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Molecular and Cellular Biology, January 2009, p. 241-253, Vol. 29, No. 1
0270-7306/09/$08.00+0     doi:10.1128/MCB.01374-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

New Role for the Protein Tyrosine Phosphatase DEP-1 in Akt Activation and Endothelial Cell Survival{triangledown}

Catherine Chabot,1 Kathleen Spring,1 Jean-Philippe Gratton,2,3,4 Mounib Elchebly,5,6 and Isabelle Royal1,3*

CRCHUM-Centre Hospitalier de l'Université de Montréal and Institut du Cancer de Montréal, Montréal, Québec, Canada H2L 4M1,1 Laboratory of Endothelial Cell Biology, Institut de Recherches Cliniques de Montréal, Montréal, Québec, Canada H2W 1R7,2 Centre de Recherche de l'Hôpital Sainte-Justine, Montréal, Québec, Canada H3T 1C5,5 Departments of Medicine,3 Pharmacology,4 Biochemistry, Université de Montréal, Montréal, Québec, Canada6

Received 29 August 2008/ Accepted 6 October 2008

Functional inactivation of the protein tyrosine phosphatase DEP-1 leads to increased endothelial cell proliferation and failure of vessels to remodel and branch. DEP-1 has also been proposed to contribute to the contact inhibition of endothelial cell growth via dephosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2), a mediator of vascular development. However, how DEP-1 regulates VEGF-dependent signaling and biological responses remains ill-defined. We show here that DEP-1 targets tyrosine residues in the VEGFR2 kinase activation loop. Consequently, depletion of DEP-1 results in the increased phosphorylation of all major VEGFR2 autophosphorylation sites, but surprisingly, not in the overall stimulation of VEGF-dependent signaling. The increased phosphorylation of Src on Y529 under these conditions results in impaired Src and Akt activation. This inhibition is similarly observed upon expression of catalytically inactive DEP-1, and coexpression of an active Src-Y529F mutant rescues Akt activation. Reduced Src activity correlates with decreased phosphorylation of Gab1, an adapter protein involved in VEGF-dependent Akt activation. Hypophosphorylated Gab1 is unable to fully associate with phosphatidylinositol 3-kinase, VEGFR2, and VE-cadherin complexes, leading to suboptimal Akt activation and increased cell death. Overall, our results reveal that despite its negative role on global VEGFR2 phosphorylation, DEP-1 is a positive regulator of VEGF-mediated Src and Akt activation and endothelial cell survival.

* Corresponding author. Mailing address: Centre de recherche du CHUM, Hôpital Notre-Dame, Pavillon J.A. de Sève Y-4605, 1560 rue Sherbrooke est, Montréal, Québec, Canada H2L 4M1. Phone: (514) 890-8000, ext. 25497. Fax: (514) 412-7591. E-mail: isabelle.royal{at}umontreal.ca

{triangledown} Published ahead of print on 20 October 2008.

Molecular and Cellular Biology, January 2009, p. 241-253, Vol. 29, No. 1
0270-7306/09/$08.00+0     doi:10.1128/MCB.01374-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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