Phosphorylation status at Smad3 linker region modulates TGF‐β‐induced EMT and cancer progression

Abstract

Smad3, a major transcription factor in transforming growth factor‐β (TGF‐β) signaling, plays critical roles in both tumor‐suppressive and pro‐oncogenic functions. Upon TGF‐β stimulation, the linker region of Smad3 becomes phosphorylated concurrently with the C‐terminal phosphorylation that is essential for the canonical TGF‐β signaling. The Smad3 linker region contains serine/threonine phosphorylation sites and can be phosphorylated by intracellular kinases, such as the mitogen‐activated protein kinase (MAPK) family, cyclin‐dependent kinase (CDK) family and glycogen synthase kinase‐3β (GSK‐3β). Previous reports based on cell culture studies by us and others demonstrated that mutation of the Smad3 linker phosphorylation sites dramatically intensifies TGF‐β responses as well as growth‐inhibitory function and epithelial‐mesenchymal transition (EMT), suggesting that Smad3 linker phosphorylation suppresses TGF‐β transcriptional activities. However, recent discoveries of Smad3‐interacting molecules that preferentially bind phosphorylated Smad3 linker serine/threonine residues have disclosed a multitude of signal transduction that either enhance or suppress TGF‐β responses associated with the Smad3 turnover or cancer progression. This review aims at providing a new insight into perplexing mechanisms of the TGF‐β signaling affected by the Smad3 linker phosphorylation and further attempts to gain clues for elimination and protection of TGF‐β‐mediated oncogenic and growth‐suppressive signals, respectively.

This article is protected by copyright. All rights reserved.

http://bit.ly/2SjNdZm