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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:617.)
© 2002 American Heart Association, Inc.

Vascular Biology

Vascular Endothelial Growth Factor Induces Shc Association With Vascular Endothelial Cadherin

A Potential Feedback Mechanism to Control Vascular Endothelial Growth Factor Receptor-2 Signaling

Adriana Zanetti; Maria Grazia Lampugnani; Giovanna Balconi; Ferruccio Breviario; Monica Corada; Luisa Lanfrancone; Elisabetta Dejana

From the Mario Negri Institute of Pharmacological Research (A.Z., M.G.L., G.B., F.B., M.C., E.D.), Milan; the FIRC Institute of Molecular Oncology (M.G.L., F.B., M.C., E.D.), Milan; the European Institute of Oncology (L.L.), Milan; and the Dipartimento di Scienze Cliniche e Biologiche (E.D.), Facoltà di Medicina e Chirurgia, Università dell’Insubria, Varese, Italy.

Correspondence to Elisabetta Dejana, Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea 62, 20157 Milan, Italy. E-mail dejana{at}marionegri.it

Vascular endothelial (VE)-cadherin is endothelium specific, mediates homophilic adhesion, and is clustered at intercellular junctions. VE-cadherin is required for normal development of the vasculature in the embryo and for angiogenesis in the adult. Here, we report that VE-cadherin is associated with VE growth factor (VEGF) receptor-2 (VEGFR-2) on the exposure of endothelial cells to VEGF. The binding parallels receptor phosphorylation on tyrosine residues, which is maximal at 5 minutes and then declines within 30 minutes. Tyrosine phosphorylation of VE-cadherin was maximal at 30 minutes after the addition of the growth factor. At this time point, the protein could be coimmunoprecipitated with the adaptor protein Shc. Pull-down experiments with different Shc domains and mutants of the VE-cadherin cytoplasmic tail have shown that Shc binds to the carboxy-terminal domain of the VE-cadherin tail through its Src homology 2 domain (SH2). We found that Shc phosphorylation lasts longer in endothelial cells carrying a targeted null mutation in the VE-cadherin gene than in VE-cadherin–positive cells. These data suggest that VE-cadherin expression exerts a negative effect on Shc phosphorylation by VEGFR-2. We speculate that VE-cadherin binding to Shc promotes its dephosphorylation through associated phosphatases.

Key Words: endothelium • vascular endothelial cadherin • Shc

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