期刊
JOURNAL OF CELL BIOLOGY
卷 208, 期 6, 页码 821-838出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201404140
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资金
- Medical Research Council [G0900098]
- Wellcome Trust [099173/Z/12/Z]
- Biotechnology and Biological Sciences Research Council [BB/J015032/1, BB/L007584/1]
- National Institutes of Health grant [RO1 HL75092]
- Biotechnology and Biological Sciences Research Council [BB/H002294/1, BB/L007584/1, BB/J015032/1] Funding Source: researchfish
- British Heart Foundation [RG/11/17/29256] Funding Source: researchfish
- Medical Research Council [G0400678, G0900098] Funding Source: researchfish
- BBSRC [BB/H002294/1, BB/L007584/1, BB/J015032/1] Funding Source: UKRI
- MRC [G0900098, G0400678] Funding Source: UKRI
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 alpha-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.
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