologodskaia M, Hanafusa H, et al. TRANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src. Mol Cell. 1999;4:1041-9 pubmed
    ..TRANCE activates the antiapoptotic serine/threonine kinase Akt/PKB through a signaling complex involving c-Src and TRAF6. A deficiency in c-Src or addition of Src family kinase inhibitors blocks TRANCE-mediated PKB activation in ..
  75. Xia X, Treanor J, Senaldi G, Khare S, Boone T, Kelley M, et al. TACI is a TRAF-interacting receptor for TALL-1, a tumor necrosis factor family member involved in B cell regulation. J Exp Med. 2000;192:137-43 pubmed
    ..The identification and characterization of the receptor for TALL-1 provides useful information for the development of a treatment for B cell-mediated autoimmune diseases such as systemic lupus erythematosus. ..
  76. Wald D, Qin J, Zhao Z, Qian Y, Naramura M, Tian L, et al. SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling. Nat Immunol. 2003;4:920-7 pubmed
    ..Finally, biochemical analysis indicated that SIGIRR binds to the TLR-IL-1R signaling components in a ligand-dependent way. Our data show that SIGIRR functions as a biologically important modulator of TLR-IL-1R signaling. ..
  77. Sato S, Sugiyama M, Yamamoto M, Watanabe Y, Kawai T, Takeda K, et al. Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory factor-3, in the Toll-li. J Immunol. 2003;171:4304-10 pubmed
    ..TNF receptor-associated factor (TRAF)6 interacted with TRIF through the TRAF domain of TRAF6 and TRAF6-binding motifs found in the N-terminal portion of TRIF...
  78. Mukundan L, Bishop G, Head K, Zhang L, Wahl L, Suttles J. TNF receptor-associated factor 6 is an essential mediator of CD40-activated proinflammatory pathways in monocytes and macrophages. J Immunol. 2005;174:1081-90 pubmed
    ..However, ligation of a CD40 mutant lacking a functional TRAF6 binding site did not initiate inflammatory cytokine production, and this mutant was found to be defective in CD40-..
  79. Xu L, Wang Y, Han K, Li L, Zhai Z, Shu H. VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell. 2005;19:727-40 pubmed
    ..Our data also indicate that VISA interacts with TRIF and TRAF6 and mediates bifurcation of the TLR3-triggered NF-kappaB and IRF-3 activation pathways...
  80. LeBlanc P, Yeretssian G, Rutherford N, Doiron K, Nadiri A, Zhu L, et al. Caspase-12 modulates NOD signaling and regulates antimicrobial peptide production and mucosal immunity. Cell Host Microbe. 2008;3:146-57 pubmed publisher
    ..Mechanistically, caspase-12 binds to Rip2, displacing Traf6 from the signaling complex, inhibiting its ubiquitin ligase activity, and blunting NF-kappaB activation...
  81. Lee J, Lee H, Lee E, Jang S, Kim H, Yoon J, et al. Down syndrome candidate region-1 protein interacts with Tollip and positively modulates interleukin-1 receptor-mediated signaling. Biochim Biophys Acta. 2009;1790:1673-80 pubmed publisher
    ..signaling by analyzing interaction between DSCR1-1S and the IL-1R pathway components Tollip, IRAK-1, and TRAF6. Co-immunoprecipitation analyses of HEK293 cells revealed that DSCR1-1S interacted with Tollip, an IRAK-1 ..
  82. Emmerich C, Ordureau A, Strickson S, Arthur J, Pedrioli P, Komander D, et al. Activation of the canonical IKK complex by K63/M1-linked hybrid ubiquitin chains. Proc Natl Acad Sci U S A. 2013;110:15247-52 pubmed publisher
    ..Our study may help to resolve the debate about the relative importance of K63-pUb and M1-pUb chains in activating the canonical IKK complex. ..
