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

Su Hyun Park, Eun Ho Jung, Geun Young Kim, Byung Chul Kim, Jae Hyang Lim, Chang Hoon Woo

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

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.

Original languageEnglish
Pages (from-to)20-25
Number of pages6
JournalMolecules and Cells
Volume38
Issue number1
DOIs
StatePublished - 2015

Keywords

  • EMT
  • Itch
  • Smad7
  • TGF-β
  • Ubiquitination

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