ITCH E3 ubiquitin ligase positively regulates TGF‐β signaling to EMT via Smad7 ubiquitination (930.6)

Abstract

Transforming growth factor‐beta (TGF‐β) has been shown to regulate pleiotropic cellular responses including cell growth, differentiation, migration, apoptosis, extracellular matrix production, and many other biological processes. Although non‐Smad signaling pathways are increasingly being reported to play many roles in TGF‐β‐mediated biological processes, Smads, especially recetor‐regulated Smads (R‐Smads), still play a central role for mediating TGF‐β signaling to endothelial mesenchemal transition (EMT) processes. Biological activity of R‐Smads is thus tightly regulated in multiple points. Inhibitory‐Smad (I‐Smad) Smad7 act as critical endogenous negative feedback regulator for Smad‐signaling pathways by inhibiting R‐Smad phosphorylation and also by inducing activated type I TGF‐β receptor degradation. Emerging roles of Smad7 in health and disease have been increasingly reported, the molecular mechanisms that regulate Smad7, however, are not well understood yet. In this study, we have shown that E3 ubiquitin ligase ITCH acts as a positive regulator of TGF‐β signaling and subsequent EMT‐related gene expression. Interestingly, ITCH‐mediated positive regulation of TGF‐β signaling was dependent on Smad7 ubiquitination and subsequent degradation. Further study revealed that ITCH acts as an E3 ubiquitin ligase for Smad7 polyubiquitination, thereby acting as an important regulator for Smad7 activity and positively regulating TGF‐β signaling and TGF‐β‐mediated biological processes. Our findings thus uncover new regulatory mechanism controlling Smad7 by ITCH.