Contact inhibition of VEGF-induced proliferation requires vascular endothelial cadherin, beta-catenin, and the phosphatase DEP-1/CD148.
Grazia Lampugnani, Maria ; Zanetti, Adriana ; Corada, Monica ; et al. ; - ASI Sponsor
May - 2003
ISSN : 0021-9525 ;
journal : The Journal of cell biology
Issue : 4
type: Article Journal
Abstract
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 beta-catenin but not p120 binding domain is unable to associate with VEGFR-2 and to induce its inactivation. beta-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-beta-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.
keywords : Animals,Antigens,CD,Cadherins,Cadherins: genetics,Cadherins: metabolism,Cell Division,Cell Division: drug effects,Cell Line,Cells,Class,Contact Inhibition,Cultured,Cytoskeletal Proteins,Cytoskeletal Proteins: metabolism,Dose-Response Relationship,Drug,Endothelial Growth Factors,Endothelial Growth Factors: pharmacology,Endothelium,Humans,Intercellular Signaling Peptides and Proteins,Intercellular Signaling Peptides and Proteins: pha,Lymphokines,Lymphokines: pharmacology,Mice,Mitogen-Activated Protein Kinases,Mitogen-Activated Protein Kinases: metabolism,Phosphorylation,Protein Binding,Protein Tyrosine Phosphatases,Protein Tyrosine Phosphatases: metabolism,Receptor-Like Protein Tyrosine Phosphatases,Trans-Activators,Trans-Activators: metabolism,Vascular,Vascular Endothelial Growth Factor A,Vascular Endothelial Growth Factor Receptor-2,Vascular Endothelial Growth Factor Receptor-2: met,Vascular Endothelial Growth Factors,Vascular: cytology,Vascular: drug effects,beta Catenin