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Itch E3 Ubiquitin Ligase Positively Regulates TGF-β Signaling to EMT via Smad7 Ubiquitination

  • Park, Su-Hyun (Department of Pharmacology, Yeungnam University College of Medicine) ;
  • Jung, Eun-Ho (Department of Pharmacology, Yeungnam University College of Medicine) ;
  • Kim, Geun-Young (Division of Cardiovascular and Rare Diseases, Center for Biomedical Sciences, Korea National Institute of Health) ;
  • Kim, Byung-Chul (Department of Biochemistry, College of Natural Sciences, Kangwon National University) ;
  • Lim, Jae Hyang (Department of Microbiology, Ewha Womans University School of Medicine) ;
  • Woo, Chang-Hoon (Department of Pharmacology, Yeungnam University College of Medicine)
  • Received : 2014.05.09
  • Accepted : 2014.10.17
  • Published : 2015.01.31

Abstract

TGF-${\beta}$ 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-${\beta}$-mediated biological processes, Smads, especially receptor-regulated Smads (R-Smads), still play a central mediatory role in TGF-${\beta}$ 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-${\beta}$ 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-${\beta}$ signaling and of subsequent EMT-related gene expression. Interestingly, the Itch-mediated positive regulation of TGF-${\beta}$ 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-${\beta}$ signaling and of TGF-${\beta}$-mediated biological processes. Accordingly, the study uncovers a novel regulatory mechanism whereby Smad7 is controlled by Itch.

Keywords

EMT;Itch;Smad7;TGF-${\beta}$;ubiquitination

Acknowledgement

Supported by : Korean Ministry of Health & Welfare, Korean National Research Foundation

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