scholarly journals Phosphorylation of VE-cadherin controls endothelial phenotypes via p120-catenin coupling and Rac1 activation

2011 ◽  
Vol 300 (1) ◽  
pp. H162-H172 ◽  
Author(s):  
Kunihiko Hatanaka ◽  
Michael Simons ◽  
Masahiro Murakami
Keyword(s):  
Cell Migration ◽  
Endothelial Cell ◽  
Vascular Permeability ◽  
Cell Junctions ◽  
Endothelial Cell Migration ◽  
Wild Type ◽  
P120 Catenin ◽  
Cell Functions ◽  
Preferential Binding ◽  
Cell Cell

To establish the role of vascular endothelial (VE)-cadherin in the regulation of endothelial cell functions, we investigated the effect of phosphorylation of a VE-cadherin site sought to be involved in p120-catenin binding on vascular permeability and endothelial cell migration. To this end, we introduced either wild-type VE-cadherin or Y658 phosphomimetic (Y658E) or dephosphomimetic (Y658F) VE-cadherin mutant constructs into an endothelial cell line (rat fat pad endothelial cells) lacking endogenous VE-cadherin. Remarkably, neither wild-type- nor Y658E VE-cadherin was retained at cell-cell contacts because of p120-catenin preferential binding to N-cadherin, resulting in the targeting of N-cadherin to cell-cell junctions and the exclusion of VE-cadherin. However, Y658F VE-cadherin was able to bind p120-catenin and to localize at adherence junctions displacing N-cadherin. This resulted in an enhanced barrier function and a complete abrogation of Rac1 activation and lamellipodia formation, thereby inhibiting cell migration. These findings demonstrate that VE-cadherin, through the regulation of Y658 phosphorylation, competes for junctional localization with N-cadherin and controls vascular permeability and endothelial cell migration.

Reactive oxygen species mediate Rac-induced loss of cell-cell adhesion in primary human endothelial cells

2002 ◽  
Vol 115 (9) ◽  
pp. 1837-1846 ◽  
Author(s):  
Sandra van Wetering ◽  
Jaap D. van Buul ◽  
Safira Quik ◽  
Frederik P. J. Mul ◽  
Eloise C. Anthony ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Endothelial Cells ◽  
Cell Migration ◽  
Cell Adhesion ◽  
Endothelial Cell ◽  
Reactive Oxygen ◽  
Small Gtpases ◽  
Endothelial Cell Migration ◽  
Oxygen Species ◽  
Cell Cell

The integrity of the endothelium is dependent on cell-cell adhesion, which is mediated by vascular-endothelial (VE)-cadherin. Proper VE-cadherin-mediated homotypic adhesion is, in turn, dependent on the connection between VE-cadherin and the cortical actin cytoskeleton. Rho-like small GTPases are key molecular switches that control cytoskeletal dynamics and cadherin function in epithelial as well as endothelial cells. We show here that a cell-penetrating, constitutively active form of Rac (Tat-RacV12) induces a rapid loss of VE-cadherin-mediated cell-cell adhesion in endothelial cells from primary human umbilical veins (pHUVEC). This effect is accompanied by the formation of actin stress fibers and is dependent on Rho activity. However,transduction of pHUVEC with Tat-RhoV14, which induces pronounced stress fiber and focal adhesion formation, did not result in a redistribution of VE-cadherin or an overall loss of cell-cell adhesion. In line with this observation, endothelial permeability was more efficiently increased by Tat-RacV12 than by Tat-RhoV14. The loss of cell-cell adhesion, which is induced by Tat-RacV12, occurred in parallel to and was dependent upon the intracellular production of reactive oxygen species (ROS). Moreover, Tat-RacV12 induced an increase in tyrosine phosphorylation of a component the VE-cadherin-catenin complex, which was identified as α-catenin. The functional relevance of this signaling pathway was further underscored by the observation that endothelial cell migration, which requires a transient reduction of cell-cell adhesion, was blocked when signaling through ROS was inhibited. In conclusion, Rac-mediated production of ROS represents a previously unrecognized means of regulating VE-cadherin function and may play an important role in the (patho)physiology associated with inflammation and endothelial damage as well as with endothelial cell migration and angiogenesis.

scholarly journals Lipid Phosphate Phosphatase 3 Stabilization of β-Catenin Induces Endothelial Cell Migration and Formation of Branching Point Structures

