Smad3 phosphorylation by cyclin-dependent kinases

Smad3, a key mediator for TGF-β antiproliferative responses, is phosphorylated by both CDK4 and CDK2 in vivo and in vitro. Except for the Rb family members, Smad3 is the only CDK4 substrate demonstrated so far. CDK phosphorylation of Smad3 inhibits its transcriptional activity and antiproliferative function. Because cancer cells often contain high levels of CDK activity, inhibition of Smad activity by CDK phosphorylation may contribute to tumorigenesis and TGF-β resistance in cancers.