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J Biol Chem, Vol. 273, Issue 12, 6599-6602, March 20, 1998

COMMUNICATION
A Recombinant Mutant Vascular Endothelial Growth Factor-C that Has Lost Vascular Endothelial Growth Factor Receptor-2 Binding, Activation, and Vascular Permeability Activities

Vladimir Joukov, Vijay Kumar, Tarja Sorsa, Elena Arighi, Herbert Weich§, Olli Saksela, and Kari Alitalo

From the Molecular/Cancer Biology Laboratory and the  Department of Virology, Haartman Institute, PL 21 Haartmaninkatu 3, University of Helsinki, 00014 Helsinki, Finland and the § Department of Gene Expression, GBF, D-38124 Braunschweig, Germany

The vascular endothelial growth factor (VEGF) and the VEGF-C promote growth of blood vessels and lymphatic vessels, respectively. VEGF activates the endothelial VEGF receptors (VEGFR) 1 and 2, and VEGF-C activates VEGFR-3 and VEGFR-2. Both VEGF and VEGF-C are also potent vascular permeability factors. Here we have analyzed the receptor binding and activating properties of several cysteine mutants of VEGF-C including those (Cys156 and Cys165), which in other platelet-derived growth factor/VEGF family members mediate interchain disulfide bonding. Surprisingly, we found that the recombinant mature VEGF-C in which Cys156 was replaced by a Ser residue is a selective agonist of VEGFR-3. This mutant, designated Delta NDelta C156S, binds and activates VEGFR-3 but neither binds VEGFR-2 nor activates its autophosphorylation or downstream signaling to the ERK/MAPK pathway. Unlike VEGF-C, Delta NDelta C156S neither induces vascular permeability in vivo nor stimulates migration of bovine capillary endothelial cells in culture. These data point out the critical role of VEGFR-2-mediated signal transduction for the vascular permeability activity of VEGF-C and strongly suggest that the redundant biological effects of VEGF and VEGF-C depend on binding and activation of VEGFR-2. The Delta NDelta C156S mutant may provide a valuable tool for the analysis of VEGF-C effects mediated selectively via VEGFR-3. The ability of Delta NDelta C156S to form homodimers also emphasizes differences in the structural requirements for VEGF and VEGF-C dimerization.

Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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