title: Itch E3 ubiquitin ligase positively regulates TGF-β signaling to EMT via Smad7 ubiquitination.
abstract: TGF-β regulates pleiotropic cellular responses including cell growth, differentiation, migration, apoptosis, extracellular matrix production, and many other biological processes. Although non-Smad signaling pathways are being increasingly reported to play many roles in TGF-β-mediated biological processes, Smads, especially receptor-regulated Smads (R-Smads), still play a central mediatory role in TGF-β signaling for epithelial-mesenchymal transition. Thus, the biological activities of R-Smads are tightly regulated at multiple points. Inhibitory Smad (I-Smad also called Smad7) acts as a critical endogenous negative feedback regulator of Smad-signaling pathways by inhibiting R-Smad phosphorylation and by inducing activated type I TGF-β receptor degradation. Roles played by Smad7 in health and disease are being increasingly reported, but the molecular mechanisms that regulate Smad7 are not well understood. In this study, we show that E3 ubiquitin ligase Itch acts as a positive regulator of TGF-β signaling and of subsequent EMT-related gene expression. Interestingly, the Itch-mediated positive regulation of TGF-β signaling was found to be dependent on Smad7 ubiquitination and its subsequent degradation. Further study revealed Itch acts as an E3 ubiquitin ligase for Smad7 polyubiquitination, and thus, that Itch is an important regulator of Smad7 activity and a positive regulator of TGF-β signaling and of TGF-β-mediated biological processes. Accordingly, the study uncovers a novel regulatory mechanism whereby Smad7 is controlled by Itch.
authors.affiliation: Department of Pharmacology, Yeungnam University College of Medicine, Daegu 705-717, Korea.
authors.forename: Su-hyun
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Pharmacology, Yeungnam University College of Medicine, Daegu 705-717, Korea.
authors.forename: Eun-Ho
authors.initials: EH
authors.lastname: Jung
authors.forename: Geun-Young
authors.initials: GY
authors.lastname: Kim
authors.forename: Byung-Chul
authors.initials: BC
authors.lastname: Kim
authors.forename: Jae Hyang
authors.initials: JH
authors.lastname: Lim
authors.affiliation: Department of Pharmacology, Yeungnam University College of Medicine, Daegu 705-717, Korea.
authors.forename: Chang-Hoon
authors.initials: CH
authors.lastname: Woo
mesh_terms: D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D012097:Repressor Proteins; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases
keywords: EMT; Itch; Smad7; TGF-β; ubiquitination