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Originally published In Press as doi:10.1074/jbc.M110842200 on November 28, 2001

J. Biol. Chem., Vol. 277, Issue 6, 4003-4009, February 8, 2002
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Flt-1-mediated Down-regulation of Endothelial Cell Proliferation through Pertussis Toxin-sensitive G Proteins, beta gamma Subunits, Small GTPase CDC42, and Partly by Rac-1*

Huiyan ZengDagger §, Dezheng Zhao, and Debabrata MukhopadhyayDagger ||

From the Dagger  Departments of Pathology and  Medicine (Division of Gastroenterology), Beth Israel Deaconess Medical Center and Harvard University School of Medicine, Boston, Massachusetts 02215

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) promotes its function primarily by activating two receptor tyrosine kinases, Flt-1 (VEGFR-1) and KDR (VEGFR-2). Recently, it has been shown that KDR is responsible for VPF/VEGF-stimulated endothelial cell (EC) proliferation and migration, whereas Flt-1 activation down-modulates KDR-mediated EC proliferation. Although KDR-mediated EC proliferation and migration have been extensively studied, much less is known about Flt-1-mediated antiproliferation. Here, we demonstrate that Flt-1-mediated antiproliferative activity can be blocked completely by the dominant negative mutant of CDC42 (CDC42-17N) and partially by a Rac1 dominant negative mutant (Rac1-17N) but is not affected by a RhoA dominant negative mutant (RhoA-19N). Both CDC42-17N and Rac1-17N increase the intracellular Ca2+ mobilization in response to VPF/VEGF but have no effect on KDR and MAPK phosphorylation. Using the chimeric-receptor EGLT in which the extracellular domain of epidermal growth factor receptor was fused to the transmembrane and intracellular domains of Flt-1, we also demonstrate that CDC42 and Rac1 are activated by EGLT. Previously, we showed that phosphatidylinositol 3-kinase is required for Flt-1-mediated antiproliferative activity, but phospholipase C is not required. As expected, CDC42 and Rac1 activation mediated by EGLT can be completely inhibited by PI3K inhibitors, wortmannin and LY294002, and the p85 dominant negative mutant but not by either the phospholipase C inhibitor, U73122, or an intracellular Ca2+ chilator BAPTA/AM. Surprisingly, pertussis toxin and overexpression of the free Gbeta gamma -specific sequestering minigene hbeta ARK1(495) also inhibit EGLT-mediated CDC42 and Rac1 activation completely. Moreover, pertussis toxin treatment also increases the intracellular Ca2+ mobilization and inhibits the antiproliferation activity, thus suggesting that pertussis toxin-sensitive G proteins and the Gbeta gamma subunits are involved in the signaling pathway of Flt-1 that down-regulates EC proliferation. Taken together, these results further expand our understanding of Flt-1-mediated antiproliferative activity in VPF/VEGF-stimulated endothelium.

* This work was supported in part by National Institutes of Health Grant CA78383 and grants from Department of Defense Breast Cancer Program and the American Cancer Society (to D. M.).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.

§ Recipient of Individual National Research Service Award fellowship.

|| To whom correspondence should be addressed: Dept. of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Ave., RN270H, Boston, MA 02215. Tel.: 617-667-7853; Fax: 617-667-3591; E-mail: dmukhopa@caregroup.harvard.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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