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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actomyosin / metabolism
  • Adherens Junctions / metabolism*
  • Animals
  • Antigens, CD / metabolism
  • Cadherins / metabolism
  • Capillary Permeability*
  • Cell Adhesion Molecules / metabolism
  • Cell Movement
  • Cells, Cultured
  • Claudin-5 / metabolism
  • Cytoskeletal Proteins / metabolism
  • Cytoskeleton / metabolism
  • Endothelial Cells / physiology*
  • Humans
  • Mechanotransduction, Cellular
  • Mice, Inbred C57BL
  • Myosins / metabolism
  • Neovascularization, Physiologic*
  • Protein Transport
  • Receptors, Cell Surface / metabolism
  • Tight Junctions / metabolism
  • Zonula Occludens-1 Protein / physiology*

Substances

  • Antigens, CD
  • CGNL1 protein, human
  • CLDN5 protein, human
  • Cadherins
  • Cell Adhesion Molecules
  • Claudin-5
  • Cytoskeletal Proteins
  • F11R protein, human
  • Receptors, Cell Surface
  • TJP1 protein, human
  • Zonula Occludens-1 Protein
  • cadherin 5
  • Actomyosin
  • Myosins