Glypican-1 is a VEGF(165) binding proteoglycan that acts as an extracellular chaperone for VEGF(165)
Gengrinovitch, S × Berman, B David, Guido Witte, L Neufeld, G Ron, D #
Amer soc biochemistry molecular biology inc
Journal of biological chemistry vol:274 issue:16 pages:10816-10822
Glypican-1 is a member of a family of glycosylphosphatidylinositol anchored cell surface heparan sulfate proteoglycans implicated in the control of cellular growth and differentiation. The 165-amino acid form of vascular endothelial growth factor (VEGF(165)) is a mitogen for endothelial cells and a potent angiogenic factor in vivo. Heparin binds to VEGF(165) and enhances its binding to VEGF receptors. However, native HSPGs that bind VEGF(165) and modulate its receptor binding have not been identified. Among the glypicans, glypican-1 is the only member that is expressed in the vascular system. We have therefore examined whether glypican-1 can interact with VEGF(165). Glypican-1 from rat myoblasts binds specifically to VEGF(165) but not to VEGF(121). The binding has an apparent dissociation constant of 3 x 10(-10) M. The binding of glypican-1 to VEGF(165) is mediated by the heparan sulfate chains of glypican-1, because heparinase treatment abolishes this interaction. Only an excess of heparin or heparan sulfates but not other types of glycosaminoglycans inhibited this interaction. VEGF(165) interacts specifically not only with rat myoblast glypican-1 but also with human endothelial cell-derived glypican-1. The binding of I-125-VEGF(165) to heparinase-treated human vascular endothelial cells is reduced following heparinase treatment, and addition of glypican-1 restores the binding. Glypican-1 also potentiates the binding of I-125-VEGF(165) to a soluble extracellular domain of the VEGF receptor KDR/flk-1. Furthermore, we show that glypican-1 acts as an extracellular chaperone that can restore the receptor binding ability of VEGF(165), which has been damaged by oxidation. Taken together, these results suggest that glypican-1 may play an important role in the control of angiogenesis by regulating the activity of VEGF(165), a regulation that may be critical under conditions such as wound repair, in which oxidizing agents that can impair the activity of VEGF are produced, and in situations were the concentrations of active VEGF are limiting.