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J. Biol. Chem., Vol. 280, Issue 21, 20833-20841, May 27, 2005

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Metastasis-associated Protein S100A4 Induces Angiogenesis through Interaction with Annexin II and Accelerated Plasmin Formation^*

Alexandre Semov, Maria J. Moreno, Anatoli Onichtchenko, Abedelnasser Abulrob, Marguerite Ball, Irena Ekiel¶, Grzegorz Pietrzynski, Danica Stanimirovic, and Valery Alakhov||

From the Supratek Pharma Inc., Montreal, Quebec H9S 1A9, Canada, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, K1A 0R6, Canada, and ^¶Biotechnology Research Institute, National Research Council of Canada, Montreal, Quebec H4P 2R2, Canada

Many advanced tumors overexpress and secrete the S100A4 protein that is known to promote angiogenesis and metastasis development. The mechanisms of this effect and the endothelial receptor for S100A4 are both still unknown. Here we report that extracellular S100A4 interacts with annexin II, an endothelial plasminogen co-receptor. Co-localization and direct binding of S100A4 and annexin II were demonstrated, and the binding site was identified in the N-terminal region of annexin II. S100A4 alone or in a complex with annexin II accelerated tissue plasminogen activator-mediated plasminogen activation in solution and on the endothelial cell surface through interaction of the S100A4 C-terminal lysines with the lysine-binding domains of plasminogen. A synthetic peptide corresponding to the N terminus of annexin II prevented S100A4-induced plasmin formation in the endothelial cell culture. Local plasmin formation induced by circulating S100A4 could contribute to tumor-induced angiogenesis and metastasis formation that makes this protein an attractive target for new anti-cancer and anti-angiogenic therapies.

Received for publication, November 9, 2004 , and in revised form, March 8, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Supratek Pharma Inc., 215 Blvd. Bouchard, Suite 1315, Dorval, Quebec H9S 1A9, Canada. Tel.: 514-422-9191; Fax: 514-422-9410; E-mail: Valery.Alakhov{at}Supratek.com.

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