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M310462200v1
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Papers In Press, published online ahead of print February 9, 2004
J. Biol. Chem, 10.1074/jbc.M310462200
Submitted on September 22, 2003
Revised on February 3, 2004
Accepted on February 9, 2004

Integrin alpha {sub}Mbeta {sub}2 orchestrates and accelerates plasminogen activation and fibrinolysis by neutrophils

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

Joseph J. Jacobs Center for Thrombosis & Vascular Biology, Cleveland Clinic Foundation, Cleveland, OH 44195

Corresponding Author: plowe{at}ccf.org

Plasmin, the pivotal thrombolytic enzyme, is generated on the surface of many cell types, where 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 alpha sub Mbeta sub 2 recognize uPA to control cell migration and adhesion. In the present study, we report that the alpha sub Mbeta sub 2 regulates neutrophil-dependent fibrinolysis. PMA-stimulated, but not resting neutrophils dissolved fibrin clots in uPA-, Plg- and alpha sub Mbeta sub 2-dependent manner. When Plg was added to PMA-stimulated neutrophils, both uPA and Plg were detected in immunoprecipitates of alpha sub Mbeta sub 2. Purified alpha sub Mbeta sub 2 directly bound uPA (Kd=40 nM) and Plg (Kd=1 mM) in a dose dependent and saturable manner. In Plg activation assays, addition of purified alpha sub Mbeta sub 2, but not a control protein, to a sc-uPA/Plg mixture, decreased the Km from 2 to 0.1 mM, thereby augmenting the overall reaction efficiency by 50-fold. The binding of sc-uPA to aMb2 was critical for the alpha sub Mbeta sub 2-mediated enhancement of Plm generation since this effect was lost when WT-sc-uPA was replaced with a kringle-less mutant (DK-sc-uPA), which does not bind to alpha sub Mbeta sub 2. Plm inactivation by alpha sub 2-antiplasmin was decreased by 60% when Plm was preincubated with purified, soluble alpha sub Mbeta sub 2. Thus, assembly of Plg and uPA on integrin alpha sub Mbeta sub 2 regulates Plm activity and, thereby, plays a crucial role in PMN-mediated thrombolysis.


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