tumor necrosis factor receptor associated peptides and proteins


Summary: Intracellular signaling peptides and proteins that bind directly or indirectly to the cytoplasmic portion of TUMOR NECROSIS FACTOR RECEPTORS.

Top Publications

  1. Zheng L, Bidere N, Staudt D, Cubre A, Orenstein J, Chan F, et al. Competitive control of independent programs of tumor necrosis factor receptor-induced cell death by TRADD and RIP1. Mol Cell Biol. 2006;26:3505-13 pubmed
    ..These single transducers determine cell fate by triggering NF-kappaB activation, apoptosis, and nonapoptotic death signals through separate and competing signaling pathways. ..
  2. Hunter C. Act1-ivating IL-17 inflammation. Nat Immunol. 2007;8:232-4 pubmed
  3. Hsu H, Shu H, Pan M, Goeddel D. TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell. 1996;84:299-308 pubmed
    ..Thus, these two TNFR1-TRADD signaling cascades appear to bifurcate at TRADD. ..
  4. Lee N, Lee S. Modulation of life and death by the tumor necrosis factor receptor-associated factors (TRAFs). J Biochem Mol Biol. 2002;35:61-6 pubmed
    ..In addition, TRAFs interact with a variety of proteins that regulate receptor-induced cell death or survival. Thus, TRAF-mediated signals may directly induce cell survival or interfere with the death receptor-induced apoptosis. ..
  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
    ..These findings provide novel insights into autoregulation and negative regulation of TLR signaling. ..
  6. Schneider Brachert W, Tchikov V, Neumeyer J, Jakob M, Winoto Morbach S, Held Feindt J, et al. Compartmentalization of TNF receptor 1 signaling: internalized TNF receptosomes as death signaling vesicles. Immunity. 2004;21:415-28 pubmed
    ..Thus, TNF receptosomes establish the different TNF signaling pathways by compartmentalization of plasma membrane-derived endocytic vesicles harboring the TNF-R1-associated DISC. ..
  7. Xu Y, Wu R, Gu Y, Yang Y, Yang M, Nwariaku F, et al. Involvement of TRAF4 in oxidative activation of c-Jun N-terminal kinase. J Biol Chem. 2002;277:28051-7 pubmed
    ..We speculate that endothelial cells may target endogenous oxidant production to specific sites critical to cytokine signaling as a mechanism for increasing signal specificity and decreasing toxicity of these reactive species. ..
  8. Sato T, Irie S, Reed J. A novel member of the TRAF family of putative signal transducing proteins binds to the cytosolic domain of CD40. FEBS Lett. 1995;358:113-8 pubmed
  9. Qian Y, Liu C, Hartupee J, Altuntas C, Gulen M, Jane wit D, et al. The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease. Nat Immunol. 2007;8:247-56 pubmed
    ..Our data show that Act1 is essential in IL-17-dependent signaling in autoimmune and inflammatory disease. ..

More Information


  1. Zapata J, Martínez García V, Lefebvre S. Phylogeny of the TRAF/MATH domain. Adv Exp Med Biol. 2007;597:1-24 pubmed
    ..However, the available information allows us to get a glimpse on the origins, distribution and evolution of the TRAF/MATH domain, which will be overviewed in this chapter. ..
  2. Chan H, Reed J. TRAF-dependent association of protein kinase Tpl2/COT1 (MAP3K8) with CD40. Biochem Biophys Res Commun. 2005;328:198-205 pubmed
    ..These results indicate a distinction between TNF Receptor family members CD40 and TNFR1 in their utilization of MAP3Ks, and demonstrate TRAF-dependence of Tpl2 association with the CD40 receptor complex. ..
  3. Hsu L, Schultz L, Mattison J, Lin Y, Chang N. Cloning and characterization of a small-size peptide Zfra that regulates the cytotoxic function of tumor necrosis factor by interacting with JNK1. Biochem Biophys Res Commun. 2005;327:415-23 pubmed
    ..While JNK1 is a downstream effector of the TNF signaling, Zfra regulation of the TNF cytotoxic function is likely due to its interaction, in part, with JNK1. ..
  4. 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
    ..Our results suggest that Act1 is involved in IL-1/Toll-mediated signaling through TRAF6. ..
  5. Park Y, Ye H, Hsia C, Segal D, Rich R, Liou H, et al. A novel mechanism of TRAF signaling revealed by structural and functional analyses of the TRADD-TRAF2 interaction. Cell. 2000;101:777-87 pubmed
    ..The stronger affinity and unique specificity of the TRADD-TRAF2 interaction are crucial for the suppression of apoptosis and provide a mechanistic basis for the perturbation of TRAF recruitment in sensitizing cell death induction. ..
