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

    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.

    Original languageEnglish
    Pages (from-to)3041-54
    Number of pages14
    JournalJournal of Cell Science
    Volume128
    Issue number16
    DOIs
    Publication statusPublished - 15 Aug 2015

    Cite this

    Timmerman, I., Heemskerk, N., Kroon, J., Schaefer, A., van Rijssel, J., Hoogenboezem, M., van Unen, J., Goedhart, J., Gadella, T. W. J., Yin, T., Wu, Y., Huveneers, S., & van Buul, J. D. (2015). A local VE-cadherin and Trio-based signaling complex stabilizes endothelial junctions through Rac1. Journal of Cell Science, 128(16), 3041-54. https://doi.org/10.1242/jcs.168674