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Regulation of Tumor Angiogenesis by Fastatin, the Fourth FAS1 Domain of ßig-h3, via vß3 Integrin

Cell and Matrix Biology National Research Laboratory, Department of Biochemistry, Kyungpook National University School of Medicine, Daegu, Korea

Requests for reprints: In-San Kim, Department of Biochemistry, Kyungpook National University School of Medicine, 101 Dongin-dong, Jung-gu, Daegu, 700-422, Korea. Phone: 82-53-420-4826; Fax: 82-53-422-1466; E-mail: iskim{at}knu.ac.kr.

We previously reported that the FAS1 domains of ßig-h3 bear motifs that mediate endothelial cell adhesion and migration via interactions with vß3 integrin and regulate angiogenesis. In the present study, we show that the fourth FAS1 domain, designated fastatin, inhibits endothelial adhesion and migration, not only to ßig-h3, but also fibronectin and vitronectin, in a RGD-dependent manner. Fastatin and other FAS1 domains suppress endothelial cell tube formation and in vivo neovascularization in a Matrigel plug assay. The antiangiogenic activity of fastatin is associated with antitumor activity in mouse tumor models. Fastatin additionally induces apoptosis in several cells expressing vß3 integrin, including endothelial cells. Binding of fastatin to vß3 integrin inhibits phosphorylation of focal adhesion kinase, Raf, extracellular signal-regulated kinase, Akt, and mammalian target of rapamycin. Fastatin is thus the first endogenous angiogenesis regulator identified that inhibits both endothelial cell migration and growth by binding to vß3 integrin. Our data suggest that FAS1 domains from all possible forms of the four human FAS1 family proteins are potential endogenous regulators for pathologic angiogenesis. Moreover, FAS1 domains such as fastatin may be developed into drugs for blocking tumor angiogenesis.

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