Requirement of receptor-bound urokinase-type plasminogen activator for integrin alpha v beta 5-directed cell migration

The urokinase plasminogen activator (uPA) interacts with its cell surface receptor (uPAR), providing an inducible, localized cell surface proteolytic activity, thereby promoting cellular invasion. Evidence is provided for a novel function of cell surface-associated uPA . uPAR. Specifically, induction of cell surface expression of uPA uPAR by growth factors or phorbol ester was necessary for vitronectin-dependent carcinoma cell migration, an event mediated by integrin alpha v beta 5. Cell migration on vitronectin was blocked with either a soluble form of uPAR, an antibody that disrupts uPA binding to uPAR, or a monoclonal antibody to alpha v beta 5. Moreover, plasminogen activator inhibitor type 2 blocked this migration event but did not affect adhesion, suggesting a direct role for uPA enzyme activity in this process and that migration but not adhesion of these cells is regulated by uPA . uPAR. Growth factor-mediated induction of uPA . uPAR on the carcinoma cell surface promotes a specific motility event mediated by integrin alpha v beta 5, since cells transfected with the beta 3 integrin subunit expressed alpha v beta 3 and migrated on vitronectin independently of growth factors or uPA . uPAR expression, This relationship between alpha v beta 5 and the uPA uPAR system has significant implications for regulation of motility events associated with development, angiogenesis, and tumor metastasis.