Involvement of the p38 mitogen-activated protein kinase pathway in transforming growth factor-β-induced gene expression

Abstract

Transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase family, is suggested to be involved in TGF-β-induced gene expression, but the signaling mechanism from TAK1 to the nucleus remains largely undefined. We have found that p38 mitogen-activated protein kinase, and its direct activator MKK6 are rapidly activated in response to TGF-β. Expression of dominant negative MKK6 or dominant negative TAK1 inhibited the TGF-β-induced transcriptional activation as well as the p38 activation. Constitutive activation of the p38 pathway in the absence of TGF-β induced the transcriptional activation, which was enhanced synergistically by coexpression of Smad2 and Smad4 and was inhibited by expression of the C-terminal truncated, dominant negative Smad4. Furthermore, we have found that activating transcription factor-2 (ATF-2), which is known as a nuclear target of p38, becomes phosphorylated in the N- terminal activation domain in response to TGF-β, that ATF-2 forms a complex with Smad4, and that the complex formation is enhanced by TGF-β. In addition, expression of a nonphosphorylatable form of ATF-2 inhibited the TGF-β-induced transcriptional activation. These results show that the p38 pathway is activated by TGF-β and is involved in the TGF-β-induced transcriptional activation by regulating the Smad-mediated pathway.