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Gene Review

TRAF2  -  TNF receptor-associated factor 2

Homo sapiens

Synonyms: E3 ubiquitin-protein ligase TRAF2, MGC:45012, TRAP, TRAP3, Tumor necrosis factor type 2 receptor-associated protein 3
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Disease relevance of TRAF2

  • CD30 induction of human immunodeficiency virus gene transcription is mediated by TRAF2 [1].
  • The KSHV oncoprotein vFLIP contains a TRAF-interacting motif and requires TRAF2 and TRAF3 for signalling [2].
  • In a selective portion of cases, examination of HRS cells for Epstein-Barr virus (EBV)-encoded RNA was performed by in situ hybridization, and the results were compared with the magnitude of TRAF1 and TRAF2 staining [3].
  • We investigated the constitutive expression of TRAF1 and TRAF2 in Hodgkin and Reed-Sternberg (HRS) cells from archived paraffin-embedded tissues obtained from 21 patients diagnosed with classical Hodgkin's disease (HD) [3].
  • Hepatitis C virus core protein potentiates TNF-alpha-induced NF-kappaB activation through TRAF2-IKKbeta-dependent pathway [4].

Psychiatry related information on TRAF2

  • The point of bifurcation of this pathway and the decision-making molecules FADD, TRAF2 and RIP are discussed [5].

High impact information on TRAF2

  • 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].
  • TRAF1 interacts with TNF-R2 indirectly through heterodimer formation with TRAF2 [7].
  • The nature of the interaction indicates that an SXXE motif may be a TRAF2-binding consensus sequence [8].
  • Dominant-negative TRAF2 inhibited activation of JNK by IRE1 [9].
  • The cytoplasmic part of IRE1 bound TRAF2, an adaptor protein that couples plasma membrane receptors to JNK activation [9].

Chemical compound and disease context of TRAF2


Biological context of TRAF2

  • Here we show that TRAF1 and TRAF2 interact with A20, a zinc finger protein, whose expression is induced by agents that activate NF-kappaB [11].
  • This treatment leads to the rapid downregulation of FLIP but not to that of TRAF2 [12].
  • Our findings provide evidence that a MC159/TRAF2/TRAF3 complex regulates a new aspect of Fas signaling, and identify MC159 FLIP as a molecule that targets multiple features of Fas-induced cell death [13].
  • These observations suggest that TRAF2 may reside in the nucleus and directly regulate transcription, independent of its role in cytoplasmic signal transduction [14].
  • In contrast, TRAF2 appears to play a positive role in B cell differentiation, and this activity is apparent even when its binding site on CD40 is disrupted [15].

Anatomical context of TRAF2

  • Transient overexpression of TRAF2, but not TRAF1, induced NF-kappaB activation and HIV-1-long terminal repeat-driven transcription in the T cell line, KT3 [1].
  • TRAF2 and TANK individually formed weak interactions with germinal center kinase (GCK)-related kinase (GCKR) [16].
  • Previously, we found that a dominant-negative TRAF2 molecule inhibits CD40-mediated Ab secretion by the mouse B cell line CH12.LX [17].
  • Rabbit antisera reactive with either amino- or carboxyl-terminal TRAF2 peptides frequently but not uniformly stain nuclei of cultured HUVEC or the established human endothelial cell line, ECV304 [14].
  • In cultured human umbilical vein endothelial cells, endogenous TRAF2 colocalizes with the membrane-organizing protein caveolin-1 at regions of enrichment subjacent to the plasma membrane as detected by confocal fluorescence microscopy [18].

Associations of TRAF2 with chemical compounds


Physical interactions of TRAF2


Regulatory relationships of TRAF2


Other interactions of TRAF2


Analytical, diagnostic and therapeutic context of TRAF2

  • A novel heterotypic association between TRAF2 and -3 was detected and confirmed by immunoprecipitation in Ramos B cells that constitutively express both TRAF2 and -3 [32].
  • Yeast two-hybrid assays and studies in HEK293 cells and primary lymphocytes indicated interactions between TRAF2 and GITR mediated by acidic residues in the cytoplasmic domain of the receptor [33].
  • The NF-kappaB activation was analyzed using the electrophoresis mobility shift assay; TRAF1, TRAF2, TANK/I-TRAF, and caspase 3 expression were studied using Western blot analysis [34].
  • The complete murine TRAF2 gene was obtained using a lambda phage and PCR cloning strategy [35].
  • These results suggest that CD30 ligation may enhance the expression of HIV via TRAF-2-mediated activation of NF-kappaB [1].


