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J. Biol. Chem., Vol. 278, Issue 28, 25591-25599, July 11, 2003

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Ganglioside GM3 Inhibits Matrix Metalloproteinase-9 Activation and Disrupts Its Association with Integrin^*

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

Gangliosides GM3 and GT1b both inhibit epithelial cell adhesion and migration on fibronectin. GT1b binds to integrin ₅₁ and blocks the integrin-fibronectin interaction; GM3 does not interact with integrin, and its effect is poorly understood. We evaluated the effects of endogenous modulation of GM3 expression on epithelial cell motility on several matrices and the mechanism of these effects. Endogenous accumulation of GM3 decreased cell migration on fibronectin, types I, IV, and VII collagen matrices; depletion of GM3 dramatically increased cell migration, regardless of matrix. GM3 overexpression and depletion in vitro correlated inversely with the expression and activity of matrix metalloproteinase-9; consistently, the cell migration stimulated by GM3 depletion is reversed by inhibition of matrix metalloproteinase-9 activity. Accumulation and depletion of GM3 in epithelial cells grown on fibronectin also correlated inversely with epidermal growth factor receptor and mitogen activated protein kinase phosphorylation and with Jun expression. Ganglioside depletion facilitated the co-immunoprecipitation of matrix metal-loproteinase-9 and integrin ₅₁, while endogenous accumulation of GM3, but not GT1b, blocked the co-immunoprecipitation. These data suggest modulation of epidermal growth factor receptor signaling and dissociation of integrin/matrix metalloproteinase-9 as mechanisms for the GM3-induced effects on matrix metalloproteinase-9 function.

Received for publication, March 3, 2003 , and in revised form, April 29, 2003.

^* This work was supported by National Institutes of Health Grant R01 AR44619. 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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