Identification of a Heparin Binding Peptide on the ExtracellularDomain of the KDR VEGF Receptor

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Dougher, M.
Torley, L.
Wasserstrom, H.
Shridaran, L.
Westdock, P.
Hileman, R.E.
Fromm, J.R.
Lyman, S.
Linhardt, Robert J.
Kaplan, J.
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Biology , Chemistry and chemical biology , Chemical and biological engineering , Biomedical engineering
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Vascular endothelial growth factor (VEGF), a potent and specific activator of endothelial cells, is expressed as multiple homodimeric forms resulting from alternative RNA splicing. VEGF121 does not bind heparin while the other three isoforms do, and it has been documented that the binding of VEGF165 to its receptor is dependent upon cell surface heparin sulfate proteoglycans. Little is known about the biochemical mechanism that allows for heparin regulation of growth factor binding. For example, it is not clear whether heparin interactions with growth factor or with cell surface receptors or both are essential for VEGF binding to its receptor. In this manuscript we provide results which are consistent with the hypothesis that an interaction between heparin and a site on the KDR receptor subtype is essential for VEGF165 binding. First, we demonstrate that expression of KDR into a CHO cell line deficient in heparan sulfate biosynthesis does not allow VEGF165 binding unless heparin is exogenously added during the binding assay. Secondly, we show that a ten amino acid synthetic peptide, corresponding to a sequence from the extracellular domain of the KDR, both inhibits VEGF165 binding to the receptor and also binds heparin with high avidity. Third, affinity purification of heparin molecules on a KDR-derived peptide affinity column, together with capillary electrophoresis and polyacrylamide electrophoresis analysis, was used to show that the KDR-derived peptide interacts with a specific subset of polysaccharide chains contained in the unfractionated heparin. Taken together, these results are consistent with the hypothesis that interactions between cell surface heparan sulfate proteoglycans and the VEGF receptor contribute to allowing maximal VEGF binding.
Growth Factors, 14, 257-268
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Identification of a Heparin Binding Peptide on the ExtracellularDomain of the KDR VEGF Receptor, M. Dougher, L. Torley, H. Wasserstrom,L. Shridaran, P. Westdock, R.E. Hileman, J.R. Fromm, S. Lyman, R.J. Linhardt,J. Kaplan, B.I. Terman Growth Factors, 14, 257-268, 1997.
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