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Vol. 18, Issue 11, 4659-4668, November 2007

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Src-mediated Phosphorylation of Hsp90 in Response to Vascular Endothelial Growth Factor (VEGF) Is Required for VEGF Receptor-2 Signaling to Endothelial NO Synthase

Martine Duval^*,, Fabrice Le Bœuf, Jacques Huot, and Jean-Philippe Gratton^*,,

*Laboratory of Endothelial Cell Biology, Institut de recherches cliniques de Montréal (IRCM), Montréal, QC, H2W 1R7, Canada; Departments of Pharmacology and Medicine, Université de Montréal, Montréal, QC, H3C 3J7, Canada; and Le Centre de Recherche en Cancérologie de l'Université Laval, Québec, QC, G1R 2J6, Canada

Submitted May 18, 2007; Revised August 29, 2007; Accepted August 31, 2007
Monitoring Editor: Martin A. Schwartz

Nitric oxide (NO) release from endothelial cells, via endothelial NO synthase (eNOS) activation, is central to the proangiogenic actions of vascular endothelial growth factor (VEGF). VEGF signaling to eNOS is principally mediated by an Akt-dependent phosphorylation of eNOS and by increased association of eNOS to the molecular chaperone, heat-shock protein 90 kDa (Hsp90). Herein, we report that VEGFR-2 activation induces tyrosine phosphorylation of VEGF receptor 2 (VEGFR-2)-associated Hsp90. Tyrosine phosphorylation of Hsp90 in response to VEGF is dependent on internalization of the VEGFR-2 and on Src kinase activation. Furthermore, we demonstrate that c-Src directly phosphorylates Hsp90 on tyrosine 300 residue and that this event is essential for VEGF-stimulated eNOS association to Hsp90 and thus NO release from endothelial cells. Our work identifies Y300 phosphorylation of Hsp90 as a novel regulated posttranslational modification of the chaperone and demonstrates its importance in the proangiogenic actions of VEGF, namely by regulating NO release from endothelial cells.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Jean-Philippe Gratton (jean-philippe.gratton{at}ircm.qc.ca)

Abbreviations used: BAECs, bovine aortic endothelial cells; eNOS, endothelial nitric oxide synthase; GA, geldanamycin; HA, hemagglutinin; Hsp90, heat-shock protein 90 kDa; HUVECs, human umbilical vein endothelial cells; NO, nitric oxide; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

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