1f3v

Structural highlights

Function

[TRADD_HUMAN] The nuclear form acts as a tumor suppressor by preventing ubiquitination and degradation of isoform p19ARF/ARF of CDKN2A by TRIP12: acts by interacting with TRIP12, leading to disrupt interaction between TRIP12 and isoform p19ARF/ARF of CDKN2A (By similarity). Adapter molecule for TNFRSF1A/TNFR1 that specifically associates with the cytoplasmic domain of activated TNFRSF1A/TNFR1 mediating its interaction with FADD. Overexpression of TRADD leads to two major TNF-induced responses, apoptosis and activation of NF-kappa-B. [TRAF2_HUMAN] Regulates activation of NF-kappa-B and JNK and plays a central role in the regulation of cell survival and apoptosis. Required for normal antibody isotype switching from IgM to IgG. Has E3 ubiquitin-protein ligase activity and promotes 'Lys-63'-linked ubiquitination of target proteins, such as BIRC3, RIPK1 and TICAM1. Is an essential constituent of several E3 ubiquitin-protein ligase complexes, where it promotes the ubiquitination of target proteins by bringing them into contact with other E3 ubiquitin ligases. Regulates BIRC2 and BIRC3 protein levels by inhibiting their autoubiquitination and subsequent degradation; this does not depend on the TRAF2 RING-type zinc finger domain.^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14]}

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

• TNF receptor-associated factor
• TNF receptor-associated factor 3D structures

References

1. ↑ Baud V, Liu ZG, 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 May 15;13(10):1297-308. PMID:10346818
2. ↑ Li X, Yang Y, Ashwell JD. TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2. Nature. 2002 Mar 21;416(6878):345-7. PMID:11907583 doi:10.1038/416345a
3. ↑ 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 Aug 14;424(6950):793-6. PMID:12917689 doi:http://dx.doi.org/10.1038/nature01803
4. ↑ He L, Grammer AC, Wu X, Lipsky PE. TRAF3 forms heterotrimers with TRAF2 and modulates its ability to mediate NF-{kappa}B activation. J Biol Chem. 2004 Dec 31;279(53):55855-65. Epub 2004 Sep 21. PMID:15383523 doi:10.1074/jbc.M407284200
5. ↑ Csomos RA, Brady GF, Duckett CS. Enhanced cytoprotective effects of the inhibitor of apoptosis protein cellular IAP1 through stabilization with TRAF2. J Biol Chem. 2009 Jul 31;284(31):20531-9. doi: 10.1074/jbc.M109.029983. Epub 2009, Jun 8. PMID:19506082 doi:10.1074/jbc.M109.029983
6. ↑ Li S, Wang L, Dorf ME. PKC phosphorylation of TRAF2 mediates IKKalpha/beta recruitment and K63-linked polyubiquitination. Mol Cell. 2009 Jan 16;33(1):30-42. doi: 10.1016/j.molcel.2008.11.023. PMID:19150425 doi:10.1016/j.molcel.2008.11.023
7. ↑ Blackwell K, Zhang L, Thomas GS, Sun S, Nakano H, Habelhah H. TRAF2 phosphorylation modulates tumor necrosis factor alpha-induced gene expression and cell resistance to apoptosis. Mol Cell Biol. 2009 Jan;29(2):303-14. doi: 10.1128/MCB.00699-08. Epub 2008 Nov 3. PMID:18981220 doi:10.1128/MCB.00699-08
8. ↑ Sondarva G, Kundu CN, Mehrotra S, Mishra R, Rangasamy V, Sathyanarayana P, Ray RS, Rana B, Rana A. TRAF2-MLK3 interaction is essential for TNF-alpha-induced MLK3 activation. Cell Res. 2010 Jan;20(1):89-98. doi: 10.1038/cr.2009.125. Epub 2009 Nov 17. PMID:19918265 doi:10.1038/cr.2009.125
9. ↑ Zhang L, Blackwell K, Shi Z, Habelhah H. The RING domain of TRAF2 plays an essential role in the inhibition of TNFalpha-induced cell death but not in the activation of NF-kappaB. J Mol Biol. 2010 Feb 26;396(3):528-39. doi: 10.1016/j.jmb.2010.01.008. Epub 2010 , Jan 11. PMID:20064526 doi:10.1016/j.jmb.2010.01.008
10. ↑ Li S, Lu K, Wang J, An L, Yang G, Chen H, Cui Y, Yin X, Xie P, Xing G, He F, Zhang L. Ubiquitin ligase Smurf1 targets TRAF family proteins for ubiquitination and degradation. Mol Cell Biochem. 2010 May;338(1-2):11-7. doi: 10.1007/s11010-009-0315-y. Epub, 2009 Nov 24. PMID:19937093 doi:10.1007/s11010-009-0315-y
11. ↑ Sasai M, Tatematsu M, Oshiumi H, Funami K, Matsumoto M, Hatakeyama S, Seya T. 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 Mar;47(6):1283-91. doi: 10.1016/j.molimm.2009.12.002. Epub 2010, Jan 4. PMID:20047764 doi:10.1016/j.molimm.2009.12.002
12. ↑ Alvarez SE, Harikumar KB, Hait NC, Allegood J, Strub GM, Kim EY, Maceyka M, Jiang H, Luo C, Kordula T, Milstien S, Spiegel S. Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2. Nature. 2010 Jun 24;465(7301):1084-8. doi: 10.1038/nature09128. PMID:20577214 doi:10.1038/nature09128
13. ↑ Yin Q, Lamothe B, Darnay BG, Wu H. Structural basis for the lack of E2 interaction in the RING domain of TRAF2. Biochemistry. 2009 Nov 10;48(44):10558-67. PMID:19810754 doi:10.1021/bi901462e
14. ↑ Zheng C, Kabaleeswaran V, Wang Y, Cheng G, Wu H. Crystal structures of the TRAF2: cIAP2 and the TRAF1: TRAF2: cIAP2 complexes: affinity, specificity, and regulation. Mol Cell. 2010 Apr 9;38(1):101-13. PMID:20385093 doi:10.1016/j.molcel.2010.03.009
15. ↑ Park YC, Ye H, Hsia C, Segal D, Rich RL, Liou HC, Myszka DG, Wu H. A novel mechanism of TRAF signaling revealed by structural and functional analyses of the TRADD-TRAF2 interaction. Cell. 2000 Jun 23;101(7):777-87. PMID:10892748