title: Overlapping and divergent signaling pathways of N-cadherin and VE-cadherin in endothelial cells.
abstract: Endothelial cells (ECs) express 2 members of the cadherin family, VE and N-cadherin. Although VE-cadherin induces EC homotypic adhesion, N-cadherin function in ECs remains largely unknown. EC-specific inactivation of either VE or N-cadherin leads to early fetal lethality suggesting that these cadherins play a nonredundant role in vascular development. We report here that VE-cadherin negatively controls junctional localization and expression of N-cadherin by limiting p120-catenin availability and reducing β-catenin transcriptional activity. Using EC lines expressing either VE or N-cadherin we found that both cadherins inhibit cell proliferation and apoptosis. Both trigger the phosphatidylinositol-3-OH-kinase (PI3K)-AKT-Forkhead-box protein-O1 (FoxO1) pathway and reduce β-catenin transcriptional activity. The extent of signaling correlates with the total level of cadherins regardless of the type of cadherin expressed. In contrast, basal and fibroblast growth factor (FGF)-induced cell motility is promoted by N-cadherin and strongly inhibited by VE-cadherin. This opposite effect is partly because of the ability of VE-cadherin to associate with FGF receptor and the density-enhanced phosphatase-1 (Dep-1) which, in turn, inhibits receptor signaling. We conclude that VE and N-cadherin have both additive and divergent effects on ECs. Differences in signaling are due, in part, to cadherin association with growth factor receptors and modulation of their downstream signaling.
authors.affiliation: FIRC Institute of Molecular Oncology, University of Milan, Milan, Italy.
authors.forename: Costanza
authors.initials: C
authors.lastname: Giampietro
authors.forename: Andrea
authors.initials: A
authors.lastname: Taddei
authors.forename: Monica
authors.initials: M
authors.lastname: Corada
authors.forename: Gian Maria
authors.initials: GM
authors.lastname: Sarra-Ferraris
authors.forename: Myriam
authors.initials: M
authors.lastname: Alcalay
authors.forename: Ugo
authors.initials: U
authors.lastname: Cavallaro
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Orsenigo
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Lampugnani
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Dejana
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D057507:Mice, 129 Strain; D018919:Neovascularization, Physiologic / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015820:Cadherins; D051858:Forkhead Transcription Factors; D042442:Vascular Endothelial Growth Factors; D051176:beta Catenin; D005346:Fibroblast Growth Factors; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt