Summary

It has been questioned whether there are receptors for urokinase-type plasminogen activator (uPA) that facilitate plasminogenactivation other than the high affinity uPA receptor(uPAR/CD87) since studies of uPAR knockout mice did not supporta major role of uPAR in plasminogen activation. uPA alsopromotes cell adhesion, chemotaxis, and proliferation besidesplasminogen activation.These uPA-induced signaling events arenot mediated by uPAR,but mediated by unidentified,lower-affinityreceptors for the uPA kringle.We found that uPA binds specificallyto integrin αvβ3 on CHO cells depleted of uPAR.Thebinding of uPA to αvβ3 required the uPA kringle domain. Theisolated uPA kringle domain binds specifically to purified,recombinantsoluble, and cell surface αvβ3, and other integrins ( α4β1and α9β 1), and induced migration of CHO cells in an αvβ3-dependent manner.The binding of the uPA kringle to αvβ3 and uPAkringle-induced αvβ-dependent cell migration were blocked byhomologous plasminogen kringles 1–3 or 1–4 (angiostatin), aknown integrin antagonist. We studied whether the binding ofuPA to integrin αvβ3 through the kringle domain plays a role inplasminogen activation. On CHO cell depleted of uPAR, uPA enhancedplasminogen activation in a kringle and αvβ3-dependentmanner.Endothelial cells bound to and migrated on uPA and uPAkringle in an αvβ3-dependent manner.These results suggest thatuPA binding to integrins through the kringle domain plays an importantrole in both plasminogen activation and uPA-induced intracellularsignaling. The uPA kringle-integrin interaction mayrepresent a novel therapeutic target for cancer, inflammation,and vascular remodeling.