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Papers In Press, published online ahead of print March 8, 2001
J. Biol. Chem, 10.1074/jbc.M009128200
Submitted on October 5, 2000
Revised on March 6, 2001
Accepted on March 8, 2001

Identification of tyrosine residues in vascular endothelial growth factor receptor-2/FLK-1 involved in activation of phosphatidylinositol-3 kinase and cell proliferation

Volkan Dayanir, Rosana D. Meyer, Kameran Lashkari, and Nader Rahimi

School of Medicine, Boston University, Boston, MA 02118

Corresponding Author: nrahimi{at}bu.edu

Activation of vascular endothelial growth factor receptor-2 (VEGFR-2) plays a critical role in vasculogenesis and angiogenesis. However, the mechanism by which VEGFR-2 activation elicits these cellular events is not fully understood. We recently constructed a chimeric receptor containing the extracellular domain of human CSF-1R/c-fms, fused with the entire transmembrane and cytoplasmic domains of murine VEGFR-2 (Rahimi et al., JBC 275: 16986-16992, 2000). In this study we used VEGFR-2 chimera (herein named CKR) to elucidate the signal transduction relay of VEGFR-2 in porcine aortic endothelial (PAE) cells. Mutation of tyrosines 799 and 1173 individually on CKR resulted in partial loss of CKR?s ability to stimulate cell growth. Double mutation of these sites caused total loss of CKR?s ability to stimulate cell growth. Interestingly, mutation of these sites had no effect on the ability of CKR to stimulate cell migration. Further analysis revealed that tyrosines 799 and 1173 are docking sites for p85 of PI-3 kinase. Pre-treatment of cells with wortmannin, an inhibitor of PI-3 kinase, and rapamycin, a potent inhibitor of S6 kinase, abrogated CKR-mediated cell growth. However, expression of a dominant negative form of ras (N17ras) and inhibition of the MAP kinase pathway by PD98059 did not attenuate CKR stimulated cell growth. Altogether, these results demonstrate that activation of VEGFR-2 results in activation of PI-3 kinase and that activation of PI-3 kinase/S6kinase pathway, but not Ras/MAPK is responsible for VEGFR-2 mediated cell growth.


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