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Vol. 10, Issue 9, 2861-2878, September 1999

Stimulation of beta 1-Integrin Function by Epidermal Growth Factor and Heregulin-beta Has Distinct Requirements for erbB2 but a Similar Dependence on Phosphoinositide 3-OH Kinase

Margaret A. Adelsman,*dagger Dagger James B. McCarthy,*Dagger and Yoji Shimizu*dagger Dagger §

 *Department of Laboratory Medicine and Pathology,  dagger Center for Immunology,  Dagger Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455

Integrins and growth factor receptors are important participants in cellular adhesion and migration. The EGF receptor (EGFR) family of tyrosine kinases and the beta 1-integrin adhesion receptors are of particular interest, given the implication for their involvement in the initiation and progression of tumorigenesis. We used adhesion and chemotaxis assays to further elucidate the relationship between these two families of transmembrane signaling molecules. Specifically, we examined integrin-mediated adhesive and migratory characteristics of the metastatic breast carcinoma cell line MDA-MB-435 in response to stimulation with growth factors that bind to and activate the EGFR or erbB3 in these cells. Although ligand engagement of the EGFR stimulated modest beta 1-dependent increases in cell adhesion and motility, heregulin-beta (HRGbeta ) binding to the erbB3 receptor initiated rapid and potent induction of breast carcinoma cell adhesion and migration and required dimerization of erbB3 with erbB2. Pharmacologic inhibitors of phosphoinositide 3-OH kinase (PI 3-K) or transient expression of dominant negative forms of PI 3-K inhibited both EGF- and HRGbeta -mediated adhesion and potently blocked HRGbeta - and EGF-induced cell motility. Our results illustrate the critical role of PI 3-K activity in signaling pathways initiated by the EGFR or erbB3 to up-regulate beta 1-integrin function.


§   Corresponding author. E-mail: shimi002{at}tc.umn.edu.


Molecular Biology of the Cell
Vol. 10, 2861-2878, September 1999
Copyright © 1999 by The American Society for Cell Biology



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