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

Title
Itch E3 Ubiquitin Ligase Positively Regulates TGF-beta Signaling to EMT via Smad7 Ubiquitination
Author(s)
우창훈박수현정은호김근영[김근영]김병철[김병철]임재향[임재향]
Keywords
PROTEIN; DIFFERENTIATION; EXPRESSION; STABILITY; NUCLEUS; MICE
Issue Date
201501
Publisher
KOREAN SOC MOLECULAR & CELLULAR BIOLOGY
Citation
MOLECULES AND CELLS, v.38, no.1, pp.20 - 25
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.
URI
http://hdl.handle.net/YU.REPOSITORY/33732http://dx.doi.org/10.14348/molcells.2015.2120
ISSN
1016-8478
Appears in Collections:
의과대학 > 약리학교실 > Articles
의과대학 > 영상의학과학교실 > Articles
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