p38 mitogen-activated protein kinase is required for TGFbeta-mediated fibroblastic transdifferentiation and cell migration

J Cell Sci. 2002 Aug 1;115(Pt 15):3193-206. doi: 10.1242/jcs.115.15.3193.


Transforming growth factor beta (TGFbeta) contributes to tumor progression by inducing an epithelial to mesenchymal transdifferentiation (EMT) and cell migration. We found that TGFbeta-induced EMT was blocked by inhibiting activation of p38 mitogen-activated protein kinase (MAPK) with H-7, a protein kinase C inhibitor, and with SB202190, a direct inhibitor of p38MAPK. Inhibition of the p38MAPK pathway affected TGFbeta-mediated phosphorylation of ATF2, but did not inhibit phosphorylation of Smad2. SB202190 impaired TGFbeta-mediated changes in cell shape and reorganization of the actin cytoskeleton. Forced expression of dominant-negative (DN) MAPK kinase 3 (MKK3) inhibited TGFbeta-mediated activation of p38MAPK and EMT. Expression of DN-p38alpha impaired TGFbeta-induced EMT. Inhibition of p38MAPK blocked TGFbeta-induced migration of non-tumor and tumor mammary epithelial cells. TGFbeta induced activation of the p38MAPK pathway within 15 minutes. Expression of TGFbeta type II (TbetaRII) and type I (TbetaRI/Alk5) kinase-inactive receptors blocked EMT and activation of p38MAPK, whereas expression of constitutively active Alk5-T204D resulted in EMT and phosphorylation of MKK3/6 and p38MAPK. Finally, dominant-negative Rac1N17 blocked TGFbeta-induced activation of the p38MAPK pathway and EMT, suggesting that Rac1 mediates activation of the p38MAPK pathway. These studies suggest that the p38MAPK pathway is required for TGFbeta-mediated EMT and cell migration.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actin Cytoskeleton / drug effects
  • Actin Cytoskeleton / metabolism
  • Activating Transcription Factor 2
  • Animals
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology*
  • Cell Movement / drug effects
  • Cell Movement / physiology*
  • Cell Size / drug effects
  • Cell Size / genetics
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cyclic AMP Response Element-Binding Protein / drug effects
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • DNA-Binding Proteins / drug effects
  • DNA-Binding Proteins / metabolism
  • Enzyme Inhibitors / pharmacology
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Humans
  • Mesoderm / cytology
  • Mesoderm / drug effects
  • Mesoderm / metabolism*
  • Mice
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / drug effects
  • Mitogen-Activated Protein Kinases / metabolism*
  • Mutation / genetics
  • Plant Proteins*
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism
  • Smad Proteins
  • Trans-Activators / drug effects
  • Trans-Activators / metabolism
  • Transcription Factors / drug effects
  • Transcription Factors / metabolism
  • Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta / pharmacology
  • Tumor Cells, Cultured
  • p38 Mitogen-Activated Protein Kinases
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism


  • ATF2 protein, human
  • Activating Transcription Factor 2
  • Atf2 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Plant Proteins
  • Receptors, Transforming Growth Factor beta
  • Smad Proteins
  • Trans-Activators
  • Transcription Factors
  • Transforming Growth Factor beta
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • rac1 GTP-Binding Protein