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J. Biol. Chem., Vol. 280, Issue 29, 26796-26804, July 22, 2005

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Epidermal Growth Factor Receptors Are Localized to Lipid Rafts That Contain a Balance of Inner and Outer Leaflet Lipids

A SHOTGUN LIPIDOMICS STUDY^*

Linda J. Pike, Xianlin Han¶, and Richard W. Gross¶||

From the Departments of Biochemistry and Molecular Biophysics, ^¶Internal Medicine, and ^||Chemistry, Washington University School of Medicine, St. Louis, Missouri 63110

The epidermal growth factor (EGF) receptor partitions into lipid rafts made using a detergent-free method, but is extracted from low density fractions by Triton X-100. By screening several detergents, we identified Brij 98 as a detergent in which the EGF receptor is retained in detergent-resistant membrane fractions. To identify the difference in lipid composition between those rafts that harbored the EGF receptor (detergent-free and Brij 98-resistant) and those that did not (Triton X-100-resistant), we used multidimensional electrospray ionization mass spectrometry to perform a lipidomics study on these three raft preparations. Although all three raft preparations were similarly enriched in cholesterol, the EGF receptor-containing rafts contained more ethanolamine glycerophospholipids and less sphingomyelin than did the non-EGF receptor-containing Triton X-100 rafts. As a result, the detergent-free and Brij 98-resistant rafts exhibited a balance of inner and outer leaflet lipids, whereas the Triton X-100 rafts contained a preponderance of outer leaflet lipids. Furthermore, in all raft preparations, the outer leaflet phospholipid species were significantly different from those in the bulk membrane, whereas the inner leaflet lipids were quite similar to those found in the bulk membrane. These findings indicate that the EGF receptor is retained only in rafts that exhibit a lipid distribution compatible with a bilayer structure and that the selection of phospholipids for inclusion into rafts occurs mainly on the outer leaflet lipids.

Received for publication, April 7, 2005 , and in revised form, May 9, 2005.

^* This work was supported by National Institutes of Health Grants GM64491 (to L. J. P.), PO1 HL57278 (to R. W. G. and X. H), and RO1 HL41250 (to R. W. G.). 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.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Tables 1–3.

To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biophysics, Washington University School of Medicine, P. O. Box 8231, 660 S. Euclid Ave., St. Louis, MO 63110. Tel.: 314-362-9502; Fax: 314-362-7183; E-mail: pike{at}wustl.edu.

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