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Phospho-caveolin-1 mediates integrin-regulated membrane domain internalization

Nature Cell Biology volume 7, pages 901–908 (2005)Cite this article

Abstract

Growth of normal cells is anchorage dependent because signalling through multiple pathways including Erk, phosphatidylinositol-3-OH kinase (PI(3)K) and Rac requires integrin-mediated cell adhesion1. Components of these pathways localize to low-density, cholesterol-rich domains in the plasma membrane named 'lipid rafts'2,3 or 'cholesterol-enriched membrane microdomains' (CEMM)4. We previously reported that integrin-mediated adhesion regulates CEMM transport such that cell detachment from the extracellular matrix triggers CEMM internalization and clearance from the plasma membrane5. We now report that this internalization is mediated by dynamin-2 and caveolin-1. Internalization requires phosphorylation of caveolin-1 on Tyr 14. A shift in localization of phospho-caveolin-1 from focal adhesions to caveolae induces CEMM internalization upon cell detachment, which mediates inhibition of Erk, PI(3)K and Rac. These data define a novel molecular mechanism for growth and tumour suppression by caveolin-1.

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Figure 1: Caveolin-1 internalization.
Figure 2: Pathway of integrin-regulated GM1 internalization.
Figure 3: Requirement for caveolin-1.
Figure 4: Phospho-caveolin-1 mediates integrin-dependent membrane domain internalization.

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Acknowledgements

We thank M. P. Lisanti for the caveolin-1-null MEFs, C. C. Mastick for the caveolinY14F vector, S. Schmid for the dynamin constructs, D. Castle for the Eps15DIII mutant and H68.4 monoclonal antibody, N. Meller for the Cdc42 inhibitor CBD-WASP, W.-P. Li, Y. Ying and J. Redick for assistance in electron microscopy analysis, M. C. Montoya and D. Megías for assistance with the Leica ultra-spectral confocal microscope, E. M. Moreno for technical assistance, and S. Schmid, M. Ginsberg, S. Shattil and K. Ley for critical reading of the manuscript. This work was supported by MEC (Spanish Ministry of Science and Education) through grants SAF2002-0245 and GEN2003-20239-C06-04 to M.A.d.P., a predoctoral fellowship (BEF-2003-2712, to A.G.-G.), and the Ramón y Cajal Program (to M.A.d.P.); and by EUROHORCS (European Heads Of Research Councils) and European Science Foundation (ESF) through a EURYI (European Young Investigator) Award to M.A.d.P.; USPHS grant RO1 GM47214 to M.A.S.; and grants from NIH and the Perot Family Foundation to R.G.W.A. A significant part of this work was performed while some of the authors were located in the Departments of Immunology (M.A.d.P. and N.B.A., from January 2003 to June 2004) and Cell Biology (M.A.d.P., N.B.A. and W.B.K. until June 2004, and M.A.S. until July 2002) at The Scripps Research Institute, CA.

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Authors and Affiliations

  1. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, 28029, Spain

    Miguel A. del Pozo, Nazilla B. Alderson & Araceli Grande-García

  2. Departments of Microbiology and Biomedical Engineering, Mellon Prostate Cancer Research Institute and Cardiovascular Research Center, University of Virginia, Charlottesville, 22908, VA, USA

    Nagaraj Balasubramanian & Martin A. Schwartz

  3. Microscopy Facility, The Scripps Research Institute, La Jolla, 92037, CA, USA

    William B. Kiosses

  4. Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, 75235, TX, USA

    Richard G. W. Anderson

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  1. Miguel A. del Pozo
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Correspondence to Miguel A. del Pozo.

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del Pozo, M., Balasubramanian, N., Alderson, N. et al. Phospho-caveolin-1 mediates integrin-regulated membrane domain internalization. Nat Cell Biol 7, 901–908 (2005). https://doi.org/10.1038/ncb1293

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