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.
Takekawa
Mutsuhiro
M
Division of Molecular Cell Signaling, Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. takekawa@ims.u-tokyo.ac.jp
Tatebayashi
Kazuo
K
Itoh
Fumio
F
Adachi
Masaaki
M
Imai
Kohzoh
K
Saito
Haruo
H
D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics* / Q000378:metabolism; D015152:Blotting, Northern; D019556:COS Cells; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism; D051901:Smad4 Protein; D019700:Thrombospondin 1 / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases; D000097642:GADD45 Proteins
D000943:Antigens, Differentiation; D004268:DNA-Binding Proteins; D020928:Mitogen-Activated Protein Kinases; D051901:Smad4 Protein; D019700:Thrombospondin 1; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases; C086470:GADD45B protein, human; D000097642:GADD45 Proteins; C497796:SMAD4 protein, human