PAI-1 inhibits urokinase-induced chemotaxis by internalizing the urokinase receptor

PAI-1 (plasminogen activator inhibitor-1) binds the urokinase-type plasminogen activator (uPA) and causes its degradation via its receptor uPAR and low-density lipoprotein receptor-related protein (LRP). While both uPA and PAI-1 are chemoattractants, we find that a preformed uPA-PAI-1 complex has no chemotactic activity and that PAI-1 inhibits uPA-induced chemotaxis. The inhibitory effect of PAI-1 on uPA-dependent chemotaxis is reversed when uPAR internalization is inhibited by the 39 kDa receptor-associated protein or by anti-LRP antibodies. Under the same conditions, the uPA-PAI-1 complex is turned into a chemoattractant causing cytoskeleton reorganization and extracellular-regulated kinase/mitogen-activated protein kinases activation. Thus, uPAR internalization by PAI-1 regulates cell migration.