title: Contact inhibition of VEGF-induced proliferation requires vascular endothelial cadherin, beta-catenin, and the phosphatase DEP-1/CD148.
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.
authors.affiliation: FIRC Institute of Molecular Oncology, 20139 Milan, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Grazia Lampugnani
authors.forename: Adriana
authors.initials: A
authors.lastname: Zanetti
authors.forename: Monica
authors.initials: M
authors.lastname: Corada
authors.forename: Takamune
authors.initials: T
authors.lastname: Takahashi
authors.forename: Giovanna
authors.initials: G
authors.lastname: Balconi
authors.forename: Ferruccio
authors.initials: F
authors.lastname: Breviario
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Orsenigo
authors.forename: Anna
authors.initials: A
authors.lastname: Cattelino
authors.forename: Rolf
authors.initials: R
authors.lastname: Kemler
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Daniel
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Dejana
mesh_terms: D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D003260:Contact Inhibition; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D008222:Lymphokines / Q000494:pharmacology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; D015534:Trans-Activators / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D042442:Vascular Endothelial Growth Factors; D051176:beta Catenin; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D003598:Cytoskeletal Proteins; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D020928:Mitogen-Activated Protein Kinases; D017027:Protein Tyrosine Phosphatases; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D042442:Vascular Endothelial Growth Factors; D051176:beta Catenin; D000099152:Cadherin 5; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; C486288:PTPRJ protein, human; C098066:Ptprj protein, mouse