title: TRAF2 multitasking in TNF receptor-induced signaling to NF-κB, MAP kinases and cell death.
abstract: Tumor Necrosis Factor (TNF) is a potent inflammatory cytokine that exerts its functions through the activation of two distinct receptors, TNFR1 and TNFR2. Both receptors can activate canonical NF-κB and JNK MAP kinase signaling, while TNFR2 can also activate non-canonical NF-κB signaling, leading to numerous changes in gene expression that drive inflammation, cell proliferation and cell survival. On the other hand, TNFR1 also activates signaling pathways leading to cell death by either apoptosis or necroptosis, depending on the cellular context. A key player in TNFR1- and TNFR2-induced signaling is the RING finger protein TRAF2, which is recruited to both receptors upon their stimulation. TRAF2 exerts multiple receptor-specific functions but also mediates cross-talk between TNFR1 and TNFR2, dictating the outcome of TNF stimulation. In this review, we provide an overview of the positive and negative regulatory role of TRAF2 in different TNFR1 and TNFR2 signaling pathways. We discuss the underlying molecular mechanism of action, distinguishing between TRAF2 scaffold and E3 ubiquitin ligase functions, and the regulation of TRAF2 by specific post-translational modifications. Finally, we elaborate on some possible strategies to modulate TRAF2 function in the context of therapeutic targeting in autoimmunity and cancer.
authors.affiliation: Inflammation Research Center, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Alice
authors.initials: A
authors.lastname: Borghi
authors.affiliation: Inflammation Research Center, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Lynn
authors.initials: L
authors.lastname: Verstrepen
authors.affiliation: Inflammation Research Center, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. Electronic address: Rudi.Beyaert@irc.vib-UGent.be.
authors.forename: Rudi
authors.initials: R
authors.lastname: Beyaert
mesh_terms: D000818:Animals; D017209:Apoptosis; D006801:Humans; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis / Q000378:metabolism*; D010766:Phosphorylation; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000737:chemistry / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D016328:NF-kappa B; C101338:PSMD2 protein, human; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D047992:TNF Receptor-Associated Factor 2; C439524:TNF protein, human; C506235:TNFRSF1A protein, human; C415902:TNFRSF1B protein, human; D014409:Tumor Necrosis Factor-alpha
keywords: Apoptosis; NF-κB; Necroptosis; TNF; TRAF2