Integrin beta 1 signaling is necessary for transforming growth factor-beta activation of p38MAPK and epithelial plasticity.

Bhowmick NA, Zent R, Ghiassi M, McDonnell M, Moses HL
J Biol Chem. 2001 276 (50): 46707-13

PMID: 11590169 · DOI:10.1074/jbc.M106176200

Transforming growth factor-beta (TGF-beta) can induce epithelial to mesenchymal transdifferentiation (EMT) in mammary epithelial cells. TGF-beta-mediated EMT involves the stimulation of a number of signaling pathways by the sequential binding of the type II and type I serine/threonine kinase receptors, respectively. Integrins comprise a family of heterodimeric extracellular matrix receptors that mediate cell adhesion and intracellular signaling, hence making them crucial for EMT progression. In light of substantial evidence indicating TGF-beta regulation of various beta(1) integrins and their extracellular matrix ligands, we examined the cross-talk between the TGF-beta and integrin signal transduction pathways. Using an inducible system for the expression of a cytoplasmically truncated dominant negative TGF-beta type II receptor, we blocked TGF-beta-mediated growth inhibition, transcriptional activation, and EMT progression. Dominant negative TGF-beta type II receptor expression inhibited TGF-beta signaling to the SMAD and AKT pathways, but did not block TGF-beta-mediated p38MAPK activation. Interestingly, blocking integrin beta(1) function inhibited TGF-beta-mediated p38MAPK activation and EMT progression. Limiting p38MAPK activity through the expression of a dominant negative-p38MAPK also blocked TGF-beta-mediated EMT. In summary, TGF-beta-mediated p38MAPK activation is dependent on functional integrin beta(1), and p38MAPK activity is required but is not sufficient to induce EMT.

MeSH Terms (29)

Cell Adhesion Cell Differentiation Cytoplasm DNA, Complementary Dose-Response Relationship, Drug Ecdysterone Enzyme Activation Epithelial Cells Extracellular Matrix Genes, Dominant Immunoblotting Integrin beta1 Ligands Mesoderm Microscopy, Fluorescence Mitogen-Activated Protein Kinases p38 Mitogen-Activated Protein Kinases Phenotype Phosphorylation Precipitin Tests Protein-Serine-Threonine Kinases Protein Binding Receptor, Transforming Growth Factor-beta Type II Receptors, Transforming Growth Factor beta Signal Transduction Spectrometry, Fluorescence Time Factors Transcriptional Activation Transforming Growth Factor beta

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