Regulated Migration of Epidermal Growth Factor Receptor from Caveolae*
- From the ‡Department of Cell Biology and Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9039 and the§Department of Medicine, University of California, San Diego, La Jolla, California 92093-0650
Abstract
In quiescent fibroblasts, epidermal growth factor (EGF) receptors (EGFR) are initially concentrated in caveolae but rapidly move out of this membrane domain in response to EGF. To better understand the dynamic localization of EGFR to caveolae, we have studied the behavior of wild-type and mutant receptors expressed in cells lacking endogenous EGFR. All of the receptors we examined, including those missing the first 274 amino acids or most of the cytoplasmic tail, were constitutively concentrated in caveolae. By contrast, migration from caveolae required EGF binding, an active receptor kinase domain, and at least one of the five tyrosine residues present in the regulatory domain of the receptor. Movement appears to be modulated by Src kinase, is blocked by activators of protein kinase C, and occurs independently of internalization by clathrin-coated pits. Two mutant receptors previously shown to induce an oncogenic phenotype lack the ability to move from caveolae in response to EGF, suggesting that a prolonged residence in this domain may contribute to abnormal cell behavior.
Footnotes
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↵* This work was supported by National Institutes of Health Grants HL 20948, GM 43169, and CA58689 and by a grant from the Perot Family Foundation.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.
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↵¶ To whom correspondence should be addressed: Dept. of Cell Biology and Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75235-9039.
- Abbreviations:
- EGF
-
epidermal growth factor
- EGFR
-
epidermal growth factor receptor
- DMEM
-
Dulbecco's modified Eagle's medium
- PMA
-
phorbol 12-myristate 13-acetate
- mAb
-
monoclonal antibody
- pAb
-
polyclonal antibody
- PAGE
-
polyacrylamide gel electrophoresis
- LPA
-
lysophosphatidic acid
- MAP
-
mitogen-activated protein
- GPCR
-
G-protein-coupled receptor
- PKC
-
protein kinase C
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- Received May 21, 1999.
- Revision received July 19, 1999.
- The American Society for Biochemistry and Molecular Biology, Inc.