  6. Chung J, Park Y, Ye H, Wu H. All TRAFs are not created equal: common and distinct molecular mechanisms of TRAF-mediated signal transduction. J Cell Sci. 2002;115:679-88 pubmed
    ..We raise additional questions and propose hypotheses regarding the molecular basis of TRAF signaling specificity. ..
  7. Regnier C, Tomasetto C, Moog Lutz C, Chenard M, Wendling C, Basset P, et al. 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;270:25715-21 pubmed
    ..Moreover, in these malignant cells, the CART1 protein is localized in the nucleus. Altogether, these observations indicate that CART1 may be involved in TNF-related cytokine signal transduction in breast carcinoma. ..
  8. Hu H, O Rourke K, Boguski M, Dixit V. A novel RING finger protein interacts with the cytoplasmic domain of CD40. J Biol Chem. 1994;269:30069-72 pubmed
    ..This is the first identification of a molecule that interacts with CD40 and whose sequence suggests a potential role in signaling. ..
  9. Lee S, Choi Y. TRAF-interacting protein (TRIP): a novel component of the tumor necrosis factor receptor (TNFR)- and CD30-TRAF signaling complexes that inhibits TRAF2-mediated NF-kappaB activation. J Exp Med. 1997;185:1275-85 pubmed
    ..Thus, TRIP acts as a receptor-proximal regulator that may influence signals responsible for cell activation/proliferation and cell death induced by members of the TNFR superfamily. ..
  10. Hsu H, Xiong J, Goeddel D. The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell. 1995;81:495-504 pubmed
    ..However, NF-kappa B activation by TRADD is not inhibited by crmA expression, demonstrating that the signaling pathways for TNF-induced cell death and NF-kappa B activation are distinct. ..
  11. Regamey A, Hohl D, Liu J, Roger T, Kogerman P, Toftgard R, et al. The tumor suppressor CYLD interacts with TRIP and regulates negatively nuclear factor kappaB activation by tumor necrosis factor. J Exp Med. 2003;198:1959-64 pubmed
    ..These findings indicate that cylindromas arise through constitutive NF-kappaB activation leading to hyperproliferation and tumor growth. ..
  12. Regnier C, Masson R, Kedinger V, Textoris J, Stoll I, Chenard M, et al. Impaired neural tube closure, axial skeleton malformations, and tracheal ring disruption in TRAF4-deficient mice. Proc Natl Acad Sci U S A. 2002;99:5585-90 pubmed
    ..Considering the normal expression pattern of TRAF4 in neural tissues, we can conclude that TRAF4 participates in neurulation in vivo. ..
  13. Wu C, Conze D, Li T, Srinivasula S, Ashwell J. Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-kappaB activation [corrected]. Nat Cell Biol. 2006;8:398-406 pubmed
    ..These results provide a mechanism for NEMO's critical role in IKK activation, and a key to understanding the link between cytokine-receptor proximal signalling and IKK and NF-kappaB activation. ..
  14. Besse A, Campos A, Webster W, Darnay B. TRAF-interacting protein (TRIP) is a RING-dependent ubiquitin ligase. Biochem Biophys Res Commun. 2007;359:660-4 pubmed
    ..Interestingly, TRIP expression was down regulated during the late stages of osteoclastogenesis. Taken together, our results demonstrate that TRIP is a novel RING-dependent Ub ligase and a binding partner for TRAFs. ..
  15. Chaigne Delalande B, Moreau J, Legembre P. Rewinding the DISC. Arch Immunol Ther Exp (Warsz). 2008;56:9-14 pubmed publisher
    ..However, the accurate molecular ordering upstream from the formation of DISC remains very puzzling and is highly debated. Herein we review some of the factors that would potentially facilitate or limit the formation of the DISC. ..
  16. Unterstab G, Ludwig S, Anton A, Planz O, Dauber B, Krappmann D, et al. Viral targeting of the interferon-{beta}-inducing Traf family member-associated NF-{kappa}B activator (TANK)-binding kinase-1. Proc Natl Acad Sci U S A. 2005;102:13640-5 pubmed
    ..Thus, our findings provide evidence for a previously undescribed mechanism by which a viral protein interferes with the induction of the antiviral IFN cascade. ..
