A local VE-cadherin and Trio-based signaling complex stabilizes endothelial junctions through Rac1

Ilse Timmerman, Niels Heemskerk, Jeffrey Kroon, Antje Schaefer, Jos van Rijssel, Mark Hoogenboezem, Jakobus van Unen, Joachim Goedhart, Theodorus W J Gadella, Taofei Yin, Yi Wu, Stephan Huveneers, Jaap D van Buul

    Research output: Contribution to journalArticleAcademicpeer-review


    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.

    Original languageEnglish
    Pages (from-to)3041-54
    Number of pages14
    JournalJournal of Cell Science
    Issue number16
    Publication statusPublished - 15 Aug 2015

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