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Epidermal Growth Factor Receptor-Dependent Regulation of Integrin-Mediated Signaling and Cell Cycle Entry in Epithelial Cells

Heather M. Bill,^1, Beatrice Knudsen,² Sheri L. Moores,³ Senthil K. Muthuswamy,^3, Vikram R. Rao,^3, Joan S. Brugge,³ and Cindy K. Miranti^1*

Van Andel Research Institute, Grand Rapids, Michigan,¹ Division of Public Health Sciences, Program in Cancer Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington,² Department of Cell Biology, Harvard Medical School, Boston, Massachusetts³

Received 20 October 2003/ Returned for modification 9 December 2003/ Accepted 16 June 2004

Integrin-mediated adhesion of epithelial cells to extracellular matrix (ECM) proteins induces prolonged tyrosine phosphorylation and partial activation of epidermal growth factor receptor (EGFR) in an integrin-dependent and EGFR ligand-independent manner. Integrin-mediated activation of EGFR in epithelial cells is required for multiple signal transduction events previously shown to be induced by cell adhesion to matrix proteins, including tyrosine phosphorylation of Shc, Cbl, and phospholipase C, and activation of the Ras/Erk and phosphatidylinositol 3'-kinase/Akt signaling pathways. In contrast, activation of focal adhesion kinase, Src, and protein kinase C, adhesion to matrix proteins, cell spreading, migration, and actin cytoskeletal rearrangements are induced independently of EGFR kinase activity. The ability of integrins to induce the activation of EGFR and its subsequent regulation of Erk and Akt activation permitted adhesion-dependent induction of cyclin D1 and p21, Rb phosphorylation, and activation of cdk4 in epithelial cells in the absence of exogenous growth factors. Adhesion of epithelial cells to the ECM failed to efficiently induce degradation of p27, to induce cdk2 activity, or to induce Myc and cyclin A synthesis; subsequently, cells did not progress into S phase. Treatment of ECM-adherent cells with EGF, or overexpression of EGFR or Myc, resulted in restoration of late-G₁ cell cycle events and progression into S phase. These results indicate that partial activation of EGFR by integrin receptors plays an important role in mediating events triggered by epithelial cell attachment to ECM; EGFR is necessary for activation of multiple integrin-induced signaling enzymes and sufficient for early events in G₁ cell cycle progression. Furthermore, these findings suggest that EGFR or Myc overexpression may provoke ligand-independent proliferation in matrix-attached cells in vivo and could contribute to carcinoma development.

Present address: Department of Pathology, Vanderbilt University, Nashville, TN 37232.

Present address: Cold Spring Harbor Labs, Cold Spring Harbor, NY 11724.

Present address: Wyeth Research, Cambridge, MA 02140.

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