p38 MAP kinase modulates Smad-dependent changes in human prostate cell adhesion.

Transforming growth factor beta (TGFbeta) regulates cell adhesion, proliferation, and differentiation in a variety of cells. Smad proteins are receptor-activated transcription factors that translocate to the nucleus in response to TGFbeta. We demonstrate here that TGFbeta increases cell adhesion in metastatic PC3-M prostate cancer cells. TGFbeta treatment of PC3-M cells leads to nuclear translocation of R-Smad proteins. We show that Smad proteins are necessary, but not sufficient, for TGFbeta-mediated cell adhesion. After showing that TGFbeta upregulated p38 MAP kinase activity in PC3-M cells, we show that inhibition of p38 MAP kinase partially blocked TGFbeta-mediated increase in cell adhesion, as well as nuclear translocation of Smad3. Finally, we show that Smad3 is phosphorylated by p38 MAP kinase in vitro. These findings implicate crosstalk between the MAP kinase and Smad signaling pathways in TGFbeta's regulation of cell adhesion in human prostate cells. This represents a mechanism by which the pleiotropic effects of TGFbeta may be channeled to modulate cell adhesion.