  1. CD30 induction of human immunodeficiency virus gene transcription is mediated by TRAF2. Tsitsikov, E.N., Wright, D.A., Geha, R.S. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  2. The KSHV oncoprotein vFLIP contains a TRAF-interacting motif and requires TRAF2 and TRAF3 for signalling. Guasparri, I., Wu, H., Cesarman, E. EMBO Rep. (2006) [Pubmed]
  3. Expression of the tumor necrosis factor receptor-associated factors (TRAFs) 1 and 2 is a characteristic feature of Hodgkin and Reed-Sternberg cells. Izban, K.F., Ergin, M., Martinez, R.L., Alkan, S. Mod. Pathol. (2000) [Pubmed]
  4. Hepatitis C virus core protein potentiates TNF-alpha-induced NF-kappaB activation through TRAF2-IKKbeta-dependent pathway. Chung, Y.M., Park, K.J., Choi, S.Y., Hwang, S.B., Lee, S.Y. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  5. Signaling for survival and apoptosis in the immune system. Mak, T.W., Yeh, W.C. Arthritis Res. (2002) [Pubmed]
  6. A novel mechanism of TRAF signaling revealed by structural and functional analyses of the TRADD-TRAF2 interaction. Park, Y.C., Ye, H., Hsia, C., Segal, D., Rich, R.L., Liou, H.C., Myszka, D.G., Wu, H. Cell (2000) [Pubmed]
  7. A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor. Rothe, M., Wong, S.C., Henzel, W.J., Goeddel, D.V. Cell (1994) [Pubmed]
  8. Structural basis for self-association and receptor recognition of human TRAF2. Park, Y.C., Burkitt, V., Villa, A.R., Tong, L., Wu, H. Nature (1999) [Pubmed]
  9. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Urano, F., Wang, X., Bertolotti, A., Zhang, Y., Chung, P., Harding, H.P., Ron, D. Science (2000) [Pubmed]
  10. Expression of ring finger-deleted TRAF2 sensitizes metastatic melanoma cells to apoptosis via up-regulation of p38, TNFalpha and suppression of NF-kappaB activities. Ivanov, V.N., Fodstad, O., Ronai, Z. Oncogene (2001) [Pubmed]
  11. The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kappaB activation. Song, H.Y., Rothe, M., Goeddel, D.V. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  12. NF-kappaB signals induce the expression of c-FLIP. Micheau, O., Lens, S., Gaide, O., Alevizopoulos, K., Tschopp, J. Mol. Cell. Biol. (2001) [Pubmed]
  13. The TRAF3-binding site of human molluscipox virus FLIP molecule MC159 is critical for its capacity to inhibit Fas-induced apoptosis. Thurau, M., Everett, H., Tapernoux, M., Tschopp, J., Thome, M. Cell Death Differ. (2006) [Pubmed]
  14. The N-terminal domains target TNF receptor-associated factor-2 to the nucleus and display transcriptional regulatory activity. Min, W., Bradley, J.R., Galbraith, J.J., Jones, S.J., Ledgerwood, E.C., Pober, J.S. J. Immunol. (1998) [Pubmed]
  15. Cutting edge: contrasting roles of TNF receptor-associated factor 2 (TRAF2) and TRAF3 in CD40-activated B lymphocyte differentiation. Hostager, B.S., Bishop, G.A. J. Immunol. (1999) [Pubmed]
  16. TANK potentiates tumor necrosis factor receptor-associated factor-mediated c-Jun N-terminal kinase/stress-activated protein kinase activation through the germinal center kinase pathway. Chin, A.I., Shu, J., Shan Shi, C., Yao, Z., Kehrl, J.H., Cheng, G. Mol. Cell. Biol. (1999) [Pubmed]
  17. Role of TNF receptor-associated factor 2 in the activation of IgM secretion by CD40 and CD120b. Hostager, B.S., Bishop, G.A. J. Immunol. (2002) [Pubmed]
  18. Caveolin-1 associates with TRAF2 to form a complex that is recruited to tumor necrosis factor receptors. Feng, X., Gaeta, M.L., Madge, L.A., Yang, J.H., Bradley, J.R., Pober, J.S. J. Biol. Chem. (2001) [Pubmed]
  19. A20 zinc finger protein inhibits TNF-induced apoptosis and stress response early in the signaling cascades and independently of binding to TRAF2 or 14-3-3 proteins. Lademann, U., Kallunki, T., Jäättelä, M. Cell Death Differ. (2001) [Pubmed]
