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Murine protein serine/threonine kinase 38 stimulates TGF-beta signaling in a kinase-dependent manner via direct phosphorylation of Smad proteins.

ABSTRACT: The present study demonstrated that murine protein serine/threonine kinase 38 (MPK38) coimmunoprecipitates with Smad proteins (Smad2, -3, -4, and -7) and that this association is mediated by the catalytic kinase domain of MPK38. The association between MPK38 and Smad2, -3, and -4 was significantly increased by TGF-? or ASK1 signals, whereas these signals decreased association of MPK38 with Smad7. MPK38 stimulated TGF-?-induced transcription required for TGF-?-mediated biological functions, such as apoptosis and cell growth arrest, in a kinase-dependent manner. Knockdown of endogenous MPK38 showed an opposite effect, inhibiting TGF-? signaling. MPK38-mediated phosphorylation of Smad proteins (Ser(245) of Smad2, Ser(204) of Smad3, Ser(343) of Smad4, and Thr(96) of Smad7) was also found to be crucial to the positive regulation of TGF-? signaling induced by MPK38. In addition, MPK38 enhanced nuclear translocation of Smad3, as well as redistribution of Smad7 from the nucleus to the cytoplasm, in response to TGF-?. Together, these results indicate that MPK38 functions as a stimulator of TGF-? signaling through direct interaction with and phosphorylation of Smad proteins.


PROVIDER: S-EPMC2945587 | BioStudies | 2010-01-01T00:00:00Z

REPOSITORIES: biostudies

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