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J. Biol. Chem., Vol. 279, Issue 35, 36481-36489, August 27, 2004

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Exogenous Ganglioside G_D1a Enhances Epidermal Growth Factor Receptor Binding and Dimerization^*

Yihui Liu, Ruixiang Li, and Stephan Ladisch

From the Glycobiology Program, Center for Cancer and Immunology Research, Children's Research Institute, Washington, D. C. 20010 and the Departments of Pediatrics and Biochemistry/Molecular Biology, The George Washington University School of Medicine, Washington, D. C. 20010

Gangliosides are shed by tumor cells and can bind to normal cells in the tumor microenvironment and affect their function. Exposure of fibroblasts to exogenous gangliosides increases epidermal growth factor (EGF)-induced fibroblast proliferation and enhances EGF receptor (EGFR)-mediated activation of the mitogen-activated protein kinase signaling pathway (Li, R., Liu, Y., and Ladisch, S. (2001) J. Biol. Chem. 276, 42782–42792). Here we report that the EGFR itself is the target of this ganglioside effect: Preincubation of normal human dermal fibroblasts with G_D1a ganglioside enhanced both EGF-induced EGFR autophosphorylation and receptortyrosine kinase activity. The enhancement was rapid (within 30 min), not due to alteration of time kinetics of the EGFR response to EGF, and reproduced in purified G_D1a-enriched cell membranes isolated from ganglioside-preincubated fibroblasts. Evaluating the initial steps underlying activation, EGF binding, and EGFR dimerization, we found that G_D1a enrichment of the cell membrane increased EGFR dimerization and the effective number of high affinity EGFR without increasing total receptor protein. Unexpectedly, G_D1a enrichment also triggered increased EGFR dimerization in the absence of growth factor. This resulted in enhanced activation of the EGFR signal transduction cascade when EGF was added. We conclude that membrane ganglioside enrichment of normal fibroblasts (such as by tumor cell ganglioside shedding) facilitates receptor-receptor interactions (possibly by altering membrane topology), causing ligand-independent EGFR dimerization and, in turn, enhanced EGF signaling.

Received for publication, March 15, 2004 , and in revised form, June 15, 2004.

^* This work was supported by National Institutes of Health Grant R01 CA61010 (to S. L.). 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: Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center, 111 Michigan Avenue, NW, Washington, D. C. 20010. Tel.: 202-884-3898; Fax: 202-884-3929; E-mail: Sladisch{at}cnmc.org.

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