A PKA-Csk-pp60Src signaling pathway regulates the switch between endothelial cell invasion and cell-cell adhesion during vascular sprouting

Abstract Angiogenesis is controlled by signals that stimulate motility in endothelial cells at the tips of vascular sprouts while maintaining cell-cell adhesion in the stalks of angiogenic sprouts. We show here that Gs-linked G protein–coupled receptor activation of cAMP-dependent protein kinase (PKA) plays an important role in regulating the switch between endothelial cell adhesion and migration by activating C-terminal Src kinase, leading to inhibition of pp60Src. Activated PKA blocks pp60Src-dependent vascular endot helial-cadherin phosphorylation, thereby stimulating cell-cell adhesion while suppressing endothelial cell polarization, motility, angiogenesis, and vascular permeability. Similar to the actions of Notch and Dll4, PKA activation blocks sprouting in newly forming embryonic blood vessels, while PKA inhibition promotes excessive sprouting in these vessels. These findings demonstrate that G protein–coupled receptors and PKA regulate vascular sprouting during angiogenesis by controlling endothelial cell migration and cell-cell adhesion through their actions on pp60Src.

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The adhesion G protein-coupled receptor G2 (ADGRG2/GPR64) constitutively activates SRE and NFκB and is involved in cell adhesion and migration

Cellular Signalling ◽

10.1016/j.cellsig.2015.08.015 ◽

2015 ◽

Vol 27 (12) ◽

pp. 2579-2588 ◽

Cited By ~ 36

Author(s):

Miriam C. Peeters ◽

Michiel Fokkelman ◽

Bob Boogaard ◽

Kristoffer L. Egerod ◽

Bob van de Water ◽

...

Keyword(s):

Cell Adhesion ◽

G Protein ◽

G Protein Coupled Receptor ◽

Cell Adhesion And Migration ◽

And Migration ◽

G Protein Coupled

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

Journal of Cell Science ◽

10.1242/jcs.115.9.1837 ◽

2002 ◽

Vol 115 (9) ◽

pp. 1837-1846 ◽

Cited By ~ 2

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.

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Chapter 3 Endothelial Cell Adhesion and Migration

Methods in Enzymology - Angiogenesis - In Vitro Systems ◽

10.1016/s0076-6879(08)02003-x ◽

2008 ◽

pp. 45-64 ◽

Cited By ~ 57

Author(s):

Cynthia A. Reinhart‐King

Keyword(s):

Cell Adhesion ◽

Endothelial Cell ◽

Cell Adhesion And Migration ◽

And Migration ◽

Endothelial Cell Adhesion

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The small GTPase Rab5c is a key regulator of trafficking of the CD93/Multimerin-2/β1 integrin complex in endothelial cell adhesion and migration

Cell Communication and Signaling ◽

10.1186/s12964-019-0375-x ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 4

Author(s):

Stefano Barbera ◽

Federica Nardi ◽

Ines Elia ◽

Giulia Realini ◽

Roberta Lugano ◽

...

Keyword(s):

Cell Adhesion ◽

Endothelial Cell ◽

Small Gtpase ◽

Β1 Integrin ◽

Cell Adhesion And Migration ◽

And Migration ◽

Endothelial Cell Adhesion

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

Molecular and Cellular Biology ◽

10.1128/mcb.00038-09 ◽

2010 ◽

Vol 30 (7) ◽

pp. 1593-1606 ◽

Cited By ~ 26

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.

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