  17. Kim Y, Morgan M, Choksi S, Liu Z. TNF-induced activation of the Nox1 NADPH oxidase and its role in the induction of necrotic cell death. Mol Cell. 2007;26:675-87 pubmed
    ..Thus our study suggests that activation of Nox1 through forming a complex with TNF signaling components plays a key role in TNF-induced necrotic cell death. ..
  18. Courtney J, Blackburn J, Sharpe P. The Ectodysplasin and NFkappaB signalling pathways in odontogenesis. Arch Oral Biol. 2005;50:159-63 pubmed
    ..Here we review recent advances in our understanding of Ectodysplasin/NFkappaB signalling in tooth development and in particular the central role of the IKK complex. ..
  19. Elgueta R, Benson M, de Vries V, Wasiuk A, Guo Y, Noelle R. Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol Rev. 2009;229:152-72 pubmed publisher
    ..Lastly, we discuss the role of CD40 as a target in harnessing anti-tumor immunity. This review underscores the essential role CD40 plays in adaptive immunity. ..
  20. Hwang I, Lee H, Yoo K, Kim J, Kim J, Kim C, et al. Rip immunoreactivity significantly decreases in the stratum oriens of hippocampal CA1 region after transient forebrain ischemia in gerbils. Brain Res. 2006;1073-1074:491-6 pubmed
  21. Smyth L, Brady H. cMet and Fas receptor interaction inhibits death-inducing signaling complex formation in endothelial cells. Hypertension. 2005;46:100-6 pubmed
    ..cMet/Fas interaction may help explain why endothelial cells are resistant to Fas-mediated apoptosis. ..
  22. Gorski L, Gronewold T, Kaiser D. A sigma(54) activator protein necessary for spore differentiation within the fruiting body of Myxococcus xanthus. J Bacteriol. 2000;182:2438-44 pubmed
    ..The act1 mutant, unable to raise the level of csgA expression, carries out only those developmental steps for which a low level of C-signaling is adequate. ..
  23. Arron J, Walsh M, Choi Y. TRAF-mediated TNFR-family signaling. Curr Protoc Immunol. 2002;Chapter 11:Unit 11.9D pubmed publisher
    ..Structural features of TRAF proteins are described along with a discussion of TRAF-interacting proteins and the signaling pathways activated by TRAF proteins. Finally, a discussion is provided on the phenotypes of TRAF-knockout mice. ..
  24. Lee K, Feig C, Tchikov V, Schickel R, Hallas C, Schütze S, et al. The role of receptor internalization in CD95 signaling. EMBO J. 2006;25:1009-23 pubmed
    ..Hence, the subcellular localization and internalization pathways of CD95 play important roles in controlling activation of distinct signaling cascades to determine divergent cellular fates. ..
  25. Morse M, Clay T, Colling K, Lyerly H. Preparation of peptide-loaded dendritic cells for cancer immunotherapy. Mol Biotechnol. 2003;25:95-9 pubmed
    ..We describe the scheme that we are currently using to generate peptide-loaded dendritic cells for our clinical trials of cancer immunotherapy. ..
  26. Kim S, Kim J, Lee D, Kwak J, Lee S. Genipin protects lipopolysaccharide-induced apoptotic liver damage in D-galactosamine-sensitized mice. Eur J Pharmacol. 2010;635:188-93 pubmed publisher
  27. Silke J, Brink R. Regulation of TNFRSF and innate immune signalling complexes by TRAFs and cIAPs. Cell Death Differ. 2010;17:35-45 pubmed publisher
  28. Polek T, Talpaz M, Spivak Kroizman T. The TNF receptor, RELT, binds SPAK and uses it to mediate p38 and JNK activation. Biochem Biophys Res Commun. 2006;343:125-34 pubmed
    ..In addition, a kinase-dead SPAK acted as an inhibitor of RELT signaling. Thus, we conclude that RELT does not rely on the canonical TRAF pathways for its function, but instead uses a kinase, SPAK, to mediate p38 and JNK activation. ..
  29. Mareninova O, Sung K, Hong P, Lugea A, Pandol S, Gukovsky I, et al. Cell death in pancreatitis: caspases protect from necrotizing pancreatitis. J Biol Chem. 2006;281:3370-81 pubmed
    ..Manipulating these signals to change the pattern of death responses presents a therapeutic strategy for treatment of pancreatitis. ..
  30. Iordanov M, Kirsch J, Ryabinina O, Wong J, Spitz P, Korcheva V, et al. Recruitment of TRADD, FADD, and caspase 8 to double-stranded RNA-triggered death inducing signaling complexes (dsRNA-DISCs). Apoptosis. 2005;10:167-76 pubmed
    ..DsRNA-DISCs contain FADD, TRADD, and caspase 8; however, several experimental approaches suggest that death ligands and death receptors (such as Fas/Apo1 and DR4/Apo2) are not involved in the formation of dsRNA-DISCs. ..
