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

J Biol Chem. 2010 Oct 1;285(40):30959-70. doi: 10.1074/jbc.M110.138370. Epub 2010 Jul 21.


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-β or ASK1 signals, whereas these signals decreased association of MPK38 with Smad7. MPK38 stimulated TGF-β-induced transcription required for TGF-β-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-β 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-β 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-β. Together, these results indicate that MPK38 functions as a stimulator of TGF-β signaling through direct interaction with and phosphorylation of Smad proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / physiology
  • Animals
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism*
  • Hep G2 Cells
  • Humans
  • MAP Kinase Kinase Kinase 5 / genetics
  • MAP Kinase Kinase Kinase 5 / metabolism
  • MAP Kinase Signaling System / physiology*
  • Mice
  • Phosphorylation / physiology
  • Smad Proteins / genetics
  • Smad Proteins / metabolism*
  • Transcription, Genetic / physiology
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Smad Proteins
  • Transforming Growth Factor beta
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 5
  • Map3k5 protein, mouse