TNF receptor-associated factor 4

Definition:

Adapter protein with E3 ligase activity that is involved in many diverse biological processes including cell proliferation, migration, differentiation, DNA repair, platelet activation or apoptosis. Promotes EGFR-mediated signaling by facilitating the dimerization of EGFR and downstream AKT activation thereby promoting cell proliferation. Ubiquitinates SMURF2 through 'Lys-48'-linked ubiquitin chain leading to SMURF2 degradation through the proteasome and subsequently osteogenic differentiation. Promotes 'Lys-63'-mediated ubiquitination of CHK1 which in turn activates cell cycle arrest and activation of DNA repair. In addition, promotes an atypical 'Lys-29'-linked ubiquitination at the C-terminal end of IRS1 which is crucial for insulin-like growth factor (IGF) signal transduction. Regulates activation of NF-kappa-B in response to signaling through Toll-like receptors. Required for normal skeleton development, and for normal development of the respiratory tract (By similarity). Required for activation of RPS6KB1 in response to TNF signaling. Modulates TRAF6 functions. Inhibits adipogenic differentiation by activating pyruvate kinase PKM activity and subsequently the beta-catenin signaling pathway.

References:

[1]. Amy N Abell, et al. MEKK4 is an effector of the embryonic TRAF4 for JNK activation. J Biol Chem. 2005 Oct 28;280(43):35793-6. [Content Brief]

[2]. You Cheng Xu, et al. Involvement of TRAF4 in oxidative activation of c-Jun N-terminal kinase. J Biol Chem. 2002 Aug 2;277(31):28051-7. [Content Brief]

[3]. 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]

[4]. Wenjuan Yu, et al. The E3 ligase TRAF4 promotes IGF signaling by mediating atypical ubiquitination of IRS-1. J Biol Chem. 2021 Jan-Jun;296:100739. [Content Brief]

[5]. Xinfang Yu, et al. Ubiquitination of the DNA-damage checkpoint kinase CHK1 by TRAF4 is required for CHK1 activation. J Hematol Oncol. 2020 May 1;13(1):40. [Content Brief]

[6]. Shuizhong Cen, et al. TRAF4 acts as a fate checkpoint to regulate the adipogenic differentiation of MSCs by activating PKM2. EBioMedicine. 2020 Apr;54:102722. [Content Brief]

[7]. Fumihiko Takeshita, et al. TRAF4 acts as a silencer in TLR-mediated signaling through the association with TRAF6 and TRIF. Eur J Immunol. 2005 Aug;35(8):2477-85. [Content Brief]

[8]. Gang Cai, et al. TRAF4 binds to the juxtamembrane region of EGFR directly and promotes kinase activation. Proc Natl Acad Sci U S A. 2018 Nov 6;115(45):11531-11536. [Content Brief]

[9]. Diana S Fleckenstein, et al. Tumor necrosis factor receptor-associated factor (TRAF) 4 is a new binding partner for the p70S6 serine/threonine kinase. Leuk Res. 2003 Aug;27(8):687-94. [Content Brief]

[10]. Valérie Kédinger, et al. Tumor necrosis factor receptor-associated factor 4 is a dynamic tight junction-related shuttle protein involved in epithelium homeostasis. PLoS One. 2008;3(10):e3518. [Content Brief]

[11]. Jinteng Li, et al. TRAF4 positively regulates the osteogenic differentiation of mesenchymal stem cells by acting as an E3 ubiquitin ligase to degrade Smurf2. Cell Death Differ. 2019 Dec;26(12):2652-2666. [Content Brief]

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