The assembly of signaling molecules surrounding the integrin family of adhesion receptors remains poorly understood. Recently, the membrane protein caveolin was found in complexes with β1 integrins. Caveolin binds cholesterol and several signaling molecules potentially linked to integrin function, e.g., Src family kinases, although caveolin has not been directly implicated in integrin-dependent adhesion. Here we report that depletion of caveolin by antisense methodology in kidney 293 cells disrupts the association of Src kinases with β1 integrins resulting in loss of focal adhesion sites, ligand-induced focal adhesion kinase (FAK) phosphorylation, and adhesion. The nonintegrin urokinase receptor (uPAR) associates with and stabilizes β1 integrin/caveolin complexes. Depletion of caveolin in uPAR-expressing 293 cells also disrupts uPAR/integrin complexes and uPAR-dependent adhesion. Further, β1 integrin/caveolin complexes could be disassociated by uPAR-binding peptides in both uPAR-transfected 293 cells and human vascular smooth muscle cells. Disruption of complexes by peptides in intact smooth muscle cells blocks the association of Src family kinases with β1 integrins and markedly impairs their migration on fibronectin. We conclude that ligand-induced signaling necessary for normal β1 integrin function requires caveolin and is regulated by uPAR. Caveolin and uPAR may operate within adhesion sites to organize kinase-rich lipid domains in proximity to integrins, promoting efficient signal transduction.
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22 March 1999
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March 22 1999
A Role for Caveolin and the Urokinase Receptor in Integrin-mediated Adhesion and Signaling
Ying Wei,
Ying Wei
*Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115; and ‡ Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba R3A 1M4, Canada
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Xiuwei Yang,
Xiuwei Yang
*Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115; and ‡ Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba R3A 1M4, Canada
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Qiumei Liu,
Qiumei Liu
*Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115; and ‡ Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba R3A 1M4, Canada
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John A. Wilkins,
John A. Wilkins
*Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115; and ‡ Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba R3A 1M4, Canada
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Harold A. Chapman
Harold A. Chapman
*Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115; and ‡ Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba R3A 1M4, Canada
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Ying Wei
*Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115; and ‡ Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba R3A 1M4, Canada
Xiuwei Yang
*Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115; and ‡ Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba R3A 1M4, Canada
Qiumei Liu
*Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115; and ‡ Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba R3A 1M4, Canada
John A. Wilkins
*Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115; and ‡ Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba R3A 1M4, Canada
Harold A. Chapman
*Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115; and ‡ Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba R3A 1M4, Canada
Address correspondence to Harold A. Chapman, M.D., Brigham and Women's Hospital, Thorn Research Building, Rm. 803, 20 Shattuck St., Boston, MA 02115. Tel.: (617) 732-6074. Fax: (617) 232-4623. E-mail: [email protected]
Y. Wei and X. Yang contributed equally to this work.
Received:
August 19 1998
Revision Received:
February 02 1999
Online ISSN: 1540-8140
Print ISSN: 0021-9525
1999
J Cell Biol (1999) 144 (6): 1285–1294.
Article history
Received:
August 19 1998
Revision Received:
February 02 1999
Citation
Ying Wei, Xiuwei Yang, Qiumei Liu, John A. Wilkins, Harold A. Chapman; A Role for Caveolin and the Urokinase Receptor in Integrin-mediated Adhesion and Signaling . J Cell Biol 22 March 1999; 144 (6): 1285–1294. doi: https://doi.org/10.1083/jcb.144.6.1285
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