Unraveling the distinct distributions of VE- and N-cadherins in endothelial cells: A key role for p120-catenin

Gentil-dit-Maurin, Alice; Oun, Stella; Almagro, Sébastien; Bouillot, Stéphanie; Courçon, Marie; Linnepe, Ruth; Vestweber, Dietmar; Huber, Philippe; Tillet, Emmanuelle

doi:10.1016/j.yexcr.2010.06.015

Cited by 25 publications

(28 citation statements)

References 49 publications

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“…Binding of p120 to cadherin intracellular tail inhibits the entry of cadherins into the degradation pathways. 19 Confirming previously published data, [20][21][22][23] both VE-and N-cadherin protein, but not mRNA levels, were reduced by knocking down p120 (supplemental Figure 2A-C). Reconstitution of VEC-null cells with a stable VE-cadherin mutant (⌬p120), which lacks the juxtamembrane cytoplasmic domain responsible for p120 recruitment, 24 did not reduce N-cadherin levels (supplemental Figure 2D) consistently with a higher level of p120 available for N-cadherin binding as previously described.…”

supporting

confidence: 89%

“…We first confirmed that the expression and junctional localization of N-cadherin is negatively modulated by VE-cadherin in cultured ECs, 10,20,21 and we extended these observations to in vivo conditions. We then found that the effect of VE-cadherin in reducing N-cadherin expression is not only because of a competing effect for p120 binding 10,20,21 but also to its ability to bind ␤-catenin and limit in this way its nuclear translocation and transcriptional activity. 17,40 We show that ␤-catenin transcriptionally up-regulates N-cadherin but reduces VE-cadherin expression.…”

mentioning

confidence: 92%

“…Reconstitution of VEC-null cells with a stable VE-cadherin mutant (⌬p120), which lacks the juxtamembrane cytoplasmic domain responsible for p120 recruitment, 24 did not reduce N-cadherin levels (supplemental Figure 2D) consistently with a higher level of p120 available for N-cadherin binding as previously described. [20][21][22] However, besides affecting N-cadherin protein stability, VEcadherin decreased the corresponding mRNA suggesting that it may have an effect also at the transcriptional level ( Figure 1B). VE-cadherin expression significantly decreases ␤-catenin translocation to the nucleus and transcriptional signaling.…”

mentioning

confidence: 99%

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Overlapping and divergent signaling pathways of N-cadherin and VE-cadherin in endothelial cells

Giampietro

Taddei

Corada

et al. 2012

Blood

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Endothelial cells (ECs) express 2 members of the cadherin family, VE and Ncadherin. 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 ␤-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 ␤-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. (Blood. 2012;119(9):2159-2170) IntroductionCell-cell adhesion is a key process in embryonic development and tissue formation. Perturbation of cell interactions, ultimately mediated by cellular adhesion molecules, leads to structural problems during tissue and organ development in embryogenesis. 1,2 The cadherin family plays important roles in establishing and maintaining cell interactions through homotypic binding and adhesive specificities. [1][2][3] This family includes the classic cadherins, which are calcium-dependent cell adhesion molecules with a unique and mostly mutually exclusive spatio-temporal expression pattern. The function of different cadherins depends on the specific cellular context. Endothelial cells (ECs) express 2 major cadherins, VE-cadherin and N-cadherin. 4 VE-cadherin is EC specific 5 and regulates vasculogenesis by inducing contact inhibition of growth, preventing cell motility and apoptosis and controlling permeability. 6,7 In contrast, N-cadherin is expressed in several cell types such as neuronal, lens, skeletal and heart muscle cells, osteoblasts, pericytes, and fibroblasts. 2,3 Moreover N-cadherin is typically expressed in mesenchymal cells, which are highly invasive and poorly polarized, and in cancer cells where it promotes motility and invasion. 8 The comparison between these 2 cadherins reveals a good homology of the overall amino acid sequences. Conservation is particularly prominent at the level of the cytoplasmic tail where catenin-binding regions are located. Although these 2 cadherins have a similar structure and b...

