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Papers In Press, published online ahead of print June 30, 2000
Department of Protein Engineering, Genentech, Inc., South San Francisco, CA 94080
Corresponding Author: devos{at}gene.com
VEGF is a pleiotrophic factor that exerts a multitude of biological effects through its interaction with two receptor tyrosine kinases, Flt-1 or VEGFR1 and KDR or VEGFR2. While it is commonly accepted that KDR is responsible for the proliferative activities of VEGF, considerable controversy and uncertainty exists about the role of the individual receptors in eliciting many of the other effects. Based on a comprehensive mutational analysis of the receptor-binding site of VEGF, an Flt-1-selective variant was created containing four substitutions from the wild-type protein. This variant bound with wild-type affinity to Flt-1, was at least 470-fold reduced in binding to KDR, and had no activity in cell based assays measuring autophosphorylation of KDR or proliferation of primary human vascular endothelial cells. Using a competitive phage display strategy, two KDR-selective variants were discovered with three and four changes from wild-type, respectively. Both variants had approximately wild-type affinity for KDR, were about 2000-fold reduced in binding to Flt-1, and showed activity comparable to the wild-type protein in KDR autophosphorylation and endothelial cell proliferation assays. These variants will serve as useful reagents in elucidating the roles of Flt-1 and KDR.
J. Biol. Chem, 10.1074/jbc.M002015200
Submitted on March 8, 2000
Accepted on June 29, 2000
Receptor-Selective Variants of Human VEGF: Generation andCharacterization
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