Phosphorylation status at Smad3 linker region modulates transforming growth factor-β-induced epithelial-mesenchymal transition and cancer progression.

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.