AmotL2 links VE-cadherin to contractile actin fibres necessary for aortic lumen expansion

Hultin, Sara; Zheng, Yi; Mojallal, Mahdi; Vertuani, Simona; Gentili, Christian; Balland, Martial; Milloud, Rachel; Belting, Heinz‐Georg; Affolter, Markus; Helker, Christian S. M.; Adams, Ralf H.; Herzog, Wiebke; Uhlén, Per; Majumdar, Årindam; Holmgren, Lars

doi:10.1038/ncomms4743

Cited by 66 publications

(94 citation statements)

References 58 publications

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“…Changes in the actin cytoskeleton have a major impact on the morphology and stability of VE-cadherin-based cell-cell junctions (Hultin et al, 2014;Noda et al, 2010;Phng et al, 2015;Sauteur et al, 2014;Schulte et al, 2011), in part by altering the magnitude and direction of the forces that are exerted on cell-cell junctions (Oldenburg and de Rooij, 2014). Distinct types of cell-cell junctions exist depending on the organization of the junctionassociated actin cytoskeleton.…”

Section: Introductionmentioning

confidence: 99%

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

Timmerman

Heemskerk

Kroon

et al. 2015

Journal of Cell Science

111

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Endothelial cell-cell junctions maintain a restrictive barrier that is tightly regulated to allow dynamic responses to permeability-inducing angiogenic factors, as well as to inflammatory agents and adherent leukocytes. The ability of these stimuli to transiently remodel adherens junctions depends on Rho-GTPase-controlled cytoskeletal rearrangements. How the activity of Rho-GTPases is spatio-temporally controlled at endothelial adherens junctions by guanine-nucleotide exchange factors (GEFs) is incompletely understood. Here, we identify a crucial role for the Rho-GEF Trio in stabilizing junctions based around vascular endothelial (VE)-cadherin (also known as CDH5). Trio interacts with VE-cadherin and locally activates Rac1 at adherens junctions during the formation of nascent contacts, as assessed using a novel FRET-based Rac1 biosensor and biochemical assays. The Rac-GEF domain of Trio is responsible for the remodeling of junctional actin from radial into cortical actin bundles, a crucial step for junction stabilization. This promotes the formation of linear adherens junctions and increases endothelial monolayer resistance. Collectively, our data show the importance of spatiotemporal regulation of the actin cytoskeleton through Trio and Rac1 at VE-cadherin-based cell-cell junctions in the maintenance of the endothelial barrier.

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Section: Introductionmentioning

confidence: 99%

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

Timmerman

Heemskerk

Kroon

et al. 2015

Journal of Cell Science

111

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“…Primary antibody diluted in blocking buffer was incubated at room temperature for 1 h. The following commercial antibodies were used; Par3 (1:100, Millipore), Trappc9 (1:25, Genetex), p100 AmotL2, Trappc10 (1:100, 1:50, Santa Cruz Biotechnology), ZO1 ( . Immunoaffinity-purified rabbit polyclonal antibodies against the C-terminal 20 amino acids of human AmotL2 was used in paraffin sections have been previously described (Hultin et al) 18 . For Amotl2, antibodies were also made against the epitope NH2-CQKAPSAVDLFKGVDDVSAE-COOH cross-reactive with human and zebrafish Amotl2.…”

Section: Resultsmentioning

confidence: 99%

“…We have previously shown that each member has a distinct role in blood vessel formation in that Amot controls migration, AmotL1 junction formation and AmotL2 aortic lumen expansion [16][17][18] . Acting as a scaffold protein, AmotL2 and its related proteins associate and join together proteins involved in junction formation, apical polarity and actin cytoskeleton 19 .…”

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confidence: 99%

AmotL2 disrupts apical–basal cell polarity and promotes tumour invasion

et al. 2014

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The establishment and maintenance of apical-basal cell polarity is essential for the functionality of glandular epithelia. Cell polarity is often lost in advanced tumours correlating with acquisition of invasive and malignant properties. Despite extensive knowledge regarding the formation and maintenance of polarity, the mechanisms that deregulate polarity in metastasizing cells remain to be fully characterized. Here we show that AmotL2 expression correlates with loss of tissue architecture in tumours from human breast and colon cancer patients. We further show that hypoxic stress results in activation of c-Fos-dependent expression of AmotL2 leading to loss of polarity. c-Fos/hypoxia-induced p60 AmotL2 interacts with the Crb3 and Par3 polarity complexes retaining them in large vesicles and preventing them from reaching the apical membrane. The resulting loss of polarity potentiates the response to invasive cues in vitro and in vivo in mice. These data provide a molecular mechanism how hypoxic stress deregulates cell polarity during tumour progression.

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“…43 They additionally show that this interaction is required for the opening of the vascular lumen during vascular development. Yamamoto and colleagues revealed the importance of b1-integrins in the stabilization of cell-cell junctions.…”

Section: Introductionmentioning

confidence: 97%

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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AmotL2 links VE-cadherin to contractile actin fibres necessary for aortic lumen expansion

Cited by 66 publications

References 58 publications

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

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

AmotL2 disrupts apical–basal cell polarity and promotes tumour invasion

Small Rho GTPase-mediated actin dynamics at endothelial adherens junctions

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