Phosphorylation status at Smad3 linker region modulates transforming growth factor-β-induced epithelial-mesenchymal transition 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 C‐terminal tail of Smad3 undergoes phosphorylation that is essential for canonical TGF‐β signaling. The Smad3 linker region contains serine/threonine phosphorylation sites and can be phosphorylated by intracellular kinases, such as the 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 showed that mutation of 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 shown a multitude of signal transductions that either enhance or suppress TGF‐β responses associated with Smad3 turnover or cancer progression. This review aims at providing new insight into the perplexing mechanisms of TGF‐β signaling affected by Smad3 linker phosphorylation and further attempts to gain insight into elimination and protection of TGF‐β‐mediated oncogenic and growth‐suppressive signals, respectively.