A role for caveolin and the urokinase receptor in integrin-mediated adhesion and signaling

The assembly of signaling molecules surrounding the integrin family of adhe sion receptors remains poorly understood. Recently, the membrane protein ca veolin was found in complexes with beta 1 integrins. Caveolin binds cholest erol and several signaling molecules potentially linked to integrin functio n, e.g., Src family kinases, although caveolin has not been directly implic ated in integrin-dependent adhesion. Here we report that depletion of caveo lin by antisense methodology in kidney 293 cells disrupts the association o f Src kinases with beta 1 integrins resulting in loss of focal adhesion sit es, ligand-induced focal adhesion kinase (FAK) phosphorylation, and adhesio n. The nonintegrin urokinase receptor (uPAR) associates with and stabilizes beta 1 integrin/caveolin complexes. Depletion of caveolin in uPAR-expressi ng 293 cells also disrupts uPAR/integrin complexes and uPAR-dependent adhes ion. Further, beta 1 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 beta 1 integ rins and markedly impairs their migration on fibronectin. We conclude that ligand-induced signaling necessary for normal beta 1 integrin function requ ires caveolin and is regulated by uPAR. Caveolin and uPAR may operate withi n adhesion sites to organize kinase-rich lipid domains in proximity to inte grins, promoting efficient signal transduction.