Evidence for a role of MSK1 in transforming growth factor-beta-mediated responses through p38alpha and Smad signaling pathways.

Smad proteins are central mediators of the transforming growth factor-beta (TGF-beta) superfamily signaling. The mitogen-activated protein kinase (MAPK) p38 is also one of the downstream targets required for TGF-beta-mediated responses. Although the interplay between the p38 and Smad signaling pathways might allow cells to display diverse patterns of responses to TGF-beta, the mechanism of this cross-talk is not well established. We report here that inhibition of the p38alpha isoform suppressed the ability of Smad3 to mediate TGF-beta-induced transcriptional responses. The inhibition of p38 activity blocked TGF-beta-mediated phosphorylation of the MSK1 kinase, a substrate of p38 that plays an important role in the remodeling of chromatin. Moreover, we observed that expression of dominant-interfering mutants of MSK1 blocked the binding of Smad3 to the coactivator p300 in response to TGF-beta signaling. These data reveal a new mechanism whereby the Smad signaling pathway and the p38 cascade are integrated in the nucleus to activate gene expression.