  31. Pobezinskaya Y, Kim Y, Choksi S, Morgan M, Li T, Liu C, et al. The function of TRADD in signaling through tumor necrosis factor receptor 1 and TRIF-dependent Toll-like receptors. Nat Immunol. 2008;9:1047-54 pubmed publisher
    ..TRADD was also required for TRIF-dependent Toll-like receptor signaling in mouse embryonic fibroblasts but not macrophages. Our findings definitively establish the biological function of TRADD in TNF signaling. ..
  32. Mahoney D, Cheung H, Mrad R, Plenchette S, Simard C, Enwere E, et al. Both cIAP1 and cIAP2 regulate TNFalpha-mediated NF-kappaB activation. Proc Natl Acad Sci U S A. 2008;105:11778-83 pubmed publisher
    ..Collectively, these data demonstrate that either cIAP1 or 2 is required for proper Rip1 polyubiquitination and NF-kappaB activation upon TNFalpha treatment. ..
  33. Wang Y, Zhang P, Liu Y, Cheng G. TRAF-mediated regulation of immune and inflammatory responses. Sci China Life Sci. 2010;53:159-68 pubmed publisher
  34. Goldammer T, Brunner R, Kata S, Womack J. Assignment of the bovine receptor-interacting serine-threonine kinase 2 gene (RIPK2) to BTA14 with somatic and radiation cell hybrids. Cytogenet Genome Res. 2006;112:341C pubmed
  35. Fleckenstein D, Dirks W, Drexler H, Quentmeier H. Tumor necrosis factor receptor-associated factor (TRAF) 4 is a new binding partner for the p70S6 serine/threonine kinase. Leuk Res. 2003;27:687-94 pubmed
    ..i) TNF-receptor activation leads to activation of the p70S6K; (ii) TRAF4 is a mediator in this TNF-induced signaling pathway; and (iii) TRAF4 inhibits Fas-induced apoptosis. ..
  36. Liu W, Xu D, Yang H, Xu H, Shi Z, Cao X, et al. Functional identification of three receptor activator of NF-kappa B cytoplasmic motifs mediating osteoclast differentiation and function. J Biol Chem. 2004;279:54759-69 pubmed
  37. Morlon A, Munnich A, Smahi A. TAB2, TRAF6 and TAK1 are involved in NF-kappaB activation induced by the TNF-receptor, Edar and its adaptator Edaradd. Hum Mol Genet. 2005;14:3751-7 pubmed
    ..These results support the involvement of the TAB2/TRAF6/TAK1 signalling complex in the Edar signal transduction pathway and have important implications for our understanding of NF-kappaB activation and EDs in human. ..
  38. Bradley J, Pober J. Tumor necrosis factor receptor-associated factors (TRAFs). Oncogene. 2001;20:6482-91 pubmed
    ..TRAF proteins are expressed in normal and diseased tissue in a regulated fashion, suggesting that they play an important role in physiological and pathological processes. ..
  39. Wang X, Narayanan M, Bruey J, Rigamonti D, Cattaneo E, Reed J, et al. Protective role of Cop in Rip2/caspase-1/caspase-4-mediated HeLa cell death. Biochim Biophys Acta. 2006;1762:742-54 pubmed
    ..Cop, as an inhibitor of an important apical caspase cell death axis, may provide a tool for modulating pathological cell death. ..
  40. Kieser A. Pursuing different 'TRADDes': TRADD signaling induced by TNF-receptor 1 and the Epstein-Barr virus oncoprotein LMP1. Biol Chem. 2008;389:1261-71 pubmed publisher
    ..This article provides an overview of TNFR1 and LMP1 signal transduction with a focus on TRADD's functions in apoptotic and transforming signaling, incorporating recent results from TRADD RNAi and knockout studies. ..
  41. Ikeda O, Sekine Y, Yasui T, Oritani K, Sugiyma K, Muromoto R, et al. STAP-2 negatively regulates both canonical and noncanonical NF-kappaB activation induced by Epstein-Barr virus-derived latent membrane protein 1. Mol Cell Biol. 2008;28:5027-42 pubmed publisher
    ..Finally, STAP-2 knockout mouse embryonic fibroblasts showed enhanced LMP1-induced cell growth. These results suggest that STAP-2 acts as an endogenous negative regulator of EBV LMP1-mediated signaling through TRAF3 and TRADD...