  83. Pype S, Declercq W, Ibrahimi A, Michiels C, Van Rietschoten J, Dewulf N, et al. TTRAP, a novel protein that associates with CD40, tumor necrosis factor (TNF) receptor-75 and TNF receptor-associated factors (TRAFs), and that inhibits nuclear factor-kappa B activation. J Biol Chem. 2000;275:18586-93 pubmed
    ..The region of the CD40 cytoplasmic domain that is required for TTRAP association overlaps with the TRAF6 recognition motif...
  84. Mochida Y, Takeda K, Saitoh M, Nishitoh H, Amagasa T, Ninomiya Tsuji J, et al. ASK1 inhibits interleukin-1-induced NF-kappa B activity through disruption of TRAF6-TAK1 interaction. J Biol Chem. 2000;275:32747-52 pubmed
    ..Overexpression of ASK1 inhibits IL-1-, TRAF6-, or TAK1-induced, but not NF-kappaB-inducing kinase-induced, NF-kappaB activation...
  85. Bradley J, Pober J. Tumor necrosis factor receptor-associated factors (TRAFs). Oncogene. 2001;20:6482-91 pubmed
    ..are thought to be important regulators of cell death and cellular responses to stress, and TRAF2, TRAF5 and TRAF6 have been demonstrated to mediate activation of NF-kappaB and JNK...
  86. Kollewe C, Mackensen A, Neumann D, Knop J, Cao P, Li S, et al. Sequential autophosphorylation steps in the interleukin-1 receptor-associated kinase-1 regulate its availability as an adapter in interleukin-1 signaling. J Biol Chem. 2004;279:5227-36 pubmed
    ..of IRAK-1 from the upstream adapters MyD88 and Tollip but leaves its interaction with the downstream adapter TRAF6 unaffected...
  87. Ishitani T, Takaesu G, Ninomiya Tsuji J, Shibuya H, Gaynor R, Matsumoto K. Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling. EMBO J. 2003;22:6277-88 pubmed
    ..TAB2, a TAK1-binding protein, is involved in IL-1-induced NF-kappaB activation by physically linking TAK1 to TRAF6. However, IL-1-induced activation of NF-kappaB is not impaired in TAB2-deficient embryonic fibroblasts...
  88. Seth R, Sun L, Ea C, Chen Z. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell. 2005;122:669-82 pubmed
    ..The transmembrane domain targets MAVS to the mitochondria, implicating a new role of mitochondria in innate immunity...
  89. Petroski M, Zhou X, Dong G, Daniel Issakani S, Payan D, Huang J. Substrate modification with lysine 63-linked ubiquitin chains through the UBC13-UEV1A ubiquitin-conjugating enzyme. J Biol Chem. 2007;282:29936-45 pubmed
    ..we have developed an in vitro system to examine the activity of the ubiquitin-conjugating enzyme UBC13-UEV1A with TRAF6 in which TRAF6 serves as both a ubiquitin ligase and substrate for modification...
  90. Xia Z, Sun L, Chen X, Pineda G, Jiang X, Adhikari A, et al. Direct activation of protein kinases by unanchored polyubiquitin chains. Nature. 2009;461:114-9 pubmed publisher
    b>TRAF6 is a ubiquitin ligase that is essential for the activation of NF-kappaB and MAP kinases in several signalling pathways, including those emanating from the interleukin 1 and Toll-like receptors...
  91. Li S, Zheng H, Mao A, Zhong B, Li Y, Liu Y, et al. Regulation of virus-triggered signaling by OTUB1- and OTUB2-mediated deubiquitination of TRAF3 and TRAF6. J Biol Chem. 2010;285:4291-7 pubmed publisher
    ..Coimmunoprecipitations indicated OTUB1 and -2 interacted with TRAF3 and TRAF6, two E3 ubiquitin ligases required for virus-triggered IRF3 and NF-kappaB activation, respectively...
  92. Mu Y, Sundar R, Thakur N, Ekman M, Gudey S, Yakymovych M, et al. TRAF6 ubiquitinates TGF? type I receptor to promote its cleavage and nuclear translocation in cancer. Nat Commun. 2011;2:330 pubmed publisher
    ..T?RI is associated with the ubiquitin ligase tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6)...