QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ringerike, T. Articles by Stang, E. Search for Related Content PubMed PubMed Citation Articles by Ringerike, T. Articles by Stang, E.

Cholesterol is important in control of EGF receptor kinase activity but EGF receptors are not concentrated in caveolae

¹ Institute of Pathology, University of Oslo, Rikshospitalet University Hospital, N-0027 Oslo, Norway
² MSD Cardiovascular Research Center, Rikshospitalet University Hospital and Department of Pharmacology, University of Oslo, N-0316 Oslo, Norway

^* Author for correspondence (e-mail: espenst{at}ulrik.uio.no )

Accepted 19 December 2001

We have investigated the localization and function of the epidermal growth factor receptor (EGFR) in normal cells, in cholesterol-depleted cells and in cholesterol enriched cells. Using immunoelectron microscopy we find that the EGFR is randomly distributed at the plasma membrane and not enriched in caveolae. Binding of EGF at 4°C does not change the localization of EGFR, and by immunoelectron microscopy we find that only small amounts of bound EGF localize to caveolae. However, upon patching of lipid rafts, we find that a significant amount of the EGFR is localized within rafts. Depletion of the plasma membrane cholesterol causes increased binding of EGF, increased dimerization of the EGFR, and hyperphosphorylation of the EGFR. Addition of cholesterol was found to reduce EGF binding and reduce EGF-induced EGFR activation. Our results suggest that the plasma membrane cholesterol content directly controls EGFR activation.

Key words: Caveolae, Caveolin, Cholesterol, EGFR, Rafts

This article has been cited by other articles:

				E. G. Hofman, M. O. Ruonala, A. N. Bader, D. van den Heuvel, J. Voortman, R. C. Roovers, A. J. Verkleij, H. C. Gerritsen, and P. M. P. van Bergen en Henegouwen EGF induces coalescence of different lipid rafts J. Cell Sci., August 1, 2008; 121(15): 2519 - 2528. [Abstract] [Full Text] [PDF]

				S. E. D. Webb, S. K. Roberts, S. R. Needham, C. J. Tynan, D. J. Rolfe, M. D. Winn, D. T. Clarke, R. Barraclough, and M. L. Martin-Fernandez Single-Molecule Imaging and Fluorescence Lifetime Imaging Microscopy Show Different Structures for High- and Low-Affinity Epidermal Growth Factor Receptors in A431 Cells Biophys. J., February 1, 2008; 94(3): 803 - 819. [Abstract] [Full Text] [PDF]

				C.-L. Chen, I-H. Liu, S. J. Fliesler, X. Han, S. S. Huang, and J. S. Huang Cholesterol suppresses cellular TGF-beta responsiveness: implications in atherogenesis J. Cell Sci., October 15, 2007; 120(20): 3509 - 3521. [Abstract] [Full Text] [PDF]

				S. Yang, M. A. Raymond-Stintz, W. Ying, J. Zhang, D. S. Lidke, S. L. Steinberg, L. Williams, J. M. Oliver, and B. S. Wilson Mapping ErbB receptors on breast cancer cell membranes during signal transduction J. Cell Sci., August 15, 2007; 120(16): 2763 - 2773. [Abstract] [Full Text] [PDF]

				S. Saffarian, Y. Li, E. L. Elson, and L. J. Pike Oligomerization of the EGF Receptor Investigated by Live Cell Fluorescence Intensity Distribution Analysis Biophys. J., August 1, 2007; 93(3): 1021 - 1031. [Abstract] [Full Text] [PDF]

				S. Adachi, T. Nagao, H. I. Ingolfsson, F. R. Maxfield, O. S. Andersen, L. Kopelovich, and I. B. Weinstein The Inhibitory Effect of (-)-Epigallocatechin Gallate on Activation of the Epidermal Growth Factor Receptor Is Associated with Altered Lipid Order in HT29 Colon Cancer Cells Cancer Res., July 1, 2007; 67(13): 6493 - 6501. [Abstract] [Full Text] [PDF]

				Y. Ning, T. Buranda, and L. G. Hudson Activated Epidermal Growth Factor Receptor Induces Integrin {alpha}2 Internalization via Caveolae/Raft-dependent Endocytic Pathway J. Biol. Chem., March 2, 2007; 282(9): 6380 - 6387. [Abstract] [Full Text] [PDF]

				M. Foti, G. Porcheron, M. Fournier, C. Maeder, and J.-L. Carpentier The neck of caveolae is a distinct plasma membrane subdomain that concentrates insulin receptors in 3T3-L1 adipocytes PNAS, January 23, 2007; 104(4): 1242 - 1247. [Abstract] [Full Text] [PDF]

				K. Savage, M. B.K. Lambros, D. Robertson, R. L. Jones, C. Jones, A. Mackay, M. James, J. L. Hornick, E. M. Pereira, F. Milanezi, et al. Caveolin 1 Is Overexpressed and Amplified in a Subset of Basal-like and Metaplastic Breast Carcinomas: A Morphologic, Ultrastructural, Immunohistochemical, and In situ Hybridization Analysis Clin. Cancer Res., January 1, 2007; 13(1): 90 - 101. [Abstract] [Full Text] [PDF]

				J. Dimitroulakos, I. A. Lorimer, and G. Goss Strategies to enhance epidermal growth factor inhibition: targeting the mevalonate pathway. Clin. Cancer Res., July 15, 2006; 12(14): 4426s - 4431s. [Abstract] [Full Text] [PDF]

