TNF receptor-associated factor 2

Definition:

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. Plays a role in mediating activation of NF-kappa-B by EIF2AK2/PKR. In complex with BIRC2 or BIRC3, promotes ubiquitination of IKBKE.

References:

[1]. Jesús Gil, et al. TRAF family proteins link PKR with NF-kappa B activation. Mol Cell Biol. 2004 May;24(10):4502-12. [Content Brief]

[2]. Xiaoming Li, et al. TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2. Nature. 2002 Mar 21;416(6878):345-7. [Content Brief]

[3]. Gautam Sondarva, et al. TRAF2-MLK3 interaction is essential for TNF-alpha-induced MLK3 activation. Cell Res. 2010 Jan;20(1):89-98. [Content Brief]

[4]. Qian Yin, et al. Structural basis for the lack of E2 interaction in the RING domain of TRAF2. Biochemistry. 2009 Nov 10;48(44):10558-67. [Content Brief]

[5]. Sergio E Alvarez, et al. Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2. Nature. 2010 Jun 24;465(7301):1084-8. [Content Brief]

[6]. Shan Li, et al. Ubiquitin ligase Smurf1 targets TRAF family proteins for ubiquitination and degradation. Mol Cell Biochem. 2010 May;338(1-2):11-7. [Content Brief]

[7]. Shitao Li, et al. PKC phosphorylation of TRAF2 mediates IKKalpha/beta recruitment and K63-linked polyubiquitination. Mol Cell. 2009 Jan 16;33(1):30-42. [Content Brief]

[8]. Liusheng He, et al. 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. [Content Brief]

[9]. Eirini Trompouki, et al. CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members. Nature. 2003 Aug 14;424(6950):793-6. [Content Brief]

[10]. Chao Zheng, et al. 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. [Content Brief]

[11]. Alicia Y Zhou, et al. IKKε-mediated tumorigenesis requires K63-linked polyubiquitination by a cIAP1/cIAP2/TRAF2 E3 ubiquitin ligase complex. Cell Rep. 2013 Mar 28;3(3):724-33. [Content Brief]

[12]. Ken Blackwell, et al. TRAF2 phosphorylation modulates tumor necrosis factor alpha-induced gene expression and cell resistance to apoptosis. Mol Cell Biol. 2009 Jan;29(2):303-14. [Content Brief]

[13]. Miwa Sasai, 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 Mar;47(6):1283-91. [Content Brief]

[14]. Rebecca A Csomos, et al. 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. [Content Brief]

[15]. Deborah N Chadee, et al. Direct activation of mitogen-activated protein kinase kinase kinase MEKK1 by the Ste20p homologue GCK and the adapter protein TRAF2. Mol Cell Biol. 2002 Feb;22(3):737-49. [Content Brief]

[16]. Laiqun Zhang, et al. 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. [Content Brief]

[17]. V Baud, et al. 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. [Content Brief]

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