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Kinase Insert Domain Receptor (KDR) Extracellular Immunoglobulin-like Domains 4–7 Contain Structural Features That Block Receptor Dimerization and Vascular Endothelial Growth Factor-induced Signaling*

Q. Tao,M. Backer,J. Backer,B. I. Terman

Published 2001 in Journal of Biological Chemistry

ABSTRACT

The vascular endothelial growth factor (VEGF) receptor tyrosine kinase subtype kinase insert domain receptor (KDR) contains seven extracellular Ig-like domains, of which the three most amino-terminal contain the necessary structural features required for VEGF binding. To clarify the functional role of KDR Ig-like domains 4–7, we compared VEGF-induced signaling in human embryonic kidney and porcine aortic endothelial cells expressing nativeversus mutant receptor proteins in which Ig-like domains 4–7, 4–6, or 7 had been deleted. Western blotting using an anti-receptor antibody indicated equivalent expression levels for each of the recombinant proteins. As expected, VEGF treatment robustly augmented native receptor autophosphorylation. In contrast, receptor autophosphorylation, as well as downstream signaling events, were VEGF-independent for cells expressing mutant receptors.125I-VEGF165 bound with equal or better affinity to mutant versus native receptor, although the number of radioligand binding sites was significantly reduced because a significant percentage of mutant, but not native, receptors were localized to the cell interior. As was the case for native KDR,125I-VEGF165 binding to the mutant receptors was dependent upon cell surface heparan sulfate proteoglycans, and125I-VEGF121 bound with an affinity equal to that of 125I-VEGF165 to the native and mutant receptors. It is concluded that KDR Ig-like domains 4–7 contain structural features that inhibit receptor signaling by a mechanism that is independent of neuropilin-1 and heparan sulfate proteoglycans. We speculate that this provides a cellular mechanism for blocking unwanted signaling events in the absence of VEGF.

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