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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.
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Submitted February 8, 2005
Accepted May 3, 2005
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*
Center for Molecular Biology of Oral Diseases, University of Illinois at Chicago, Chicago, IL, USA
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA
* Corresponding author; email: stolson{at}uic.edu.
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 serpins ability to inhibit proliferation, migration, capillary-like tube formation, 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 antiproliferative activity of the cleaved serpin. Surprisingly, mutation of Lys 114, 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 which is responsible for turning off the antiangiogenic activity of the native serpin.
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