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

Transforming growth factor-beta (TGF-beta)-activated kinase 1 (TAK1), a mem ber of the mitogen-activated protein kinase kinase kinase family, is sugges ted to be involved in TGF-beta induced gene expression, but the signaling m echanism from TAK1 to the nucleus remains largely undefined. We have found that p38 mitogen-activated protein kinase, and its direct activator MKK6 ar e rapidly activated in response to TGF-beta. Expression of dominant negativ e MKK6 or dominant negative TAK1 inhibited the TGF-beta-induced transcripti onal activation as well as the p38 activation. Constitutive activation of t he p38 pathway :in the absence of TGF-beta induced the transcriptional acti vation, which was enhanced synergistically by coexpression of Smad2 and Sma d4 and was inhibited by expression of the C-terminal truncated, dominant ne gative Smad4. Furthermore, we have found that activating transcription fact or-2 (ATF-2), which is known as a nuclear target of p38, becomes phosphoryl ated in the N-terminal activation domain in response to TGF-beta, that ATF- 2 forms a complex with Smad4, and that the complex formation is enhanced by TGF-beta. In addition, expression of a nonphosphorylatable form of ATF-2 i nhibited the TGF-beta-induced transcriptional activation. These results sho w that the p38 pathway is activated by TGF-beta and is involved in the TGF- beta-induced transcriptional activation by regulating the Smad-mediated pat hway.