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Prepublished online as a Blood First Edition Paper on September 26, 2002; DOI 10.1182/blood-2002-06-1842.
Submitted June 20, 2002
Accepted September 17, 2002
Convergence of the adhesive and fibrinolytic systems: recognition of urokinase by integrin  M ß2 as well as the urokinase receptor regulates cell adhesion and migration
Elzbieta Pluskota, Dmitry A Soloviev, and Edward F Plow*
Department of Molecular Cardiology, Cleveland Clinic Foundation, Cleveland, OH, USA
* Corresponding author; email: plowe{at}ccf.org.
Previous studies demonstrated that integrin  Mß2 (CD11b/18, Mac-1) forms a physical complex with the urokinase-type plasminogen activator receptor (uPAR/CD87) on leukocytes. In this study, we utilized human peripheral blood neutrophils and transfected cells expressing Mß2, uPAR or both receptors to show that the integrin can directly interact with urokinase (uPA).Mß2 supported adhesion and migration of these cells to uPA; and, in each case, blockade of Mß2 suppressed the response. Within uPA, both the kringle and proteolytic domains are recognized by Mß2, which are distinct from the growth factor domain that binds to uPAR. Within the M subunit of the integrin, the I-domain interacts with uPA, which is distinct from the region that interacts with uPAR. On cells expressing both uPAR and Mß2, both receptors mediated adhesion and migration. This cooperation was particular apparent in the responses of neutrophils to uPA, where blockade of Mß2 reduced uPAR-mediated responses and engagement of uPAR enhanced recognition of uPA by Mß2. Thus, recognition of uPA by Mß2 allows for formation of a multicontact trimolecular complex, in which a single uPA ligand may bind simultaneously to both uPAR and Mß2. This complex may play an important role in the control of inflammatory cell migration and vascular homeostasis.
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