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 language | English |
|---|---|
| Pages (from-to) | 3041-54 |
| Number of pages | 14 |
| Journal | Journal of Cell Science |
| Volume | 128 |
| Issue number | 16 |
| DOIs | |
| Publication status | Published - 15 Aug 2015 |
Cite this
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A local VE-cadherin and Trio-based signaling complex stabilizes endothelial junctions through Rac1. / Timmerman, Ilse; Heemskerk, Niels; Kroon, Jeffrey; Schaefer, Antje; van Rijssel, Jos; Hoogenboezem, Mark; van Unen, Jakobus; Goedhart, Joachim; Gadella, Theodorus W J; Yin, Taofei; Wu, Yi; Huveneers, Stephan; van Buul, Jaap D.
In: Journal of Cell Science, Vol. 128, No. 16, 15.08.2015, p. 3041-54.Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - A local VE-cadherin and Trio-based signaling complex stabilizes endothelial junctions through Rac1
AU - Timmerman, Ilse
AU - Heemskerk, Niels
AU - Kroon, Jeffrey
AU - Schaefer, Antje
AU - van Rijssel, Jos
AU - Hoogenboezem, Mark
AU - van Unen, Jakobus
AU - Goedhart, Joachim
AU - Gadella, Theodorus W J
AU - Yin, Taofei
AU - Wu, Yi
AU - Huveneers, Stephan
AU - van Buul, Jaap D
N1 - © 2015. Published by The Company of Biologists Ltd.
PY - 2015/8/15
Y1 - 2015/8/15
N2 - 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.
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.
KW - Actin Cytoskeleton/genetics
KW - Antigens, CD/genetics
KW - Cadherins/genetics
KW - Capillary Permeability/genetics
KW - Endothelial Cells/metabolism
KW - Endothelium, Vascular/metabolism
KW - GTP Phosphohydrolases/metabolism
KW - Guanine Nucleotide Exchange Factors/genetics
KW - Human Umbilical Vein Endothelial Cells
KW - Humans
KW - Intercellular Junctions/genetics
KW - Protein-Serine-Threonine Kinases/genetics
KW - Signal Transduction/genetics
KW - rac1 GTP-Binding Protein/genetics
U2 - 10.1242/jcs.168674
DO - 10.1242/jcs.168674
M3 - Article
VL - 128
SP - 3041
EP - 3054
JO - Journal of Cell Science
JF - Journal of Cell Science
SN - 0021-9533
IS - 16
ER -