Journal of Biological Chemistry
Volume 276, Issue 5, 2 February 2001, Pages 3222-3230
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MECHANISMS OF SIGNAL TRANSDUCTION
Analysis of Biological Effects and Signaling Properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2): A REASSESSMENT USING NOVEL RECEPTOR-SPECIFIC VASCULAR ENDOTHELIAL GROWTH FACTOR MUTANTS*

https://doi.org/10.1074/jbc.M002016200Get rights and content
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Endothelial cells express two related vascular endothelial growth factor (VEGF) receptor tyrosine kinases, KDR (kinase-insert domain containing receptor, or VEGFR-2) and Flt-1 (fms-like tyrosine kinase, or VEGFR-1). Although considerable experimental evidence links KDR activation to endothelial cell mitogenesis, there is still significant uncertainty concerning the role of individual VEGF receptors for other biological effects such as vascular permeability. VEGF mutants that bind to either KDR or Flt-1 with high selectivity were used to determine which of the two receptors serves to mediate different VEGF functions. In addition to mediating mitogenic signaling, selective KDR activation was sufficient for the activation of intracellular signaling pathways implicated in cell migration. KDR stimulation caused tyrosine phosphorylation of both phosphatidylinositol 3-kinase and phospholipase Cγ in primary endothelial cells and stimulated cell migration. KDR-selective VEGF was also able to induce angiogenesis in the rat cornea to an extent indistinguishable from wild type VEGF. We also demonstrate that KDR, but not Flt-1, stimulation is responsible for the induction of vascular permeability by VEGF.

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Published, JBC Papers in Press, October 31, 2000, DOI 10.1074/jbc.M002016200

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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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To whom correspondence should addressed: Dept. of Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080. Tel.: 650-225-2968; Fax: 650-225-6327; E-mail: [email protected].