Heterologous desensitization of EGF receptors and PDGF receptors by sequestration in caveolae

Sergey V. Matveev; Eric J. Smart

doi:10.1152/ajpcell.00349.2001

$Abstract 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-β-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 Footnotes This work was supported by National Heart, Lung, and Blood Institute Grants HL-62844, HL-58475, and HL-64056 (E. J. Smart). Address for reprint requests and other correspondence: E. J. Smart, Univ. of Kentucky, Dept. of Physiology, 800 Rose St., MS 508 C, Lexington, KY 40536 (E-mail: ejsmart@uky.edu ). 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. 10.1152/ajpcell.00349.2001 Copyright © 2002 the American Physiological Society$

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Heterologous desensitization of EGF receptors and PDGF receptors by sequestration in caveolae

Matveev, Sergey V.; Smart, Eric J.

Follow AJP - Cell Physiology , Volume 282 (4): C935 The American Physiological Society – Apr 1, 2002

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Heterologous desensitization of EGF receptors and PDGF receptors by sequestration in caveolae

Matveev, Sergey V.; Smart, Eric J.

Follow AJP - Cell Physiology , Volume 282 (4): C935 The American Physiological Society – Apr 1, 2002

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