  42. Glanz A, Albrecht J, Heinemann S, Fleckenstein B, Isakov N, Biesinger B. NF-kappaB activation by the viral oncoprotein StpC enhances IFN-gamma production in T cells. Immunol Cell Biol. 2008;86:622-30 pubmed publisher
    ..These observations suggest that NF-kappaB induction by StpC contributes to the Th1-like phenotype of virus-transformed human T cells. ..
  43. Francks C, Paracchini S, Smith S, Richardson A, Scerri T, Cardon L, et al. A 77-kilobase region of chromosome 6p22.2 is associated with dyslexia in families from the United Kingdom and from the United States. Am J Hum Genet. 2004;75:1046-58 pubmed
    ..In addition, the QTL effect may be largely limited to the severe range of reading disability. ..
  44. Ma Y, Temkin V, Liu H, Pope R. NF-kappaB protects macrophages from lipopolysaccharide-induced cell death: the role of caspase 8 and receptor-interacting protein. J Biol Chem. 2005;280:41827-34 pubmed
    ..These observations demonstrate that following TLR4 ligation by lipopolysaccharide, NF-kappaB is a critical determinant of macrophage life or death, whereas caspase 8 determines the pathway employed. ..
  45. Guasparri I, Wu H, Cesarman E. The KSHV oncoprotein vFLIP contains a TRAF-interacting motif and requires TRAF2 and TRAF3 for signalling. EMBO Rep. 2006;7:114-9 pubmed publisher
    ..TRAF2, but not TRAF3, mediates the association of vFLIP with the IkappaB kinase complex. These data indicate that vFLIP uses TRAF2 and TRAF3 for signalling to NF-kappaB, which is crucial for KSHV-associated lymphomagenesis...
  46. Morgan M, Thorburn J, Pandolfi P, Thorburn A. Nuclear and cytoplasmic shuttling of TRADD induces apoptosis via different mechanisms. J Cell Biol. 2002;157:975-84 pubmed
    ..These data indicate that nucleocytoplasmic shuttling of TRADD leads to the activation of distinct apoptosis mechanisms that connect the death receptor apparatus to nuclear events. ..
  47. Dardick C, Ronald P. Plant and animal pathogen recognition receptors signal through non-RD kinases. PLoS Pathog. 2006;2:e2 pubmed
    ..These data indicate that kinases associated with PRRs can largely be predicted by the lack of a single conserved residue and reveal new potential plant PRR subfamilies. ..
  48. Pryhuber G, Huyck H, Roper J, Cornejo J, O Reilly M, Pierce R, et al. Acute tumor necrosis factor-alpha-induced liver injury in the absence of tumor necrosis factor receptor-associated factor 1 gene expression. Am J Pathol. 2005;166:1637-45 pubmed
    ..These studies suggest that TRAF1 provides negative feedback for TNF-alpha synthesis and limits TNFRI-mediated systemic effects of TNF-alpha originating in the lung. ..
  49. Bergeron S, Beauchemin M, Bertrand R. Camptothecin- and etoposide-induced apoptosis in human leukemia cells is independent of cell death receptor-3 and -4 aggregation but accelerates tumor necrosis factor-related apoptosis-inducing ligand-mediated cell death. Mol Cancer Ther. 2004;3:1659-69 pubmed
    ..These findings suggest that DR4 aggregation mediated by camptothecin or VP-16 could represent a mean that accelerates TRAIL-induced apoptosis. ..
  50. Tchikov V, Schütze S. Immunomagnetic isolation of tumor necrosis factor receptosomes. Methods Enzymol. 2008;442:101-23 pubmed publisher
  51. Glossop J, Dawes P, Nixon N, Mattey D. Polymorphism in the tumour necrosis factor receptor II gene is associated with circulating levels of soluble tumour necrosis factor receptors in rheumatoid arthritis. Arthritis Res Ther. 2005;7:R1227-34 pubmed
    ..Our data indicate that the T676G polymorphism in TNF-RII is associated with levels of sTNFRs released from peripheral blood T cells, and with circulating levels of sTNFR in patients with RA. ..
  52. 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
  53. Pointon J, Harvey D, Karaderi T, Appleton L, Farrar C, Stone M, et al. The chromosome 16q region associated with ankylosing spondylitis includes the candidate gene tumour necrosis factor receptor type 1-associated death domain (TRADD). Ann Rheum Dis. 2010;69:1243-6 pubmed publisher
    ..It will require additional work to identify the primary genetic association(s) with AS. ..