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confidence: 89%

mentioning

confidence: 92%

mentioning

confidence: 99%

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Overlapping and divergent signaling pathways of N-cadherin and VE-cadherin in endothelial cells

Giampietro

Taddei

Corada

et al. 2012

Blood

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“…At first glance this would seem to be at odds with the findings of this study, which showed no change in albumin permeability with a loss of p120 and decreased VE-cadherin levels. However, we have found that bovine cells possess a higher amount of N-cadherin compared with VEcadherin (14), and a recent study by Gentil-dit-Maurin et al (17) suggested that these two cadherins participate in different signaling pathways due to differential association with lipid rafts. Because HDMECS express higher levels of VE-cadherin compared with N-cadherin, signaling differences may exist between the bovine and human endothelial cells, thereby explaining the difference in albumin permeability found between cell types following a decrease in p120 and VE-cadherin.…”

Section: Discussionmentioning

confidence: 56%

p120 regulates endothelial permeability independently of its NH₂terminus and Rho binding

Herron

Lowery

Hollister

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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The association of p120-catenin (p120) with the juxtamembrane domain (JMD) of vascular endothelial (VE)-cadherin is required to maintain VE-cadherin levels and transendothelial resistance (TEER) of endothelial cell monolayers. To distinguish whether decreased TEER was due to a loss of p120 and not to the decrease in VE-cadherin, we established a system in which p120 was depleted by short hairpin RNA delivered by lentivirus and VE-cadherin was restored via expression of VE-cadherin fused to green fluorescent protein (GFP). Loss of p120 resulted in decreased TEER, which was associated with decreased expression of VE-cadherin, β-catenin, plakoglobin, and α-catenin. Decreased TEER was rescued by restoration of p120 but not by the expression of VE-cadherin-GFP, despite localization of VE-cadherin-GFP at cell-cell borders. Expression of VE-cadherin-GFP restored levels of β-catenin and α-catenin but not plakoglobin, indicating that p120 may be important for recruitment of plakoglobin to the VE-cadherin complex. To evaluate the role of p120 interaction with Rho GTPase in regulating endothelial permeability, we expressed a recombinant form of p120, lacking the NH(2) terminus and containing alanine substitutions, that eliminates binding of Rho to p120. Expression of this isoform restored expression of the adherens junction complex and rescued permeability as measured by TEER. These results demonstrate that p120 is required for maintaining VE-cadherin expression and TEER independently of its NH(2) terminus and its role in regulating Rho.

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“…53,54 Distribution of N-cadherin proteins in vitro however was proven to be mostly non-junctional 53 with exclusion of N-cadherin from endothelial junctions caused by a competition with VE-cadherin. [55][56][57] Nevertheless, endothelial-specific deletion of N-cadherin in mice results in early embryonic lethality due to severe vascular defects underlining the importance of N-cadherin in the endothelium. 58 Analysis of the cardiovascular phenotypes in zebrafish glo mutants revealed that even though the morphology of the heart tube is highly distorted, cardiomyocytes had differentiated and cardiac contraction was present.…”

Section: Endothelial Cell-cell Adhesion In Developmentmentioning

confidence: 99%

Endothelial cell–cell adhesion during zebrafish vascular development

Lagendijk

Yap

Hogan³

2014

Cell Adhesion & Migration

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Unraveling the distinct distributions of VE- and N-cadherins in endothelial cells: A key role for p120-catenin

Cited by 25 publications

References 49 publications

Overlapping and divergent signaling pathways of N-cadherin and VE-cadherin in endothelial cells

Overlapping and divergent signaling pathways of N-cadherin and VE-cadherin in endothelial cells

p120 regulates endothelial permeability independently of its NH₂terminus and Rho binding

Endothelial cell–cell adhesion during zebrafish vascular development

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Unraveling the distinct distributions of VE- and N-cadherins in endothelial cells: A key role for p120-catenin

Cited by 25 publications

References 49 publications

Overlapping and divergent signaling pathways of N-cadherin and VE-cadherin in endothelial cells

Overlapping and divergent signaling pathways of N-cadherin and VE-cadherin in endothelial cells

p120 regulates endothelial permeability independently of its NH2terminus and Rho binding

Endothelial cell–cell adhesion during zebrafish vascular development

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p120 regulates endothelial permeability independently of its NH₂terminus and Rho binding