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The minimal active domain of endostatin is a heparin-binding motif that mediates inhibition of tumor vascularization
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- Olsson, Anna-Karin (author)
- Uppsala universitet,Institutionen för genetik och patologi
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- Johansson, Irja (author)
- Uppsala universitet,Institutionen för genetik och patologi
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- Åkerud, Helena (author)
- Uppsala universitet,Institutionen för genetik och patologi
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- Sasaki, Takako (author)
- Timpl, Rupert (author)
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- (creator_code:org_t)
- 2004
- 2004
- English.
- In: Cancer Research. - 0008-5472 .- 1538-7445. ; 64:24, s. 9012-9017
- Journal article (peer-reviewed)
Abstract
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- Endostatin constitutes the COOH-terminal 20,000 Da proteolytic fragment of collagen XVIII and has been shown to possess antiangiogenic and antitumorigenic properties. In the present study, we have investigated the role of the heparin-binding sites in the in vivo mechanism of action of endostatin. The majority of the heparin binding is mediated by arginines 155/158/184/270 in endostatin, but there is also a minor site constituted by arginines 193/194. Using endostatin mutants lacking either of these two sites, we show that inhibition of fibroblast growth factor-2-induced angiogenesis in the chicken chorioallantoic membrane requires both heparin-binding sites. In contrast, inhibition of vascular endothelial growth factor-A-induced chorioallantoic membrane angiogenesis by endostatin was only dependent on the minor heparin-binding site (R193/194). These arginines were also required for endostatin to inhibit fibroblast growth factor-2- and vascular endothelial growth factor-A-induced chemotaxis of primary endothelial cells. Moreover, we show that a synthetic peptide corresponding to amino acids 180-199 of human endostatin (which covers the minor heparin-binding site) inhibits endothelial cell chemotaxis and reduces tumor vascularization in vivo. Substitution of arginine residues 193/194 for alanine attenuates the antiangiogenic effects of the peptide. These data show an essential role for heparin binding in the antiangiogenic action of endostatin.
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