ZO-1 controls endothelial adherens junctions, cell-cell tension, angiogenesis, and barrier formation.
Bottom Line: ZO-1 depletion led to tight junction disruption, redistribution of active myosin II from junctions to stress fibers, reduced tension on VE-cadherin and loss of junctional mechanotransducers such as vinculin and PAK2, and induced vinculin dissociation from the α-catenin-VE-cadherin complex.Claudin-5 depletion only mimicked ZO-1 effects on barrier formation, whereas the effects on mechanotransducers were rescued by inhibition of ROCK and phenocopied by JAM-A, JACOP, or p114RhoGEF down-regulation.ZO-1 was required for junctional recruitment of JACOP, which, in turn, recruited p114RhoGEF.
Affiliation: Department of Cell Biology, UCL Institute of Ophthalmology, University College London, London EC1V 9EL, England, UK.Show MeSH
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Mentions: We next asked whether these changes resulted in altered tensile force on the junctional complex. We used a FRET biosensor based on VE-cadherin that carries an elastic force sensor within the cytoplasmic domain between the p120 and the β-catenin binding sites (Grashoff et al., 2010; Conway et al., 2013). Fig. 2 (A and B) shows that the sensor was sensitive to the presence of the β-catenin binding site, which indicates that the probe responded to forces that act on VE-cadherin. Depletion of ZO-1 also led to increased FRET efficiency, indicating that the tensile force acting on VE-cadherin was diminished (Fig. 2, A and B). Therefore, reduced ZO-1 expression stimulated a reduction in the tension on VE-cadherin, which suggests that ZO-1 regulates tension on adherens junctions.
Affiliation: Department of Cell Biology, UCL Institute of Ophthalmology, University College London, London EC1V 9EL, England, UK.