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 language | English (US) |
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Pages (from-to) | 3193-3206 |
Number of pages | 14 |
Journal | Journal of cell science |
Volume | 115 |
Issue number | 15 |
State | Published - Aug 1 2002 |
Keywords
- Cell migration
- Epithelial-mesenchymal transition
- Rac1
- TGFβ
- p38MAPK
ASJC Scopus subject areas
- Cell Biology