IS PLASMINOGEN-ACTIVATOR INHIBITOR-1 THE MOLECULAR SWITCH THAT GOVERNS UROKINASE RECEPTOR-MEDIATED CELL-ADHESION AND RELEASE

Induction of the urokinase type plasminogen activator receptor (uPAR) promotes cell adhesion through its interaction with vitronectin (VN) i n the extracellular matrix, and facilitates cell migration and invasio n by localizing uPA to the cell surface. We provide evidence that this balance between cell adhesion and cell detachment is governed by PA i nhibitor-1 (PAI-1). First, we demonstrate that uPAR and PAI-1 bind to the same site in VN (i.e., the amino-terminal somatomedin B domain; SM B), and that PAI-1 competes with uPAR for binding to SMB. Domain swapp ing and mutagenesis studies indicate that the uPAR-binding sequence is located within the central region of the SMB domain, a region previou sly shown to contain the PAI-l-binding motif. Second, we show that PAI -I dissociates bound VN from uPAR and detaches U937 cells from their V N substratum. This PAI-1 mediated release of cells from VN appears to occur independently of its ability to function as a protease inhibitor , and may help to explain why high PAI-1 levels indicate a poor progno sis for many cancers. Finally, we show that uPA can rapidly reverse th is effect of PAI-1. Taken together? these results suggest a dynamic re gulatory role for PAI-1 and uPA in uPAR-mediated cell adhesion and rel ease.