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University of Kentucky Medical School, Department of Physiology, Lexington, Kentucky 40536
Epidermal growth factor
(EGF) and platelet-derived growth factor (PDGF) receptors have been
reported to signal via caveolin-containing membranes called caveolae.
In contrast, others report that EGF and PDGF receptors are exclusively
associated with caveolin-devoid membranes called rafts. Our subcellular
fractionation and coimmunoprecipitation studies demonstrate that, in
the absence of ligand, EGF and PDGF receptors are associated with
rafts. However, in the presence of ligand, EGF and PDGF receptors
transiently associate with caveolae. Surprisingly, pretreatment of
cells with EGF prevents PDGF-dependent phosphorylation of PDGF
receptors and extracellular signal-regulated kinase (ERK) 1/2 kinase
activation. Furthermore, cells pretreated with PDGF prevent
EGF-dependent phosphorylation of EGF receptors and ERK1/2 kinase
activation. Radioligand binding studies demonstrate that incubation of
cells with EGF or PDGF causes both EGF and PDGF receptors to be
reversibly sequestered from the extracellular space. Experiments with
methyl-
-cyclodextrin, filipin, and antisense caveolin-1 demonstrate
that sequestration of the receptors is dependent on cholesterol and
caveolin-1. We conclude that ligand-induced stimulation of EGF or PDGF
receptors can cause the heterologous desensitization of the other
receptor by sequestration in cholesterol-rich, caveolin-containing
membranes or caveolae.
caveolae; signaling; desensitization
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