This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Google Scholar
Right arrow Articles by Cerezo, A.
Right arrow Articles by del Pozo, M. A.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cerezo, A.
Right arrow Articles by del Pozo, M. A.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, September 2009, p. 5046-5059, Vol. 29, No. 18
0270-7306/09/$08.00+0     doi:10.1128/MCB.00315-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Absence of Caveolin-1 Increases Proliferation and Anchorage- Independent Growth by a Rac-Dependent, Erk-Independent Mechanism{triangledown}

Ana Cerezo,1,{dagger} Marta C. Guadamillas,1,{dagger} Jacky G. Goetz,1 Sara Sánchez-Perales,1 Eric Klein,2 Richard K. Assoian,2 and Miguel A. del Pozo1*

Integrin Signaling Laboratory, Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares, Melchor Fernández Almagro 3, 28029 Madrid, Spain,1 Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-60842

Received 11 March 2009/ Returned for modification 18 April 2009/ Accepted 10 July 2009

Anchorage-independent growth (AIG) of cancer cells requires escape from integrin-mediated signals. A protein frequently downregulated in cancer, caveolin-1 (Cav1), mediates integrin control of several growth-regulatory pathways. We report that loss of Cav1 results in faster exit from quiescence and progress through the cell cycle, proliferation without anchorage to substrate, and absence of cyclin D1 downregulation upon serum deprivation or detachment. Surprisingly, this proliferative advantage is independent of Erk-mitogen-activated protein kinase signaling; instead, cyclin expression and cell cycle progression in the absence of Cav1 are driven by increased membrane order and Rac targeting. AIG was induced in Cav1-expressing cells by forced membrane targeting of Rac1 or by inhibiting Cav1-mediated internalization of plasma membrane ordered domains at which Rac1 accumulates. Restoring Rho activity, which is downregulated after loss of Cav1, antagonizes Rac1 and prevents cyclin D1 accumulation after serum starvation or loss of adhesion. Anchorage independence and increased proliferation in Cav1-deficient tumoral and null cells are thus due to an increased fraction of active Rac1 at membrane ordered domains. These results provide insight into the mechanisms regulating growth of cancer cells, which frequently lose Cav1 function.

* Corresponding author. Mailing address: Integrin Signaling Laboratory, Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares, Melchor Fernández Almagro 3, 28029 Madrid, Spain. Phone: 34 914531212. Fax: 34 914531265. E-mail: madelpozo{at}cnic.es

{triangledown} Published ahead of print on 20 July 2009.

{dagger} These authors contributed equally to this work.

Molecular and Cellular Biology, September 2009, p. 5046-5059, Vol. 29, No. 18
0270-7306/09/$08.00+0     doi:10.1128/MCB.00315-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»