p38 mitogen-activated protein kinase is required for TGFβ-mediated fibroblastic transdifferentiation and cell migration
Open Access
- 1 August 2002
- journal article
- Published by The Company of Biologists in Journal of Cell Science
- Vol. 115 (15), 3193-3206
- https://doi.org/10.1242/jcs.115.15.3193
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 that Rac1 mediates activation of the p38MAPK pathway. These studies suggest that the p38MAPK pathway is required for TGFβ-mediated EMT and cell migration.Keywords
This publication has 59 references indexed in Scilit:
- Integrin β1 Signaling Is Necessary for Transforming Growth Factor-β Activation of p38MAPK and Epithelial PlasticityJournal of Biological Chemistry, 2001
- Transforming Growth Factor-β1 Mediates Epithelial to Mesenchymal Transdifferentiation through a RhoA-dependent MechanismMolecular Biology of the Cell, 2001
- Phosphatidylinositol 3-Kinase Function Is Required for Transforming Growth Factor β-mediated Epithelial to Mesenchymal Transition and Cell MigrationJournal of Biological Chemistry, 2000
- Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory responseNature Cell Biology, 1999
- Characterization of Rac and Cdc42 Activation in Chemoattractant-stimulated Human Neutrophils Using a Novel Assay for Active GTPasesJournal of Biological Chemistry, 1999
- TGFβ2 and TGFβ3 Have Separate and Sequential Activities during Epithelial–Mesenchymal Cell Transformation in the Embryonic HeartDevelopmental Biology, 1999
- p38 Mitogen-Activated Protein Kinase Can Be Involved in Transforming Growth Factor β Superfamily Signal Transduction in Drosophila Wing MorphogenesisMolecular and Cellular Biology, 1999
- Genetic events and the role of TGFβ in epithelial tumour progressionThe Journal of Pathology, 1999
- TGFβ in prostate cancer: A growth inhibitor that can enhance tumorigenicityThe Prostate, 1997
- Evidence for a Role of Rho-like GTPases and Stress-activated Protein Kinase/c-Jun N-terminal Kinase (SAPK/JNK) in Transforming Growth Factor β-mediated SignalingPublished by Elsevier ,1997