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Blood, 1 September 2005, Vol. 106, No. 5, pp. 1621-1628. Prepublished online as a Blood First Edition Paper on May 19, 2005; DOI 10.1182/blood-2005-02-0547. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-02-0547v1 106/5/1621    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 Zhang, W. Articles by Olson, S. T. Search for Related Content PubMed PubMed Citation Articles by Zhang, W. Articles by Olson, S. T. Related Collections Hemostasis, Thrombosis, and Vascular Biology Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY The heparin-binding site of antithrombin is crucial for antiangiogenic activity Weiqing Zhang, Richard Swanson, Gonzalo Izaguirre, Yan Xiong, Lester F. Lau, and Steven T. Olson From the Center for Molecular Biology of Oral Diseases and the Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, IL. The heparin-binding site of antithrombin is shown here to play a crucial role in mediating the antiangiogenic activity of conformationally altered cleaved and latent forms of the serpin. Blocking the heparin-binding site of cleaved or latent antithrombin by complexation with a high-affinity heparin pentasaccharide abolished the serpin's ability to inhibit proliferation, migration, capillary-like tube formation, basic fibroblast growth factor (bFGF) signaling, and perlecan gene expression in bFGF-stimulated human umbilical vein endothelial cells. Mutation of key heparin binding residues, when combined with modifications of Asn-linked carbohydrate chains near the heparin-binding site, also could abrogate the anti-proliferative activity of the cleaved serpin. Surprisingly, mutation of Lys114, which blocks anticoagulant activation of antithrombin by heparin, caused the native protein to acquire antiproliferative activity without the need for conformational change. Together, these results indicate that the heparin-binding site of antithrombin is of crucial importance for mediating the serpin's antiangiogenic activity and that heparin activation of native antithrombin constitutes an antiangiogenic switch that is responsible for turning off the antiangiogenic activity of the native serpin. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: N. Parmar, L. R. Berry, M. Post, and A. K. C. Chan Effect of covalent antithrombin-heparin complex on developmental mechanisms in the lung Am J Physiol Lung Cell Mol Physiol, March 1, 2009; 296(3): L394 - L403. [Abstract] [Full Text] [PDF] B. Richard, R. Swanson, S. Schedin-Weiss, B. Ramirez, G. Izaguirre, P. G. W. Gettins, and S. T. Olson Characterization of the Conformational Alterations, Reduced Anticoagulant Activity, and Enhanced Antiangiogenic Activity of Prelatent Antithrombin J. Biol. Chem., May 23, 2008; 283(21): 14417 - 14429. [Abstract] [Full Text] [PDF] W. Zhang, R. Swanson, Y. Xiong, B. Richard, and S. T. Olson Antiangiogenic Antithrombin Blocks the Heparan Sulfate-dependent Binding of Proangiogenic Growth Factors to Their Endothelial Cell Receptors: EVIDENCE FOR DIFFERENTIAL BINDING OF ANTIANGIOGENIC AND ANTICOAGULANT FORMS OF ANTITHROMBIN TO PROANGIOGENIC HEPARAN SULFATE DOMAINS J. Biol. Chem., December 8, 2006; 281(49): 37302 - 37310. [Abstract] [Full Text] [PDF] W. Zhang, Y.-J. Chuang, T. Jin, R. Swanson, Y. Xiong, L. Leung, and S. T. Olson Antiangiogenic antithrombin induces global changes in the gene expression profile of endothelial cells. Cancer Res., May 15, 2006; 66(10): 5047 - 5055. [Abstract] [Full Text] [PDF]

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