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J. Biol. Chem., Vol. 279, Issue 17, 18063-18072, April 23, 2004

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Integrin _M2 Orchestrates and Accelerates Plasminogen Activation and Fibrinolysis by Neutrophils^*

Elzbieta Pluskota, Dmitry A. Soloviev, Khalil Bdeir, Douglas B. Cines, and Edward F. Plow¶

From the Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Molecular Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio 44195 and the Department of Pathology and Laboratory Medicine, University of Pennsylvania Hospitals, Philadelphia, Pennsylvania 19104

Plasmin, the pivotal thrombolytic enzyme, is generated on the surface of many cell types, where urokinase receptor (uPAR)-bound urokinase (uPA) activates cell-bound plasminogen (Plg). It has been reported that neutrophils mediate endogenous thrombolysis involving a uPA-dependent mechanism, and we previously demonstrated that both uPAR and integrin _M2 recognize uPA to control cell migration and adhesion. In the present study, we report that the _M2 regulates neutrophil-dependent fibrinolysis. Phorbol 12-myristate 13-acetate (PMA)-stimulated but not resting neutrophils dissolved fibrin clots, and this activity was not only uPA- and Plg-dependent but also _M2-dependent. Purified _M2 directly bound uPA (K_d = 40 nM) and Plg (K_d = 1 µM) in a dose-dependent and saturable manner. In Plg activation assays, addition of purified _M2, but not a control protein, to a single chain uPA (sc-uPA)/Plg mixture, decreased the K_m from 2 to 0.1 µM, thereby augmenting the overall reaction efficiency by 50-fold. The binding of sc-uPA to _M2 was critical for the _M2-mediated enhancement of plasmin (Plm) generation, because this effect was lost when WT-sc-uPA was replaced with a kringle-less mutant (K-sc-uPA), which does not bind to _M2. Plm inactivation by ₂-antiplasmin was significantly delayed when Plm was preincubated with purified, soluble _M2. When Plg was added to PMA-stimulated neutrophils, both uPA and Plg were co-immunoprecipitated with _M2. Thus, assembly of Plg and uPA on integrin _M2 regulates Plm activity and, thereby, plays a crucial role in neutrophil-mediated thrombolysis.

Received for publication, September 22, 2003 , and in revised form, February 3, 2004.

^* This work was supported in part by National Institutes of Health Grants HL66197, HL17964, and HL60169 and American Heart Association Scientist Development Grant 0335088N (to E. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, NB50, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195. Tel.: 216-445-8201; Fax: 216-445-8204; E-mail: plowe{at}ccf.org.

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