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Published 27 May 2003. doi:10.1083/jcb.200209019
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© The Rockefeller University Press, 0021-9525/2003/5/793 $5.00
The Journal of Cell Biology, Volume 161, Number 4, 793-804

Article

 Contact inhibition of VEGF-induced proliferation requires vascular endothelial cadherin, ß-catenin, and the phosphatase DEP-1/CD148

Maria Grazia Lampugnani1,2, Adriana Zanetti2, Monica Corada1,2, Takamune Takahashi4, Giovanna Balconi2, Ferruccio Breviario1,2, Fabrizio Orsenigo1, Anna Cattelino1, Rolf Kemler5, Thomas O. Daniel6 and Elisabetta Dejana1,2,3

1 FIRC Institute of Molecular Oncology, 20139 Milan, Italy
2 Mario Negri Institute for Pharmacological Research, 20157 Milan, Italy
3 University of Milan, School of Sciences, 20100 Milan, Italy
4 Division of Nephrology, Department Medicine and Cell Biology, Vanderbilt University, Nashville, TN 37235
5 Max Planck Institute of Immunology, D-79108 Freiburg, Germany
6 Immunex Corp., Seattle, WA 98101

Address correspondence to Elisabetta Dejana, FIRC Institute of Molecular Oncology, Via Adamello, 16-20139, Milan, Italy. Tel.: 39-02-574303-234. Fax: 39-02574303-244. E-mail: dejana{at}ifom-firc.it

Confluent endothelial cells respond poorly to the proliferative signals of VEGF. Comparing isogenic endothelial cells differing for vascular endothelial cadherin (VE-cadherin) expression only, we found that the presence of this protein attenuates VEGF-induced VEGF receptor (VEGFR) 2 phosphorylation in tyrosine, p44/p42 MAP kinase phosphorylation, and cell proliferation. VE-cadherin truncated in ß-catenin but not p120 binding domain is unable to associate with VEGFR-2 and to induce its inactivation. ß-Catenin–null endothelial cells are not contact inhibited by VE-cadherin and are still responsive to VEGF, indicating that this protein is required to restrain growth factor signaling. A dominant-negative mutant of high cell density–enhanced PTP 1 (DEP-1)//CD148 as well as reduction of its expression by RNA interference partially restore VEGFR-2 phosphorylation and MAP kinase activation. Overall the data indicate that VE-cadherin–ß-catenin complex participates in contact inhibition of VEGF signaling. Upon stimulation with VEGF, VEGFR-2 associates with the complex and concentrates at cell–cell contacts, where it may be inactivated by junctional phosphatases such as DEP-1. In sparse cells or in VE-cadherin–null cells, this phenomenon cannot occur and the receptor is fully activated by the growth factor.

Key Words: endothelium; cadherins; catenins; vascular endothelial growth factor; proliferation

M.G. Lampugnani and A. Zanetti contributed equally to this work.

The online version of this manuscript includes supplemental material.

* Abbreviations used in this paper: DEP-1, high cell density–enhanced PTP 1; E-cadherin, epithelial cadherin; HUVEC, human umbilical vein endothelial cells; PI3, phosphatidylinositol 3; PTP, phosphotyrosine phosphatase; RNAi, RNA interference; siRNA, short interfering RNA; VE-cadherin, vascular endothelial cadherin; VEGFR, VEGF receptor.


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