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J. Biol. Chem., Vol. 277, Issue 49, 47028-47034, December 6, 2002
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From the Departments of Pediatrics and Dermatology, Children's
Memorial Institute for Education and Research, Northwestern University
Medical School, Chicago, Illinois 60614
Although caveolin-1 is thought to facilitate the
interaction of receptors and signaling components, its role in
epidermal growth factor receptor (EGFR) signaling remains poorly
understood. Ganglioside GM3 inhibits EGFR autophosphorylation and may
thus affect the interaction of caveolin-1 and the EGFR. We report here that endogenous overexpression of GM3 leads to the clustering of GM3 on
the cell membrane of the keratinocyte-derived SCC12 cell line and
promotes co-immunoprecipitation of caveolin-1 and GM3 with the EGFR.
Overexpression of GM3 does not affect EGFR distribution but shifts
caveolin-1 to the detergent-soluble, EGFR-containing region;
consistently, caveolin-1 is retained in the detergent-insoluble membrane when ganglioside is depleted. GM3 overexpression inhibits EGFR
tyrosine phosphorylation and receptor dimerization and concurrently increases both the content and tyrosine phosphorylation of
EGFR-associated caveolin-1, providing evidence that tyrosine
phosphorylation of caveolin-1 inhibits EGFR signaling. Consistently,
depletion of ganglioside both increases EGFR phosphorylation and
prevents the EGF-induced tyrosine phosphorylation of caveolin-1. GM3
also induces delayed serine phosphorylation of EGFR-unassociated
caveolin-1, suggesting a role for serine phosphorylation of caveolin-1
in regulating EGFR signaling. These studies suggest that GM3 modulates the caveolin-1/EGFR association and is critical for the EGF-induced tyrosine phosphorylation of caveolin-1 that is associated with its
inhibition of EGFR activation.
Ganglioside Induces Caveolin-1 Redistribution and Interaction
with the Epidermal Growth Factor Receptor*
*
This work was supported by the National Institutes of Health
Grant R01 AR44619.The costs of publication of this
article were defrayed in part by the
payment of page charges. The 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@northwestern.edu.
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