1. A local VE-cadherin and Trio-based signaling complex stabilizes endothelial junctions through Rac1
- Author
-
Ilse Timmerman, Jeffrey Kroon, Niels Heemskerk, Yi I. Wu, Jakobus van Unen, Jos van Rijssel, Antje Schaefer, Theodorus W. J. Gadella, Joachim Goedhart, Taofei Yin, Mark Hoogenboezem, Jaap D. van Buul, Stephan Huveneers, CCA - Immuno-pathogenesis, Faculteit der Geneeskunde, Molecular Cytology (SILS, FNWI), and Landsteiner Laboratory
- Subjects
rac1 GTP-Binding Protein ,Cell ,RAC1 ,Protein Serine-Threonine Kinases ,Biology ,Cell junction ,GTP Phosphohydrolases ,Capillary Permeability ,Adherens junction ,Endothelial barrier ,Antigens, CD ,Human Umbilical Vein Endothelial Cells ,medicine ,Guanine Nucleotide Exchange Factors ,Humans ,Cytoskeleton ,Molecular Biology ,Actin ,Cadherin ,Endothelial Cells ,Correction ,Cell Biology ,Cadherins ,Actin cytoskeleton ,Cell biology ,Actin Cytoskeleton ,Intercellular Junctions ,medicine.anatomical_structure ,Förster resonance energy transfer ,Endothelium, Vascular ,VE-cadherin ,Signal Transduction ,Developmental Biology - 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 to inflammatory agents and adherent leukocytes. The ability of these stimuli to transiently remodel adherens junctions depends on Rho-GTPase-controlled cytoskeletal rearrangements. How the activity of Rho-GTPases is spatio-temporally controlled at endothelial adherens junctions by guanine-nucleotide exchange factors (GEFs) is incompletely understood. Here, we identify a crucial role for the Rho-GEF Trio in stabilizing junctions based around vascular endothelial (VE)-cadherin (also known as CDH5). Trio interacts with VE-cadherin and locally activates Rac1 at adherens junctions during the formation of nascent contacts, as assessed using a novel FRET-based Rac1 biosensor and biochemical assays. The Rac-GEF domain of Trio is responsible for the remodeling of junctional actin from radial into cortical actin bundles, a crucial step for junction stabilization. This promotes the formation of linear adherens junctions 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 in the maintenance of the endothelial barrier.
- Published
- 2015