2010 ◽  
Vol 30 (7) ◽  
pp. 1593-1606 ◽  
Author(s):  
Joseph O. Humtsoe ◽  
Mingyao Liu ◽  
Asrar B. Malik ◽  
Kishore K. Wary
Keyword(s):  
Cell Adhesion ◽  
Endothelial Cell ◽  
De Novo ◽  
Endothelial Cell Migration ◽  
Dependent Manner ◽  
P120 Catenin ◽  
Branching Point ◽  
Lipid Phosphate ◽  
Underlying Mechanisms ◽  
Cell Cell

ABSTRACT Endothelial cell (EC) migration, cell-cell adhesion, and the formation of branching point structures are considered hallmarks of angiogenesis; however, the underlying mechanisms of these processes are not well understood. Lipid phosphate phosphatase 3 (LPP3) is a recently described p120-catenin-associated integrin ligand localized in adherens junctions (AJs) of ECs. Here, we tested the hypothesis that LPP3 stimulates β-catenin/lymphoid enhancer binding factor 1 (β-catenin/LEF-1) to induce EC migration and formation of branching point structures. In subconfluent ECs, LPP3 induced expression of fibronectin via β-catenin/LEF-1 signaling in a phosphatase and tensin homologue (PTEN)-dependent manner. In confluent ECs, depletion of p120-catenin restored LPP3-mediated β-catenin/LEF-1 signaling. Depletion of LPP3 resulted in destabilization of β-catenin, which in turn reduced fibronectin synthesis and deposition, which resulted in inhibition of EC migration. Accordingly, reexpression of β-catenin but not p120-catenin in LPP3-depleted ECs restored de novo synthesis of fibronectin, which mediated EC migration and formation of branching point structures. In confluent ECs, however, a fraction of p120-catenin associated and colocalized with LPP3 at the plasma membrane, via the C-terminal cytoplasmic domain, thereby limiting the ability of LPP3 to stimulate β-catenin/LEF-1 signaling. Thus, our study identified a key role for LPP3 in orchestrating PTEN-mediated β-catenin/LEF-1 signaling in EC migration, cell-cell adhesion, and formation of branching point structures.

Tissue factor pathway inhibitor (TFPI) interferes with endothelial cell migration by inhibition of both the Erk pathway and focal adhesion proteins

2008 ◽  
Vol 99 (03) ◽  
pp. 576-585 ◽  
Author(s):  
Mathieu Provençal ◽  
Marisol Michaud ◽  
Édith Beaulieu ◽  
David Ratel ◽  
Georges-Étienne Rivard ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Migration ◽  
Endothelial Cell ◽  
Tissue Factor ◽  
Focal Adhesion ◽  
Tissue Factor Pathway Inhibitor ◽  
Endothelial Cell Migration ◽  
Cell Functions ◽  
Tissue Factor Pathway

SummaryTissue factor pathway inhibitor (TFPI) is a plasma Kunitz-type serine protease inhibitor that is mainly known for its inhibition of tissue factor-mediated coagulation. In addition to its anticoagulant properties, emerging data show that TFPI may also regulate endothelial cell functions via a non-haemostatic pathway. In this work we demonstrate that at concentrations within the physiological range,TFPI inhibits both endothelial cell migration and their differentiation into capillary-like structures in vitro. These effects were specific to endothelial cells since no inhibitory effect was observed on the migration of tumor (glio- blastoma) cells. Inhibition of endothelial cell migration was correlated with a concomitant loss in cell adhesion,suggesting an alteration of focal adhesion complex integrity. Accordingly,we observed thatTFPI inhibited the phosphorylation of focal adhesion kinase and paxillin,two key proteins involved in the scaffolding of these complexes, and that this effect was specific to endothelial cells. These results suggest that TFPI influences the angiogenic process via a non-haemostatic pathway, by downregulating the migratory mechanisms of endothelial cells.

scholarly journals Modulation of endothelial cell migration by extracellular nucleotides

2005 ◽  
Vol 93 (04) ◽  
pp. 735-742 ◽  
Author(s):  
Laurie Erb ◽  
Katarzyna Koziak ◽  
Robert Jarzyna ◽  
Marcia Wink ◽  
Olaf Guckelberger ◽  
...  
Keyword(s):  
Cell Migration ◽  
Endothelial Cell ◽  
P2 Receptors ◽  
Cellular Adhesion ◽  
Extracellular Nucleotides ◽  
Endothelial Cell Migration ◽  
Free Calcium ◽  
Receptor Subtypes ◽  
Dependent Manner ◽  
Cell Functions

