RT Journal Article
SR Electronic
T1 A local VE-cadherin and Trio-based signaling complex stabilizes endothelial junctions through Rac1
JF Journal of Cell Science
JO J. Cell Sci.
FD The Company of Biologists Ltd
SP 3041
OP 3054
DO 10.1242/jcs.168674
VO 128
IS 16
A1 Timmerman, Ilse
A1 Heemskerk, Niels
A1 Kroon, Jeffrey
A1 Schaefer, Antje
A1 van Rijssel, Jos
A1 Hoogenboezem, Mark
A1 van Unen, Jakobus
A1 Goedhart, Joachim
A1 Gadella, Theodorus W. J.
A1 Yin, Taofei
A1 Wu, Yi
A1 Huveneers, Stephan
A1 van Buul, Jaap D.
YR 2015
UL http://jcs.biologists.org/content/128/16/3041.abstract
AB 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.