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J. Biol. Chem., Vol. 276, Issue 24, 21916-21923, June 15, 2001

This Article Full Text Full Text (PDF) All Versions of this Article: 276/24/21916    most recent M100763200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tao, Q. Articles by Terman, B. I. Search for Related Content PubMed PubMed Citation Articles by Tao, Q. Articles by Terman, B. I. Social Bookmarking                      What's this?

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^*

Qi Tao, Marina V. Backer^§, Joseph M. Backer^§, and Bruce I. Terman^¶

From the  Cardiology Division, Department of Medicine, and the Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461 and ^§ Sibtech, Newington, Connecticut 06111

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 native versus 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, and ¹²⁵I-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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