SummaryExtracellular nucleotides bind to type-2 purinergic/pyrimidinergic (P2) receptors that mediate various responses, such as cell activation, proliferation and apoptosis, implicated in inflammatory processes. The role of P2 receptors and their associated signal transduction pathways in endothelial cell responses has not been fully investigated. Here, it is shown that stimulation of human umbilical vein endothelial cells (HUVEC) with extracellular ATP or UTP increased intracellular free calcium ion concentrations ([Ca2+]i), induced phosphorylation of focal adhesion kinase (FAK), p130cas and paxillin, and caused cytoskeletal rearrangements with consequent cell migration. Furthermore, UTP increased migration of HUVEC in a phosphatidylinositol 3-kinase (PI3-K)-dependent manner. BAPTA or thapsigargin inhibited the extracellular nucleotide-induced increase in [Ca2+]i, a response crucial for both FAK phosphorylation and cell migration. Furthermore, long-term exposure of HUVEC to ATP and UTP, agonists of the G protein-coupled P2Y2 and P2Y4 receptor subtypes, caused upregulation of αv integrin expression, a cell adhesion molecule known to directly interact with P2Y2 receptors. Our results suggest that extracellular nucleotides modulate signaling pathways in HUVEC influencing cell functions, such as cytoskeletal changes, cellular adhesion and motility, typically associated with integrin-activation and the action of growth factors. We propose that P2Y2 and possibly P2Y4 receptors mediate those responses that are important in vascular inflammation, atherosclerosis and angiogenesis.

scholarly journals RAF dimers control vascular permeability and cytoskeletal rearrangements at endothelial cell‐cell junctions

FEBS Journal ◽  
2019 ◽  
Vol 286 (12) ◽  
pp. 2277-2294 ◽  
Author(s):  
Coralie Dorard ◽  
Botond Cseh ◽  
Karin Ehrenreiter ◽  
Reiner Wimmer ◽  
Andrea Varga ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Vascular Permeability ◽  
Cell Junctions ◽  
Cytoskeletal Rearrangements ◽  
Cell Cell

PDZRN3 destabilizes endothelial cell-cell junctions through a PKCζ-containing polarity complex to increase vascular permeability

2017 ◽  
Vol 10 (464) ◽  
pp. eaag3209 ◽  
Author(s):  
Raj N. Sewduth ◽  
Héléna Kovacic ◽  
Béatrice Jaspard-Vinassa ◽  
Vincent Jecko ◽  
Thomas Wavasseur ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Vascular Permeability ◽  
Cell Junctions ◽  
Cell Cell

PECAM-1 isoform-specific regulation of kidney endothelial cell migration and capillary morphogenesis

2007 ◽  
Vol 292 (6) ◽  
pp. C2070-C2083 ◽  
Author(s):  
Shuji Kondo ◽  
Elizabeth A. Scheef ◽  
Nader Sheibani ◽  
Christine M. Sorenson
Keyword(s):  
Cell Migration ◽  
Cell Adhesion ◽  
Endothelial Cell ◽  
Vascular Development ◽  
Focal Adhesions ◽  
Endothelial Cell Migration ◽  
Extracellular Matrix Protein ◽  
Wild Type ◽  
Renal Vasculature ◽  
Capillary Morphogenesis

Platelet endothelial cell adhesion molecule-1 (PECAM-1) has been implicated in angiogenesis through its involvement in endothelial cell-cell and cell-matrix interactions and signal transduction. Recent studies indicate that the cytoplasmic domain of PECAM-1 plays an important role in its cell adhesive and signaling properties. However, the role PECAM-1 isoforms play during angiogenic events such as cell adhesion and migration requires further delineation. To gain insight into the role PECAM-1 plays during vascular development and angiogenesis, we examined the expression pattern of PECAM-1 isoforms during kidney vascularization. We show that multiple isoforms of PECAM-1 are expressed during renal vascular development with different frequencies. The PECAM-1 that lacks exons 14 and 15 (Δ14&15) was the predominant isoform detected in the renal vasculature. To further study PECAM-1 isoform-specific functions we isolated kidney endothelial cells (EC) from wild-type and PECAM-1-deficient (PECAM-1−/−) mice with B4-lectin-coated magnetic beads. PECAM-1−/− kidney EC showed reduced migration, inability to undergo capillary morphogenesis in Matrigel, dense peripheral focal adhesions, and peripheral cortical actin distribution compared with wild-type cells. PECAM-1−/− kidney EC secreted increased amounts of fibronectin and decreased amounts of tenascin-C and thrombospondin-1. Reexpression of Δ14&15, but not full-length, PECAM-1 in PECAM-1−/− kidney EC restored cell migration and capillary morphogenesis defects. Thus PECAM-1 may regulate the adhesive and migratory properties of kidney EC in an isoform-specific fashion through modulation of integrin activity and extracellular matrix protein expression. Our results indicate that regulated expression of specific PECAM-1 isoforms may enable EC to accommodate the different stages of angiogenesis.

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