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

Andrei V. Bakin, Cammie Rinehart, Anne K. Tomlinson, Carlos L. Arteaga

Research output: Contribution to journalArticlepeer-review

349 Scopus citations

Abstract

Transforming growth factor β (TGFβ) contributes to tumor progression by inducing an epithelial to mesenchymal transdifferentiation (EMT) and cell migration. We found that TGFβ-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 TGFβ-mediated phosphorylation of ATF2, but did not inhibit phosphorylation of Smad2. SB202190 impaired TGFβ-mediated changes in cell shape and reorganization of the actin cytoskeleton. Forced expression of dominant-negative (DN) MAPK kinase 3 (MKK3) inhibited TGFβ-mediated activation of p38MAPK and EMT. Expression of DN-p38α impaired TGFβ-induced EMT. Inhibition of p38MAPK blocked TGFβ-induced migration of non-tumor and tumor mammary epithelial cells. TGFβ induced activation of the p38MAPK pathway within 15 minutes. Expression of TGFβ type II (TβRII) and type I (TβRI/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 TGFβ-induced activation of the p38MAPK pathway and EMT, suggesting the Rac1 mediates activation of the p38MPAK pathway. These studies suggest that the p38MAPK is required for TGFβ-mediated EMT and cell migration.

Original languageEnglish (US)
Pages (from-to)3193-3206
Number of pages14
JournalJournal of cell science
Volume115
Issue number15
StatePublished - Aug 1 2002

Keywords

  • Cell migration
  • Epithelial-mesenchymal transition
  • Rac1
  • TGFβ
  • p38MAPK

ASJC Scopus subject areas

  • Cell Biology

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