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Blood, 1 February 2005, Vol. 105, No. 3, pp. 1021-1028. Prepublished online as a Blood First Edition Paper on September 7, 2004; DOI 10.1182/blood-2004-03-0995. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-03-0995v1 105/3/1021    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Higazi, A. A.-R. Articles by Cines, D. B. Search for Related Content PubMed PubMed Citation Articles by Higazi, A. A.-R. Articles by Cines, D. B. Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Regulation of the single-chain urokinase–urokinase receptor complex activity by plasminogen and fibrin: novel mechanism of fibrin specificity Abd Al-Roof Higazi, Feras Ajawi, Sa'ed Akkawi, Edna Hess, Alice Kuo, and Douglas B. Cines From the Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, and the Department of Clinical Biochemistry, Hadassah Medical Center, Jerusalem, Israel. Activation of plasminogen by urokinase plasminogen activator (uPA) plays important roles in several physiologic and pathologic conditions. Cells secrete uPA as a single-chain molecule (scuPA). scuPA can be activated by proteolytic cleavage to a 2-chain enzyme (tcuPA). scuPA is also activated when it binds to its receptor (uPAR). The mechanism by which the enzymatic activity of the scuPA/suPAR complex is regulated is only partially understood. We now report that the plasminogen activator activity of the scuPA/suPAR complex is inhibited by Glu- and Lys-plasminogen, but not by mini-plasminogen. In contrast, neither Glunor Lys-plasminogen inhibits the activation of plasminogen by 2-chain uPA. Inhibition of scuPA/suPAR activity was evident at a Glu-plasminogen concentration of approximately 100 nM, and at physiologic plasma concentrations inhibition was nearly complete. A plasminogen fragment containing kringles 1-3 inhibited the enzymatic activity of scuPA/suPAR with an inhibition constant (Ki) equal to 1.9 µM, increased the Michaelis constant (Km) of scuPA/suPAR from 18 nM to 49 nM, and decreased the catalytic constant (Kcat) approximately 3-fold from 0.035 sec—1 to 0.011 sec—1. Inhibition of scuPA/suPAR by plasminogen was completely abolished in the presence of fibrin clots. These studies provide insight into the regulation of uPA-mediated plasminogen activation and identify a novel mechanism for its fibrin specificity. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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