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Blood, 15 November 2003, Vol. 102, No. 10, pp. 3600-3608. Prepublished online as a Blood First Edition Paper on July 24, 2003; DOI 10.1182/blood-2003-03-0949. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-03-0949v1 102/10/3600    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Bdeir, K. Articles by Cines, D. B. Search for Related Content PubMed PubMed Citation Articles by Bdeir, K. 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 The kringle stabilizes urokinase binding to the urokinase receptor Khalil Bdeir, Alice Kuo, Bruce S. Sachais, Ann H. Rux, Yasmina Bdeir, Andrew Mazar, Abd Al-Roof Higazi, and Douglas B. Cines From the Department of Pathology and Laboratory Medicine and Department of Medicine, University of Pennsylvania, Philadelphia; Attenuon, San Diego, CA; and the Department of Clinical Biochemistry, Hadassah Medical Organization, Jerusalem, Israel. The structural basis of the interaction between single-chain urokinase-type plasminogen activator (scuPA) and its receptor (uPAR) is incompletely defined. Several observations indicated the kringle facilitates the binding of uPA to uPAR. A scuPA variant lacking the kringle (K-scuPA) bound to soluble uPAR (suPAR) with the similar on-rate but with a faster off-rate than wild-type (WT)-scuPA. Binding of K-scuPA, but not WT-scuPA, to suPAR was comparably inhibited by its growth factor domain (GFD) and amino-terminal fragment (ATF). ATF and WT-scuPA, but not GFD, scuPA lacking the GFD (GFD-scuPA), or K-scuPA reconstituted the isolated domains of uPAR. ATF completely inhibited the enzymatic activity of WT-scuPA-suPAR unlike comparable concentrations of GFD. Variants containing mutations that alter the charge, length, or flexibility of linker sequence (residues 43-49) between the GFD and the kringle displayed a lower affinity for uPAR, were unable to reconstitute uPAR domains, and their binding to uPAR was inhibited by GFD in the same manner as K-scuPA. A scuPA variant in which the charged amino acids in the heparin binding site (HBS) in the kringle domain were mutated to alanines behaved like K-scuPA, indicating that that the structure of the kringle as well as its interaction with the GFD govern receptor binding. These data demonstrate an important role for the kringle in stabilizing the binding of scuPA to uPAR. (Blood. 2003;102:3600-3608) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Shetty, J. Padijnayayveetil, T. Tucker, D. Stankowska, and S. Idell The fibrinolytic system and the regulation of lung epithelial cell proteolysis, signaling, and cellular viability Am J Physiol Lung Cell Mol Physiol, December 1, 2008; 295(6): L967 - L975. [Abstract] [Full Text] [PDF] V. Stepanova, T. Lebedeva, A. Kuo, S. Yarovoi, S. Tkachuk, S. Zaitsev, K. Bdeir, I. Dumler, M. S. Marks, Y. Parfyonova, et al. 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Bdeir Urokinase induces activation of STAT3 in lung epithelial cells Am J Physiol Lung Cell Mol Physiol, October 1, 2006; 291(4): L772 - L780. [Abstract] [Full Text] [PDF] B.-S. Ding, C. Gottstein, A. Grunow, A. Kuo, K. Ganguly, S. M. Albelda, D. B. Cines, and V. R. Muzykantov Endothelial targeting of a recombinant construct fusing a PECAM-1 single-chain variable antibody fragment (scFv) with prourokinase facilitates prophylactic thrombolysis in the pulmonary vasculature Blood, December 15, 2005; 106(13): 4191 - 4198. [Abstract] [Full Text] [PDF] S.-H. Kwak, S. Mitra, K. Bdeir, D. Strassheim, J. S. Park, J. Y. Kim, S. Idell, D. Cines, and E. Abraham The kringle domain of urokinase-type plasminogen activator potentiates LPS-induced neutrophil activation through interaction with {alpha}V{beta}3 integrins J. Leukoc. Biol., October 1, 2005; 78(4): 937 - 945. [Abstract] [Full Text] [PDF] F. Mahdi, Z. Shariat-Madar, A. Kuo, M. Carinato, D. B. Cines, and A. H. 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