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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 (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 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 Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 24, 2004 Accepted August 12, 2004 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 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Clinical Biochemistry, Hadassah Medical Center, Jerusalem, Israel Department of Clinical Biochemistry, Hadassah Medical Center, Jerusalem, Israel Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA * Corresponding author; email: higazi{at}mail.med.upenn.edu. Activation of plasminogen by urokinase plasminogen activator (uPA) plays important roles in several physiological and pathological conditions. Cells secrete uPA as a single-chain molecule (scuPA). scuPA can be activated by proteolytic cleavage to a two-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 Glu- nor Lys-plasminogen inhibits the activation of plasminogen by two-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 a Ki = 1.9 microM, increased the Km of scuPA/suPAR from 18 nM to 49 nM and decreased the Kcat approximately 3-fold from 0.035 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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