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J. Biol. Chem., Vol. 279, Issue 39, 41179-41188, September 24, 2004

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Angiopoietin-3 Is Tethered on the Cell Surface via Heparan Sulfate Proteoglycans^*

Yin Xu, Yao-juan Liu, and Qin Yu

From the Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Angiopoietins are a family of factors that play important roles in angiogenesis, and their receptor, Tie-2 receptor tyrosine kinase, is expressed primarily by endothelial cells. Three angiopoietins have been identified so far, angiopoietin-1 (Ang-1), angiopietin-2 (Ang-2), and angiopoietin-3 (Ang-3). It has been established that Ang-1 and Tie-2 play essential roles in embryonic angiogenesis. We have demonstrated recently that, unlike Ang-2, Ang-1 binds to the extracellular matrix, which regulates the availability and activity of Ang-1 (Xu, Y., and Yu, Q. (2001) J. Biol. Chem. 276, 34990-34998). However, the role and biochemical characteristics of Ang-3 are unknown. In our current study, we demonstrated that, unlike Ang-1 and Ang-2, Ang-3 is tethered on cell surface via heparan sulfate proteoglycans (HSPGs), especially perlecan. The cell surface-bound Ang-3 is capable of binding to its receptor, Tie-2; suggesting HSPGs concentrate Ang-3 on the cell surface and present Ang-3 to its receptor to elicit specific local reaction. Mutagenesis experiment revealed that the coiled-coil domain of Ang-3 is responsible for its binding to the cell surface. In addition, we demonstrated that the cell surface-bound Ang-3 but not soluble Ang-3 induces retraction and loss of integrity of endothelial monolayer, indicating the binding of Ang-3 to the cell surface via HSPGs is required for this bioactivity of Ang-3.

Received for publication, January 12, 2004 , and in revised form, July 27, 2004.

^* This work was supported by funds from the University of Pennsylvania, School of Veterinary Medicine and by National Institutes of Health Grant 5RO1HL074117. 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: Dept. of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, 372E (Old Vet), 3800 Spruce St., Philadelphia, PA 19104. Tel.: 215-898-2967; Fax: 215-898-0719; E-mail: qyu{at}vet.upenn.edu.

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