Convergence of the adhesive and fibrinolytic systems: recognition of urokinase by integrin αMβ2 as well as by the urokinase receptor regulates cell adhesion and migration

Abstract

Previous studies demonstrated that integrin αMβ2 (CD11b/18, Mac-1) forms a physical complex with the urokinase-type plasminogen activator receptor (uPAR/CD87) on leukocytes. In this study, we used human peripheral blood neutrophils and transfected cells expressing αMβ2, uPAR, or both receptors to show that the integrin can directly interact with urokinase (uPA). We demonstrate that αMβ2 supported adhesion and migration of these cells to uPA, and, in each case, blockade of αMβ2 suppressed the response. Within uPA, both the kringle and proteolytic domains are recognized by αMβ2, which are distinct from the growth factor domain that binds to uPAR. Within the αM subunit of the integrin, the I domain interacts with uPA, which is distinct from the region that interacts with uPAR. On cells expressing uPAR and αMβ2, both receptors mediated adhesion and migration. This cooperation was particularly apparent in the responses of neutrophils to uPA, where blockade of αMβ2 reduced uPAR-mediated responses and engagement of uPAR enhanced recognition of uPA by αMβ2. Thus, recognition of uPA by αMβ2 allows for formation of a multicontact trimolecular complex, in which a single uPA ligand may bind simultaneously to both uPAR and αMβ2. This complex may play an important role in the control of inflammatory cell migration and vascular homeostasis.