  20. Tumor necrosis factor receptor-associated factor (TRAF) 5 and TRAF2 are involved in CD30-mediated NFkappaB activation. Aizawa, S., Nakano, H., Ishida, T., Horie, R., Nagai, M., Ito, K., Yagita, H., Okumura, K., Inoue, J., Watanabe, T. J. Biol. Chem. (1997) [Pubmed]
  21. Anatomy of TRAF2. Distinct domains for nuclear factor-kappaB activation and association with tumor necrosis factor signaling proteins. Takeuchi, M., Rothe, M., Goeddel, D.V. J. Biol. Chem. (1996) [Pubmed]
  22. TNF-mediated activation of the stress-activated protein kinase pathway: TNF receptor-associated factor 2 recruits and activates germinal center kinase related. Shi, C.S., Leonardi, A., Kyriakis, J., Siebenlist, U., Kehrl, J.H. J. Immunol. (1999) [Pubmed]
  23. Sphingosine kinase interacts with TRAF2 and dissects tumor necrosis factor-alpha signaling. Xia, P., Wang, L., Moretti, P.A., Albanese, N., Chai, F., Pitson, S.M., D'Andrea, R.J., Gamble, J.R., Vadas, M.A. J. Biol. Chem. (2002) [Pubmed]
  24. The role of TRAF2 binding to the type I interferon receptor in alternative NF kappaB activation and antiviral response. Yang, C.H., Murti, A., Pfeffer, S.R., Fan, M., Du, Z., Pfeffer, L.M. J. Biol. Chem. (2008) [Pubmed]
  25. Human glutathione S-transferase P1-1 interacts with TRAF2 and regulates TRAF2-ASK1 signals. Wu, Y., Fan, Y., Xue, B., Luo, L., Shen, J., Zhang, S., Jiang, Y., Yin, Z. Oncogene (2006) [Pubmed]
  26. Regulation of the deubiquitinating enzyme CYLD by IkappaB kinase gamma-dependent phosphorylation. Reiley, W., Zhang, M., Wu, X., Granger, E., Sun, S.C. Mol. Cell. Biol. (2005) [Pubmed]
  27. A novel p75TNF receptor isoform mediating NFkappa B activation. Seitz, C., Muller, P., Krieg, R.C., Mannel, D.N., Hehlgans, T. J. Biol. Chem. (2001) [Pubmed]
  28. CD95 and TRAF2 promote invasiveness of pancreatic cancer cells. Trauzold, A., Röder, C., Sipos, B., Karsten, K., Arlt, A., Jiang, P., Martin-Subero, J.I., Siegmund, D., Müerköster, S., Pagerols-Raluy, L., Siebert, R., Wajant, H., Kalthoff, H. FASEB J. (2005) [Pubmed]
  29. The tumor necrosis factor receptor 2 signal transducers TRAF2 and c-IAP1 are components of the tumor necrosis factor receptor 1 signaling complex. Shu, H.B., Takeuchi, M., Goeddel, D.V. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  30. Activation of stress-activated protein kinase/c-Jun N-terminal kinase, but not NF-kappaB, by the tumor necrosis factor (TNF) receptor 1 through a TNF receptor-associated factor 2- and germinal center kinase related-dependent pathway. Shi, C.S., Kehrl, J.H. J. Biol. Chem. (1997) [Pubmed]
  31. ATAR, a novel tumor necrosis factor receptor family member, signals through TRAF2 and TRAF5. Hsu, H., Solovyev, I., Colombero, A., Elliott, R., Kelley, M., Boyle, W.J. J. Biol. Chem. (1997) [Pubmed]
  32. TRAF3 forms heterotrimers with TRAF2 and modulates its ability to mediate NF-{kappa}B activation. He, L., Grammer, A.C., Wu, X., Lipsky, P.E. J. Biol. Chem. (2004) [Pubmed]
  33. Glucocorticoid-induced TNF receptor, a costimulatory receptor on naive and activated T cells, uses TNF receptor-associated factor 2 in a novel fashion as an inhibitor of NF-kappa B activation. Esparza, E.M., Arch, R.H. J. Immunol. (2005) [Pubmed]
  34. Expression of the tumor necrosis factor receptor-associated factors 1 and 2 and regulation of the nuclear factor-kappaB antiapoptotic activity in human gliomas. Conti, A., Ageunnouz, M., La Torre, D., Cardali, S., Angileri, F.F., Buemi, C., Tomasello, C., Iacopino, D.G., D'Avella, D., Vita, G., Tomasello, F. J. Neurosurg. (2005) [Pubmed]
  35. Complete structural characterisation of the mammalian and Drosophila TRAF genes: implications for TRAF evolution and the role of RING finger splice variants. Grech, A., Quinn, R., Srinivasan, D., Badoux, X., Brink, R. Mol. Immunol. (2000) [Pubmed]
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