A local VE-cadherin and Trio-based signaling complex stabilizes endothelial junctions through Rac1

Timmerman, Ilse; Heemskerk, Niels; Kroon, Jeffrey; Schaefer, Antje; Rijssel, Jos van; Hoogenboezem, Mark; Unen, Jakobus van; Goedhart, Joachim; Gadella, Theodorus W. J.; Yin, Taofei; Wu, Yi; Huveneers, Stephan; Buul, Jaap D. van

doi:10.1242/jcs.179424

Cited by 51 publications

(36 citation statements)

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“…This local Rac1 activity co-localized with a-catenin, one of the VE-cadherin complex members, and likely stabilized the nascent contacts by promoting the formation of cortical actin bundles. 22 In line with this finding, a rapid increase in Rac1 activity upon VE-cadherin homotypic adhesion was detected biochemically, which was induced using beads coated with the VE-cadherin ectodomain. Thus, as was shown for E-, M-and N-cadherin, [64][65][66][67] we showed that VEcadherin can signal in an outside-in fashion to activate Rac1, providing a bidirectional feedback mechanism.…”

Section: Endothelial Adherens Junction Control By Rho Gtpasessupporting

confidence: 67%

“…We recently showed that binding of the GEF Trio to VE-cadherin is a crucial event to stabilize endothelial cell-cell junctions. 22 Trio displays 2 GEF domains of distinct specificity, enabling activation of multiple Rho GTPases: Rac1, RhoG and RhoA. 23,24 Our findings suggest that by activating Rac1 at junctions, Trio promotes the formation of cortical actin bundles adjacent to the junction, which is concomitant with the stabilization of cell-cell junctions and supports endothelial barrier function.…”

Section: Introductionmentioning

confidence: 79%

“…Subsequent trans-interactions between VE-cadherins from adjacent endothelial cells trigger outside-in signaling resulting in the recruitment of Trio to the intracellular tail of VE-cadherin and a local Trio-mediated activation of Rac1, specifically at the cell-cell junctions. 22 This local Rac1 activity supports reorganization of the actin cytoskeleton in close proximity to the nascent contacts, promoting the switch of FAJs into linear junctions. In this model, Trio facilitates the transition from nascent-to-stable VE-cadherin-based cell-cell junctions and promotes the integrity of the endothelial monolayer.…”

Section: Endothelial Adherens Junction Control By Rho Gtpasesmentioning

confidence: 91%

“…61,62 In addition, Rac1 activation downstream of thrombin promotes reassembly of cell-cell junctions during the endothelial barrier recovery phase. 22,63 To promote (re)assembly of cell-cell junctions, Rac1 induces formation of lamellipodia protrusions. Using a novel FRET-based Rac1 biosensor we observed a global increase of Rac1 activation in these protrusions at the periphery of the endothelial cell.…”

Section: Endothelial Adherens Junction Control By Rho Gtpasesmentioning

confidence: 99%

“…Thus, as was shown for E-, M-and N-cadherin, [64][65][66][67] we showed that VEcadherin can signal in an outside-in fashion to activate Rac1, providing a bidirectional feedback mechanism. 22 Of note, ongoing local remodeling of cell-cell junctions is observed even in apparently stable endothelial monolayers. The involvement of Rac1 in maintenance of the endothelial barrier may, in part, reflect its requirement during cell-cell junction reassembly.…”

Section: Endothelial Adherens Junction Control By Rho Gtpasesmentioning

confidence: 99%

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Small Rho GTPase-mediated actin dynamics at endothelial adherens junctions

Buul

Timmerman

2016

Small GTPases

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VE-cadherin-based cell-cell junctions form the major restrictive barrier of the endothelium to plasma proteins and blood cells. The function of VE-cadherin and the actin cytoskeleton are intimately linked. Vascular permeability factors and adherent leukocytes signal through small Rho GTPases to tightly regulate actin cytoskeletal rearrangements in order to open and re-assemble endothelial cell-cell junctions in a rapid and controlled manner. The Rho GTPases are activated by guanine nucleotide exchange factors (GEFs), conferring specificity and context-dependent control of cell-cell junctions. Although the molecular mechanisms that couple cadherins to actin filaments are beginning to be elucidated, specific stimulus-dependent regulation of the actin cytoskeleton at VEcadherin-based junctions remains unexplained. Accumulating evidence has suggested that depending on the vascular permeability factor and on the subcellular localization of GEFs, cell-cell junction dynamics and organization are differentially regulated by one specific Rho GTPase. In this Commentary, we focus on new insights how the junctional actin cytoskeleton is specifically and locally regulated by Rho GTPases and GEFs in the endothelium.

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Section: Endothelial Adherens Junction Control By Rho Gtpasessupporting

confidence: 67%

Section: Introductionmentioning

confidence: 79%

Section: Endothelial Adherens Junction Control By Rho Gtpasesmentioning

confidence: 91%

Section: Endothelial Adherens Junction Control By Rho Gtpasesmentioning

confidence: 99%

Section: Endothelial Adherens Junction Control By Rho Gtpasesmentioning

confidence: 99%

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Small Rho GTPase-mediated actin dynamics at endothelial adherens junctions

Buul

Timmerman

2016

Small GTPases

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Characterization of Genetically Encoded FRET Biosensors for Rho-Family GTPases

Donnelly

Miskolci

Garrastegui

et al. 2018

Methods in Molecular Biology

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Genetically encoded FRET-based biosensors are increasingly popular and useful tools for examining signaling pathways with high spatial and temporal resolution in living cells. Here, we show basic techniques used to characterize and to validate single-chain, genetically encoded Förster resonance energy transfer (FRET) biosensors of the Rho GTPase-family proteins. Methods described here are generally applicable to other genetically encoded FRET-based biosensors by modifying the tested conditions to include additional/different regulators and inhibitors, as appropriate for the specific protein of interest.

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Recent insights into endothelial control of leukocyte extravasation

Hordijk

2016

Cell. Mol. Life Sci.

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In the process of leukocyte migration from the circulation across the vascular wall, the crosstalk with endothelial cells that line the blood vessels is essential. It is now firmly established that in endothelial cells important signaling events are initiated upon leukocyte adhesion that impinge on the regulation of cell-cell contact and control the efficiency of transendothelial migration. In addition, several external factors such as shear force and vascular stiffness were recently identified as important regulators of endothelial signaling and, consequently, leukocyte transmigration. Here, I review recent insights into endothelial signaling events that are linked to leukocyte migration across the vessel wall. In this field, protein phosphorylation and Rho-mediated cytoskeletal dynamics are still widely studied using increasingly sophisticated mouse models. In addition, activation of tyrosine phosphatases, changes in endothelial cell stiffness as well as different vascular beds have all been established as important factors in endothelial signaling and leukocyte transmigration. Finally, I address less-well-studied but interesting components in the endothelium that also control transendothelial migration, such as the ephrins and their Eph receptors, that provide novel insights in the complexity associated with this process.

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A local VE-cadherin and Trio-based signaling complex stabilizes endothelial junctions through Rac1

Abstract: There was an error published in J. Cell Sci. 128, 3041-3054.The name of Dr Fukuhara was incomplete in the acknowledgements section. The complete acknowledgements section should read as below.

Cited by 51 publications

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Small Rho GTPase-mediated actin dynamics at endothelial adherens junctions

Small Rho GTPase-mediated actin dynamics at endothelial adherens junctions

Characterization of Genetically Encoded FRET Biosensors for Rho-Family GTPases

Recent insights into endothelial control of leukocyte extravasation

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