Evidence for a Role of MSK1 in Transforming Growth Factor-β-mediated Responses through p38α and Smad Signaling Pathways

Abstract Smad proteins are central mediators of the transforming growth factor-β (TGF-β) superfamily signaling. The mitogen-activated protein kinase (MAPK) p38 is also one of the downstream targets required for TGF-β-mediated responses. Although the interplay between the p38 and Smad signaling pathways might allow cells to display diverse patterns of responses to TGF-β, the mechanism of this cross-talk is not well established. We report here that inhibition of the p38α isoform suppressed the ability of Smad3 to mediate TGF-β-induced transcriptional responses. The inhibition of p38 activity blocked TGF-β-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-β 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.