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Prepublished online as a Blood First Edition Paper on September 26, 2002; DOI 10.1182/blood-2002-06-1842.
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Blood, 15 February 2003, Vol. 101, No. 4, pp. 1582-1590
PHAGOCYTES
Convergence of the adhesive and fibrinolytic systems: recognition
of urokinase by integrin  M 2 as well as
by the urokinase receptor regulates cell adhesion and
migration
Elzbieta Pluskota,
Dmitry
A. Soloviev, and
Edward F. Plow
From the Joseph J. Jacobs Center for Thrombosis and
Vascular Biology, Department of Molecular Cardiology, Cleveland Clinic
Foundation, Cleveland, OH.
Previous studies demonstrated that integrin
 M 2 (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
M2, uPAR, or both receptors to show that
the integrin can directly interact with urokinase (uPA). We demonstrate
that M2 supported adhesion and
migration of these cells to uPA, and, in each case, blockade of
M2 suppressed the response. Within uPA,
both the kringle and proteolytic domains are recognized by M2, 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 uPAR and
M2, both receptors mediated adhesion and
migration. This cooperation was particularly apparent in the responses
of neutrophils to uPA, where blockade of
M2 reduced uPAR-mediated responses and
engagement of uPAR enhanced recognition of uPA by
M2. Thus, recognition of uPA by
M2 allows for formation of a multicontact
trimolecular complex, in which a single uPA ligand may bind
simultaneously to both uPAR and M2. This
complex may play an important role in the control of inflammatory cell
migration and vascular homeostasis.
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