1. N-cadherin signaling via Trio assembles adherens junctions to restrict endothelial permeability.
- Author
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Kruse K, Lee QS, Sun Y, Klomp J, Yang X, Huang F, Sun MY, Zhao S, Hong Z, Vogel SM, Shin JW, Leckband DE, Tai LM, Malik AB, and Komarova YA
- Subjects
- Adherens Junctions ultrastructure, Animals, Antigens, CD genetics, Antigens, CD metabolism, Aorta cytology, Aorta metabolism, Brain cytology, Brain metabolism, Cadherins deficiency, Cadherins metabolism, Endothelial Cells ultrastructure, Female, Gene Expression Regulation, Guanine Nucleotide Exchange Factors metabolism, Humans, Lung cytology, Lung metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Neuropeptides genetics, Neuropeptides metabolism, Pericytes ultrastructure, Permeability, Phosphoproteins metabolism, Primary Cell Culture, Protein Serine-Threonine Kinases metabolism, Signal Transduction, rac1 GTP-Binding Protein genetics, rac1 GTP-Binding Protein metabolism, rho GTP-Binding Proteins genetics, rho GTP-Binding Proteins metabolism, rhoA GTP-Binding Protein, Adherens Junctions metabolism, Cadherins genetics, Endothelial Cells metabolism, Guanine Nucleotide Exchange Factors genetics, Pericytes metabolism, Phosphoproteins genetics, Protein Serine-Threonine Kinases genetics
- Abstract
Vascular endothelial (VE)-cadherin forms homotypic adherens junctions (AJs) in the endothelium, whereas N-cadherin forms heterotypic adhesion between endothelial cells and surrounding vascular smooth muscle cells and pericytes. Here we addressed the question whether both cadherin adhesion complexes communicate through intracellular signaling and contribute to the integrity of the endothelial barrier. We demonstrated that deletion of N-cadherin ( Cdh2 ) in either endothelial cells or pericytes increases junctional endothelial permeability in lung and brain secondary to reduced accumulation of VE-cadherin at AJs. N-cadherin functions by increasing the rate of VE-cadherin recruitment to AJs and induces the assembly of VE-cadherin junctions. We identified the dual Rac1/RhoA Rho guanine nucleotide exchange factor (GEF) Trio as a critical component of the N-cadherin adhesion complex, which activates both Rac1 and RhoA signaling pathways at AJs. Trio GEF1-mediated Rac1 activation induces the recruitment of VE-cadherin to AJs, whereas Trio GEF2-mediated RhoA activation increases intracellular tension and reinforces Rac1 activation to promote assembly of VE-cadherin junctions and thereby establish the characteristic restrictive endothelial barrier., (© 2018 Kruse et al.)
- Published
- 2019
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