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J. Biol. Chem., Vol. 278, Issue 49, 48770-48778, December 5, 2003

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Ganglioside GM3 Blocks the Activation of Epidermal Growth Factor Receptor Induced by Integrin at Specific Tyrosine Sites^*

Xiao-Qi Wang, Ping Sun, and Amy S. Paller

From the Departments of Pediatrics and Dermatology, Children's Memorial Institute for Education and Research, Northwestern University Medical School, Chicago, Illinois 60614

The epidermal growth factor receptor (EGFR) can be activated by both direct ligand binding and cross-talk with other molecules, such as integrins. This integrin-mediated cross-talk with growth factor receptors participates in regulating cell proliferation, survival, migration, and invasion. Previous studies have shown that ligand-dependent EGFR activation is inhibited by GM3, the predominant ganglioside of epithelial cells, but the effect of GM3 on ligand-independent, integrin-EGFR cross-talk is unknown. Using a squamous carcinoma cell line we show that endogenous accumulation of GM3 disrupts the ligand-independent association of the integrin ₁ subunit with EGFR and results in inhibition of cell proliferation. Consistently, endogenous depletion of GM3 markedly increases the association of EGFR with tyrosine-phosphorylated integrin ₁ and promotes cell proliferation. The ligand-independent stimulation of EGFR does not require focal adhesion kinase phosphorylation or cytoskeletal rearrangement. Stimulation of EGFR and mitogen-activated protein kinase signaling by GM3 depletion involves the phosphorylation of EGFR at tyrosine residues 845, 1068, and 1148 but not 1086 or 1173. The specific blockade of phosphorylation at Tyr-845 with Src family kinase inhibition and at Tyr-1148 with phosphatidylinositol 3-kinase inhibition suggests that GM3 inhibits integrin-induced, ligand-independent EGFR phosphorylation (cross-talk) through suppression of Src family kinase and phosphatidylinositol 3-kinase signaling.

Received for publication, August 11, 2003 , and in revised form, September 11, 2003.

^* This work was supported by National Institutes of Health Grant R01 AR44619 and the Fujisawa Healthcare, Inc. Research Endowment. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Division of Dermatology 107, Children's Memorial Hospital, 2300 Children's Plaza, Chicago, IL 60614. Tel.: 773-880-3681; Fax: 773-880-3025; E-mail: apaller{at}northwestern.edu.

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