Abstract
Endothelial cell-cell junctions maintain a restrictive barrier that is tightly regulated to allow dynamic responses to permeability-inducing angiogenic factors as well as inflammatory agents and adherent leukocytes. The ability of these stimuli to transiently remodel adherens junctions (AJs) depends on Rho-GTPase-controlled cytoskeletal rearrangements. How activity of Rho-GTPases is spatio-temporally controlled at endothelial AJs by guanine-nucleotide exchange factors (GEFs) is incompletely understood. Here, we identify a crucial role for the Rho-GEF Trio in stabilizing VE-cadherin-based junctions. Trio interacts with VE-cadherin and locally activates Rac1 at AJs during nascent contact formation, assessed using a novel FRET-based Rac1 biosensor and biochemical assays. The Rac-GEF domain of Trio is responsible for remodeling of junctional actin from radial to cortical actin bundles, a critical step for junction stabilization. This promotes the formation of linear AJs and increases endothelial monolayer resistance. Collectively, our data show the importance of spatio-temporal regulation of the actin cytoskeleton through Trio and Rac1 at VE-cadherin-based cell-cell junctions to maintain the endothelial barrier.
Original language | English |
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Pages (from-to) | 3041-3054 |
Number of pages | 14 |
Journal | Journal of Cell Science |
Volume | 128 |
Issue number | 16 |
Early online date | 26 Jun 2015 |
DOIs | |
Publication status | Published - 15 Aug 2015 |
Keywords
- Actin Cytoskeleton/genetics
- Antigens, CD/genetics
- Cadherins/genetics
- Capillary Permeability/genetics
- Endothelial Cells/metabolism
- Endothelium, Vascular/metabolism
- GTP Phosphohydrolases/metabolism
- Guanine Nucleotide Exchange Factors/genetics
- Human Umbilical Vein Endothelial Cells
- Humans
- Intercellular Junctions/genetics
- Protein-Serine-Threonine Kinases/genetics
- Signal Transduction/genetics
- rac1 GTP-Binding Protein/genetics