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J Cell Biol. 2015 Mar 16;208(6):821-38. doi: 10.1083/jcb.201404140. Epub 2015 Mar 9.

ZO-1 controls endothelial adherens junctions, cell-cell tension, angiogenesis, and barrier formation.

Author information

1
Department of Cell Biology, UCL Institute of Ophthalmology, University College London, London EC1V 9EL, England, UK.
2
National Heart and Lung Institute (NHLI) Vascular Sciences Unit, Imperial Centre for Translational and Experimental Medicine (ICTEM), Hammersmith Hospital, Imperial College London, London W12 0NN, England, UK.
3
Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA 23284.
4
Department of Medicine and Department of Cell Biology, Yale University, New Haven, CT 06520 Department of Medicine and Department of Cell Biology, Yale University, New Haven, CT 06520.
5
Department of Cell Biology, UCL Institute of Ophthalmology, University College London, London EC1V 9EL, England, UK m.balda@ucl.ac.uk.

Abstract

Intercellular junctions are crucial for mechanotransduction, but whether tight junctions contribute to the regulation of cell-cell tension and adherens junctions is unknown. Here, we demonstrate that the tight junction protein ZO-1 regulates tension acting on VE-cadherin-based adherens junctions, cell migration, and barrier formation of primary endothelial cells, as well as angiogenesis in vitro and in vivo. 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. ZO-1 is thus a central regulator of VE-cadherin-dependent endothelial junctions that orchestrates the spatial actomyosin organization, tuning cell-cell tension, migration, angiogenesis, and barrier formation.

PMID:
25753039
PMCID:
PMC4362456
DOI:
10.1083/jcb.201404140
[Indexed for MEDLINE]
Free PMC Article

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