Endostatin (ES), a proteolytic fragment of collagen, inhibits endothelial cell migration and is a potent angiogenesis inhibitor in animal model systems. However, its mechanism of action is not well understood. For example, it has not been clear whether ES action requires binding to heparan sulfate proteoglycans (HSPGs). Karumanchi et al. report that ES binds with low affinity to glycosyl-phosphatidylinositol anchored HSPGs called glypicans that are present on the surface of both endothelial and nonendothelial cells. Binding in vivo specifically required the presence of a heparan sulfate-glycosaminoglyan moiety on the glypicans. When glypican-1 expression was blocked in endothelial cells by antisense-based inhibition, ES binding decreased. Consequently, the ability of ES to inhibit endothelial cell migration in response to a particular form of vascular endothelial growth factor (VEGF) also decreased. Although some forms of VEGF require glypican to bind to their own receptor, the authors used a form of VEGF that does not require cell-surface proteoglycan for signaling to show that ES inhibited VEGF actions by inhibiting intracellular VEGF-mediated signaling and not by competing for glypican binding. ES also inhibited hepatocyte growth factor (HGF)-induced branching of nonepithelial renal tubular cells by binding to glypican-4. The authors suggest that glypicans are low-affinity receptors that present ES to a high-affinity receptor that has yet to be identified.
S. A. Karumanchi, V. Jha, R. Ramchandran, A. Karihaloo, L. Tsiokas, B. Chan, M. Dhanabal, J. Hanai, G. Venkataraman, Z. Shriver, N. Keiser, R. Kalluri, H. Zeng, D. Mukhopadhyay, R. L. Chen, A. D. Lander, K. Hagihara, Y. Yamaguchi, R. Sasisekharan, L. Cantley, V. P. Sukhatme, Cell surface glypicans are low-affinity endostatin receptors. Mol. Cell 7, 811-822 (2001). [Online Journal]