Journal of Biological Chemistry
Volume 276, Issue 50, 14 December 2001, Pages 46707-46713
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MECHANISMS OF SIGNAL TRANSDUCTION
Integrin β1 Signaling Is Necessary for Transforming Growth Factor-β Activation of p38MAPK and Epithelial Plasticity*

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Transforming growth factor-β (TGF-β) can induce epithelial to mesenchymal transdifferentiation (EMT) in mammary epithelial cells. TGF-β-meditated 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-β regulation of various β1 integrins and their extracellular matrix ligands, we examined the cross-talk between the TGF-β and integrin signal transduction pathways. Using an inducible system for the expression of a cytoplasmically truncated dominant negative TGF-β type II receptor, we blocked TGF-β-mediated growth inhibition, transcriptional activation, and EMT progression. Dominant negative TGF-β type II receptor expression inhibited TGF-β signaling to the SMAD and AKT pathways, but did not block TGF-β-mediated p38MAPK activation. Interestingly, blocking integrin β1 function inhibited TGF-β-mediated p38MAPK activation and EMT progression. Limiting p38MAPK activity through the expression of a dominant negative-p38MAPK also blocked TGF-β-mediated EMT. In summary, TGF-β-mediated p38MAPK activation is dependent on functional integrin β1, and p38MAPK activity is required but is not sufficient to induce EMT.

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Published, JBC Papers in Press, October 5, 2001, DOI 10.1074/jbc.M106176200

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This work was supported by a Department of Defense US Army Medical Research and Materiel Command Grant BC991184 (to N. A. B.), National Kidney Foundation Young Investigator Grant (to R. Z.), Public Health Service Grants CA42572 and CA85492 (to H. L. M.), and Vanderbilt-Ingram Cancer Center Support Grant CA68485. Fluorescence microscopy images were acquired through the use of the Vanderbilt University Medical Center Cell Imaging Core Resource, (supported by National Institutes of Health Grants CA68485 and DK20593).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.