KDR extracellular Ig-like domains 4-7 contain structural features that block receptor dimerization and VEGF-induced signaling

doi:10.1074/jbc.M100763200

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Papers In Press, published online ahead of print March 16, 2001
J. Biol. Chem, 10.1074/jbc.M100763200
Submitted on January 26, 2001
Revised on March 9, 2001
Accepted on March 15, 2001

KDR extracellular Ig-like domains 4-7 contain structural features that block receptor dimerization and VEGF-induced signaling

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

Medicine / Cardiology, Albert Einstein College of Medicine, Bronx, NY 10461

Corresponding Author: terman{at}aecom.yu.edu

The Vascular Endothelial Growth Factor (VEGF) receptor tyrosine kinase subtype KDR contains seven extracellular Ig-like domains, of which the three most amino-terminal contain the necessary structural features required for VEGF binding. In order to clarify the functional role of KDR Ig-like domains 4-7, we compared VEGF-induced signaling in HEK293 and PAE 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 down-stream 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, due to the fact that 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 (HSPGs), and 125I-VEGF121 bound with an equal affinity as 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 HSPGs. We speculate that this provides a cellular mechanism for blocking unwanted signaling events in the absence of VEGF.

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