Epac1 and PDZ-GEF cooperate in Rap1 mediated endothelial junction control
pmid: 21840392
Epac1 and PDZ-GEF cooperate in Rap1 mediated endothelial junction control
Epac1 and its effector Rap1 are important mediators of cAMP induced tightening of endothelial junctions and consequential increased barrier function. We have investigated the involvement of Rap1 signalling in basal, unstimulated, barrier function of a confluent monolayer of HUVEC using real time Electric Cell-substrate Impedance Sensing. Depletion of Rap1, but not Epac1, results in a strong decrease in barrier function. This decrease is also observed when cells are depleted of the cAMP independent Rap exchange factors PDZ-GEF1 and 2, showing that PDZ-GEFs are responsible for Rap1 activity in control of basal barrier function. Monolayers of cells depleted of PDZ-GEF or Rap1 show an irregular, zipper-like organization of VE-cadherin and live imaging of VE-cadherin-GFP reveals enhanced junction motility upon depletion of PDZ-GEF or Rap1. Importantly, activation of Epac1 increases the formation of cortical actin bundles at the cell-cell junctions, inhibits junction motility and restores barrier function of PDZ-GEFs depleted, but not Rap1 depleted cells. We conclude that PDZ-GEF activates Rap1 under resting conditions to stabilize cell-cell junctions and maintain basal integrity. Activation of Rap1 by cAMP/Epac1 induces junctional actin to further tighten cell-cell contacts.
- Utrecht University Netherlands
- Royal Netherlands Academy of Arts and Sciences (KNAW) Netherlands
- Hubrecht Institute for Developmental Biology and Stem Cell Research Netherlands
- University Medical Center Utrecht Netherlands
- Royal Netherlands Academy of Arts and Sciences Netherlands
ADP Ribose Transferases, Botulinum Toxins, Telomere-Binding Proteins, Nerve Tissue Proteins, Adherens Junctions, Cadherins, Time-Lapse Imaging, Actins, Shelterin Complex, HEK293 Cells, Microscopy, Fluorescence, Antigens, CD, Gene Knockdown Techniques, Cyclic AMP, Electric Impedance, Human Umbilical Vein Endothelial Cells, Guanine Nucleotide Exchange Factors, Humans, RNA Interference, Endothelium, Vascular
ADP Ribose Transferases, Botulinum Toxins, Telomere-Binding Proteins, Nerve Tissue Proteins, Adherens Junctions, Cadherins, Time-Lapse Imaging, Actins, Shelterin Complex, HEK293 Cells, Microscopy, Fluorescence, Antigens, CD, Gene Knockdown Techniques, Cyclic AMP, Electric Impedance, Human Umbilical Vein Endothelial Cells, Guanine Nucleotide Exchange Factors, Humans, RNA Interference, Endothelium, Vascular
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