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J. Biol. Chem., Vol. 282, Issue 11, 7758-7769, March 16, 2007

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The Scaffolding Adapter Gab1 Mediates Vascular Endothelial Growth Factor Signaling and Is Required for Endothelial Cell Migration and Capillary Formation^*

Mélanie Laramée, Catherine Chabot¹, Monikca Cloutier, Raphaëlle Stenne, Marina Holgado-Madruga, Albert J. Wong, and Isabelle Royal^¶2

From the Centre de Recherche du Centre Hospitalier de l'Université de Montréal/Institut du Cancer de Montréal and ^¶Département de Médecine de l'Université de Montréal, Montréal, Québec H2L 4M1, Canada and the Department of Neurosurgery, Stanford University Medical Center, Stanford, California 94305

Vascular endothelial growth factor (VEGF) is involved in the promotion of endothelial cell proliferation, migration, and capillary formation. These activities are mainly mediated by the VEGFR2 receptor tyrosine kinase that upon stimulation, promotes the activation of numerous proteins including phospholipase C (PLC), phosphatidylinositol 3-kinase (PI3K), Akt, Src, and ERK1/2. However, the VEGFR2-proximal signaling events leading to the activation of these targets remain ill defined. We have identified the Gab1 adapter as a novel tyrosine-phosphorylated protein in VEGF-stimulated cells. In bovine aortic endothelial cells, Gab1 associates with VEGFR2, Grb2, PI3K, SHP2, Shc, and PLC, and its overexpression enhances VEGF-dependent cell migration. Importantly, silencing of Gab1 using small interfering RNAs leads to the impaired activation of PLC, ERK1/2, Src, and Akt; blocks VEGF-induced endothelial cell migration; and perturbs actin reorganization and capillary formation. In addition, co-expression of VEGFR2 with Gab1 mutants unable to bind SHP2 or PI3K in human embryonic kidney 293 cells and bovine aortic endothelial cells mimics the defects observed in Gab1-depleted cells. Our work thus identifies Gab1 as a novel critical regulatory component of endothelial cell migration and capillary formation and reveals its key role in the activation of VEGF-evoked signaling pathways required for angiogenesis.

Received for publication, December 11, 2006

^* This work was supported by grants from The Cancer Research Society Inc., La Fondation du Centre Hospitalier de l'Université de Montréal, and Canadian Institutes of Health Research Grant MOP-77612 (to I. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by studentships from Université de Montréal (Molecular Biology Programs; Faculty of Graduate Studies) and the Montreal Cancer Institute (Fondation Marc Bourgie and Canderel).

² To whom correspondence should be addressed: Centre de Recherche du CHUM, Hôpital Notre-Dame, Pavillon J.A. de Sève Y-4605, 1560 Rue Sherbrooke Est, Montréal, Québec H2L 4M1, Canada. Tel.: 514-890-8000 ext. 25497; Fax: 514-412-7591; E-mail: isabelle.royal{at}umontreal.ca.

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