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Down-regulation of Integrin ₂ Surface Expression by Mutant Epidermal Growth Factor Receptor (EGFRvIII) Induces Aberrant Cell Spreading and Focal Adhesion Formation

¹ Health Sciences Center, College of Pharmacy and ² Chemical and Nuclear Engineering Department, University of New Mexico, Albuquerque, New Mexico; and ³ Department of Cell and Molecular Biology, Northwestern University Feinberg Medical School, Chicago, Illinois

Requests for reprints: Laurie G. Hudson, College of Pharmacy, MSC09 5360, University of New Mexico, Albuquerque, NM 87131-0001. Phone: 505-272-2482; Fax: 505-272-6749; E-mail: lghudson{at}unm.edu.

Elevated expression or activity of the epidermal growth factor receptor (EGFR) is common in ovarian cancer and is associated with poor patient prognosis. A naturally occurring EGFR mutation termed variant III (EGFRvIII) has been detected in many human tumors, including those of the ovary. This mutant receptor does not bind EGF; however, it is constitutively active as detected by receptor dimerization, autophosphorylation, and stimulation of signal transduction cascades. To identify the consequences of EGFRvIII expression in ovarian tumor cells, we introduced EGFRvIII into the epithelial ovarian cancer cell line OVCA 433. The EGFRvIII-transfected cells displayed a motile phenotype, defects in cell spreading, and decreased integrin ₂ protein expression as detected by Western blot analysis and flow cytometry. Inhibition of EGFRvIII catalytic activity using the EGFR-selective tyrphostin AG1478 restored integrin ₂ expression within 4 to 8 hours after treatment. The modulation of integrin ₂ expression corresponded to marked changes in the actin cytoskeleton as detected by redistribution of filamentous-actin. Furthermore, focal adhesions were evident only when EGFRvIII activity was inhibited. Together, these findings suggest that expression of the constitutively active mutant EGFRvIII promotes changes in cell shape and focal adhesion formation, mediated in part through specific modulation of integrin ₂ expression and function. We conclude that EGFR-activating mutations, such as EGFRvIII, in ovarian cancer may contribute to a more aggressive disease.

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