				J.-X. Zhu, S. Goldoni, G. Bix, R. T. Owens, D. J. McQuillan, C. C. Reed, and R. V. Iozzo Decorin Evokes Protracted Internalization and Degradation of the Epidermal Growth Factor Receptor via Caveolar Endocytosis J. Biol. Chem., September 16, 2005; 280(37): 32468 - 32479. [Abstract] [Full Text] [PDF]

				J. A. Olivares-Reyes, B. H. Shah, J. Hernandez-Aranda, A. Garcia-Caballero, M. P. Farshori, J. A. Garcia-Sainz, and K. J. Catt Agonist-Induced Interactions between Angiotensin AT1 and Epidermal Growth Factor Receptors Mol. Pharmacol., August 1, 2005; 68(2): 356 - 364. [Abstract] [Full Text] [PDF]

				G. Orr, D. Hu, S. Ozcelik, L. K. Opresko, H. S. Wiley, and S. D. Colson Cholesterol Dictates the Freedom of EGF Receptors and HER2 in the Plane of the Membrane Biophys. J., August 1, 2005; 89(2): 1362 - 1373. [Abstract] [Full Text] [PDF]

				L. J. Pike, X. Han, and R. W. Gross Epidermal Growth Factor Receptors Are Localized to Lipid Rafts That Contain a Balance of Inner and Outer Leaflet Lipids: A SHOTGUN LIPIDOMICS STUDY J. Biol. Chem., July 22, 2005; 280(29): 26796 - 26804. [Abstract] [Full Text] [PDF]

				C. Puri, D. Tosoni, R. Comai, A. Rabellino, D. Segat, F. Caneva, P. Luzzi, P. P. Di Fiore, and C. Tacchetti Relationships between EGFR Signaling-competent and Endocytosis-competent Membrane Microdomains Mol. Biol. Cell, June 1, 2005; 16(6): 2704 - 2718. [Abstract] [Full Text] [PDF]

				A. J. Mantha, J. E.L. Hanson, G. Goss, A. E. Lagarde, I. A. Lorimer, and J. Dimitroulakos Targeting the Mevalonate Pathway Inhibits the Function of the Epidermal Growth Factor Receptor Clin. Cancer Res., March 15, 2005; 11(6): 2398 - 2407. [Abstract] [Full Text] [PDF]

				S. B. Sato, K. Ishii, A. Makino, K. Iwabuchi, A. Yamaji-Hasegawa, Y. Senoh, I. Nagaoka, H. Sakuraba, and T. Kobayashi Distribution and Transport of Cholesterol-rich Membrane Domains Monitored by a Membrane-impermeant Fluorescent Polyethylene Glycol-derivatized Cholesterol J. Biol. Chem., May 28, 2004; 279(22): 23790 - 23796. [Abstract] [Full Text] [PDF]

				P. V. Burgos, C. Klattenhoff, E. de la Fuente, A. Rigotti, and A. Gonzalez Cholesterol depletion induces PKA-mediated basolateral-to-apical transcytosis of the scavenger receptor class B type I in MDCK cells PNAS, March 16, 2004; 101(11): 3845 - 3850. [Abstract] [Full Text] [PDF]

				E. J. Westover, D. F. Covey, H. L. Brockman, R. E. Brown, and L. J. Pike Cholesterol Depletion Results in Site-specific Increases in Epidermal Growth Factor Receptor Phosphorylation due to Membrane Level Effects: STUDIES WITH CHOLESTEROL ENANTIOMERS J. Biol. Chem., December 19, 2003; 278(51): 51125 - 51133. [Abstract] [Full Text] [PDF]

				E. Odintsova, J. Voortman, E. Gilbert, and F. Berditchevski Tetraspanin CD82 regulates compartmentalisation and ligand-induced dimerization of EGFR J. Cell Sci., November 15, 2003; 116(22): 4557 - 4566. [Abstract] [Full Text] [PDF]

				B. D. Wyse, I. A. Prior, H. Qian, I. C. Morrow, S. Nixon, C. Muncke, T. V. Kurzchalia, W. G. Thomas, R. G. Parton, and J. F. Hancock Caveolin Interacts with the Angiotensin II Type 1 Receptor during Exocytic Transport but Not at the Plasma Membrane J. Biol. Chem., June 20, 2003; 278(26): 23738 - 23746. [Abstract] [Full Text] [PDF]

				H. Abrahamsen, T. Vang, and K. Tasken Protein Kinase A Intersects Src Signaling in Membrane Microdomains J. Biol. Chem., May 2, 2003; 278(19): 17170 - 17177. [Abstract] [Full Text] [PDF]

				L. J. Pike Lipid rafts: bringing order to chaos J. Lipid Res., April 1, 2003; 44(4): 655 - 667. [Abstract] [Full Text] [PDF]

				X. Chen and M. D. Resh Cholesterol Depletion from the Plasma Membrane Triggers Ligand-independent Activation of the Epidermal Growth Factor Receptor J. Biol. Chem., December 13, 2002; 277(51): 49631 - 49637. [Abstract] [Full Text] [PDF]

				X.-Q. Wang, P. Sun, and A. S. Paller Ganglioside Induces Caveolin-1 Redistribution and Interaction with the Epidermal Growth Factor Receptor J. Biol. Chem., November 27, 2002; 277(49): 47028 - 47034. [Abstract] [Full Text] [PDF]

				J. M. Han, Y. Kim, J. S. Lee, C. S. Lee, B. D. Lee, M. Ohba, T. Kuroki, P.-G. Suh, and S. H. Ryu Localization of Phospholipase D1 to Caveolin-enriched Membrane via Palmitoylation: Implications for Epidermal Growth Factor Signaling Mol. Biol. Cell, November 1, 2002; 13(11): 3976 - 3988. [Abstract] [Full Text] [PDF]