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© The Rockefeller University Press, 0021-9525/1999//1285 $5.00
The Journal of Cell Biology, Volume 144, Number 6, , 1999 1285-1294

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A Role for Caveolin and the Urokinase Receptor in Integrin-mediated Adhesion and Signaling



Ying Wei*, Xiuwei Yang*, Qiumei Liu*, John A. Wilkins{ddagger}, and Harold A. Chapman*

* Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115; and {ddagger} Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba R3A 1M4, Canada

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.

Key Words: urokinase receptor • caveolin • integrins • adhesion • cell signaling

Abbreviations used in this paper: FAK, focal adhesion kinase; MAPK, mitogen-activated protein kinase; SMC, smooth muscle cells; uPAR, urokinase receptor.

Y. Wei and X. Yang contributed equally to this work.


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