Smad-dependent GADD45beta expression mediates delayed activation of p38 MAP kinase by TGF-beta.

Transforming growth factor-beta (TGF-beta), when bound to its specific receptor, activates the transcription factor Smad by phosphorylation. TGF-beta also activates the p38 MAPK pathway, but there seem to be disparate mechanisms for the early p38 activation and delayed p38 activation. In this report, we demonstrate that Smad-dependent expression of GADD45beta is responsible for the delayed activation of p38 by TGF-beta. The GADD45beta protein binds and activates MTK1 (= MEKK4), which is a member of the MAPKKK family kinases and an upstream activator of the p38 MAPK cascade. Both TGF-beta-induced GADD45beta expression and the delayed p38 activation require functional Smad proteins. Antisense inhibition of GADD45beta expression suppresses the TGF-beta-induced delayed p38 activation, whereas overexpression of GADD45beta activates the p38 MAPK via MTK1. Expression of the angiogenesis inhibitor thrombospondin-1 (TSP-1) is induced by TGF-beta via Smad-dependent p38 activation. Thus TGF-beta-induced p38 activation, mediated by GADD45beta expression, may play an important role in the biological effects of TGF-beta.