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 surf ace receptor (uPAR), providing an inducible, localized cell surface pr oteolytic activity, thereby promoting cellular invasion. Evidence is p rovided for a novel function of cell surface-associated uPA . uPAR. Sp ecifically, induction of cell surface expression of uPA uPAR by growth factors or phorbol ester was necessary for vitronectin-dependent carc inoma cell migration, an event mediated by integrin alpha v beta 5. Ce ll migration on vitronectin was blocked with either a soluble form of uPAR, an antibody that disrupts uPA binding to uPAR, or a monoclonal a ntibody to alpha v beta 5. Moreover, plasminogen activator inhibitor t ype 2 blocked this migration event but did not affect adhesion, sugges ting a direct role for uPA enzyme activity in this process and that mi gration but not adhesion of these cells is regulated by uPA . uPAR. Gr owth factor-mediated induction of uPA . uPAR on the carcinoma cell sur face promotes a specific motility event mediated by integrin alpha v b eta 5, since cells transfected with the beta 3 integrin subunit expres sed alpha v beta 3 and migrated on vitronectin independently of growth factors or uPA . uPAR expression, This relationship between alpha v b eta 5 and the uPA uPAR system has significant implications for regulat ion of motility events associated with development, angiogenesis, and tumor metastasis.