title: Regulation of TGF-β family signalling by ubiquitination and deubiquitination.
abstract: Members of the transforming growth factor-β (TGF-β) family, including TGF-βs, activin and bone morphogenetic proteins (BMPs), are multifunctional proteins that regulate a wide variety of cellular responses, such as proliferation, differentiation, migration and apoptosis. TGF-β family signalling is mainly mediated by membranous serine/threonine kinase receptors and intracellular Smad proteins. This signalling is tightly regulated by various post-translational modifications including ubiquitination. Several E3 ubiquitin ligases play a crucial role in the recognition and ubiquitin-dependent degradation of TGF-β family receptors, Smad proteins and their interacted proteins to regulate positively and negatively TGF-β family signalling. In contrast, non-degradative ubiquitin modifications also regulate TGF-β family signalling. Recently, in addition to protein ubiquitination, deubiquitination by deubiquitinating enzymes has been reported to control TGF-β family signalling pathways. Interestingly, more recent studies suggest that TGF-β signalling is not only regulated via ubiquitination and/or deubiquitination, but also it relies on ubiquitination for its effect on other pathways. Thus, ubiquitin modifications play key roles in TGF-β family signal transduction and cross-talk between TGF-β family signalling and other signalling pathways. Here, we review the current understandings of the positive and negative regulatory mechanisms by ubiquitin modifications that control TGF-β family signalling.
authors.affiliation: Department of Molecular Medicine for Pathogenesis, Ehime University Graduate School of Medicine; Division of Bio-imaging, Proteo-Science Center, Ehime University; Translational Research Center, Ehime University Hospital; and Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Shitsukawa, Toon, Ehime 791-0295, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Imamura
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Oshima
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Hikita
mesh_terms: D000818:Animals; D006801:Humans; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D016212:Transforming Growth Factor beta
keywords: E3 ubiquitin ligases; TGF-βubiquitination; Ubiquitin-proteasome system; deubiquitination