Moreover, as the signaling pathways controlled by TRAF proteins are often regulated through ubiquitination events, several family members, including TRAF2, 3, 5, and 6, also act as E3 ubiquitin ligase enzymes (Ha et al., 2009 Xie, 2013). For this, TRAF proteins function as molecular scaffolds that assist the ligand‐induced recruitment of other signaling proteins to the TNF‐R signaling complexes. In the context of TNF‐R signaling, TRAF proteins are primarily involved in regulating the activation state of mitogen‐activated protein kinases (MAPKs) and NF‐κB. Amino acids numbering refers to the human proteins. The last member of the TRAF family identified, TRAF7, lacks the TRAF domain, which is replaced by seven repeats of the WD domain (Zotti et al., 2012).ĭomain organization of the seven TRAF proteins. The carboxy‐terminus portion of TRAF proteins is made of the extensive TRAF domain, which mediates oligomerization reactions and interactions with partner proteins (Ha et al., 2009 Xie, 2013). The RING finger domain is common to many E3 ubiquitin ligases, constituting the core of the ubiquitin ligase catalytic domain. All family members, with the exception of TRAF1, contain a RING finger domain localized at their amino‐terminus, followed by one or more zinc finger domains (Fig. Structurally, TRAF proteins share a typical modular organization of conserved domains. Upon binding of their respective ligands, these receptors transmit in the cell a wide range of different extracellular signals that regulate important and fundamental biological processes, including embryonic development and morphogenesis, the innate and acquired immune responses, cell survival and proliferation, tissues homeostasis, and stress responses (Ha et al., 2009 Xie, 2013). The seven TRAF proteins were originally discovered as signal transducing components of the TNF‐R superfamily members (Ha et al., 2009 Xie, 2013). Journal of Cellular Physiology Published by Wiley Periodicals, Inc. In this paper, we review and discuss the literature recently produced on this subject. In the last few years, it has become increasingly evident the involvement of TRAF7, the last member of the TRAF family to be discovered, in the genesis and progression of several human cancers, placing TRAF7 in the spotlight as a novel tumor suppressor protein. Given the wide variety of stimuli intracellularly conveyed by TRAF proteins, they are physiologically involved in multiple biological processes, including embryonic development, tissue homeostasis, and regulation of innate and adaptive immune responses. Functionally, TRAFs act both as a scaffold and/or enzymatic proteins to regulate activation of mitogen‐activated protein kinases (MAPKs) and transcription factors of nuclear factor‐κB family (NF‐κB). The seven members of the tumor necrosis factor receptor (TNF‐R)‐associated factor (TRAF) family of intracellular proteins were originally discovered and characterized as signaling adaptor molecules coupled to the cytoplasmic regions of receptors of the TNF‐R superfamily.
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