PLASMINOGEN-ACTIVATOR INHIBITOR-1 REPRESSES INTEGRIN-MEDIATED AND VITRONECTIN-MEDIATED CELL-MIGRATION INDEPENDENTLY OF ITS FUNCTION AS AN INHIBITOR OF PLASMINOGEN ACTIVATION

Cell migration involves the integrins, their extracellular matrix liga nds, and pericellular proteolytic enzyme systems. We have studied the role of plasminogen activator inhibitor-1 (PAI-1) in cell migration, u sing human amnion WISH cells and human epidermoid carcinoma HEp-2 cell s in an assay measuring migration from microcarrier beads and a modifi ed Boyden-chamber assay. Active, but not latent or reactive center-cle aved, PAI-1 inhibited migration. A PAI-1 mutant without ability to inh ibit plasminogen activation was as active as wild-type PAI-1 as a migr ation inhibitor, showing that inhibition of plasminogen activation was not involved. PAI-1 specifically interfered with integrin- and vitron ectin-mediated migration: Migration onto vitronectin coated but not on to fibronectin-coated surfaces was inhibited by PAI-1, a cyclic RGD pe ptide inhibited migration, and both cell lines expressed vitronectin-b inding alpha(v)-integrins. In addition, active PAI-1, but not latent o r reactive center-cleaved PAI-1, inhibited vitronectin binding to inte grins in an in vitro binding assay, without affecting binding of fibro nectin. Monoclonal antibodies against the urokinase receptor, another vitronectin binding protein, did not affect cell migration in the bead s assay, while some inhibitory effect was observed in the Bogden-chamb er assay. We conclude that PAI-1, independently of its role as a prote inase inhibitor, inhibits cell migration by competing for vitronectin binding to integrins, while the interference of PAI-1 with binding of vitronectin to the urokinase receptor may play a secondary role. These data define a novel function for the serpin PAI-1, enabling it to reg ulate cell migration over vitronectin-rich extracellular matrix in the body. (C) 1997 Academic Press.