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Rap-afadin axis in control of Rho signaling and endothelial barrier recovery
Activation of the Rho GTPase pathway determines endothelial cell (EC) hyperpermeability after injurious stimuli. To date, feedback mechanisms of Rho down-regulation critical for barrier restoration remain poorly understood. We tested a hypothesis that Rho down-regulation and barrier recovery of agon...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756920/ https://www.ncbi.nlm.nih.gov/pubmed/23864716 http://dx.doi.org/10.1091/mbc.E13-02-0098 |
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author | Birukova, Anna A. Tian, Xinyong Tian, Yufeng Higginbotham, Katherine Birukov, Konstantin G. |
author_facet | Birukova, Anna A. Tian, Xinyong Tian, Yufeng Higginbotham, Katherine Birukov, Konstantin G. |
author_sort | Birukova, Anna A. |
collection | PubMed |
description | Activation of the Rho GTPase pathway determines endothelial cell (EC) hyperpermeability after injurious stimuli. To date, feedback mechanisms of Rho down-regulation critical for barrier restoration remain poorly understood. We tested a hypothesis that Rho down-regulation and barrier recovery of agonist-stimulated ECs is mediated by the Ras family GTPase Rap1. Thrombin-induced EC permeability driven by rapid activation of the Rho GTPase pathway was followed by Src kinase–dependent phosphorylation of the Rap1-specific guanine nucleotide exchange factor (GEF) C3G, activation of Rap1, and initiation of EC barrier recovery. Knockdown experiments showed that Rap1 activation was essential for down-regulation of Rho signaling and actin stress fiber dissolution. Rap1 activation also enhanced interaction between adherens junction (AJ) proteins VE-cadherin and p120-catenin and stimulated AJ reannealing mediated by the Rap1 effector afadin. This mechanism also included Rap1-dependent membrane translocation of the Rac1-specific GEF Tiam1 and activation of Rac1-dependent peripheral cytoskeletal dynamics, leading to resealing of intercellular gaps. These data demonstrate that activation of the Rap1-afadin axis is a physiological mechanism driving restoration of barrier integrity in agonist-stimulated EC monolayers via negative-feedback regulation of Rho signaling, stimulation of actin peripheral dynamics, and reestablishment of cell–cell adhesive complexes. |
format | Online Article Text |
id | pubmed-3756920 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-37569202013-11-16 Rap-afadin axis in control of Rho signaling and endothelial barrier recovery Birukova, Anna A. Tian, Xinyong Tian, Yufeng Higginbotham, Katherine Birukov, Konstantin G. Mol Biol Cell Articles Activation of the Rho GTPase pathway determines endothelial cell (EC) hyperpermeability after injurious stimuli. To date, feedback mechanisms of Rho down-regulation critical for barrier restoration remain poorly understood. We tested a hypothesis that Rho down-regulation and barrier recovery of agonist-stimulated ECs is mediated by the Ras family GTPase Rap1. Thrombin-induced EC permeability driven by rapid activation of the Rho GTPase pathway was followed by Src kinase–dependent phosphorylation of the Rap1-specific guanine nucleotide exchange factor (GEF) C3G, activation of Rap1, and initiation of EC barrier recovery. Knockdown experiments showed that Rap1 activation was essential for down-regulation of Rho signaling and actin stress fiber dissolution. Rap1 activation also enhanced interaction between adherens junction (AJ) proteins VE-cadherin and p120-catenin and stimulated AJ reannealing mediated by the Rap1 effector afadin. This mechanism also included Rap1-dependent membrane translocation of the Rac1-specific GEF Tiam1 and activation of Rac1-dependent peripheral cytoskeletal dynamics, leading to resealing of intercellular gaps. These data demonstrate that activation of the Rap1-afadin axis is a physiological mechanism driving restoration of barrier integrity in agonist-stimulated EC monolayers via negative-feedback regulation of Rho signaling, stimulation of actin peripheral dynamics, and reestablishment of cell–cell adhesive complexes. The American Society for Cell Biology 2013-09-01 /pmc/articles/PMC3756920/ /pubmed/23864716 http://dx.doi.org/10.1091/mbc.E13-02-0098 Text en © 2013 Birukova et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology. |
spellingShingle | Articles Birukova, Anna A. Tian, Xinyong Tian, Yufeng Higginbotham, Katherine Birukov, Konstantin G. Rap-afadin axis in control of Rho signaling and endothelial barrier recovery |
title | Rap-afadin axis in control of Rho signaling and endothelial barrier recovery |
title_full | Rap-afadin axis in control of Rho signaling and endothelial barrier recovery |
title_fullStr | Rap-afadin axis in control of Rho signaling and endothelial barrier recovery |
title_full_unstemmed | Rap-afadin axis in control of Rho signaling and endothelial barrier recovery |
title_short | Rap-afadin axis in control of Rho signaling and endothelial barrier recovery |
title_sort | rap-afadin axis in control of rho signaling and endothelial barrier recovery |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756920/ https://www.ncbi.nlm.nih.gov/pubmed/23864716 http://dx.doi.org/10.1091/mbc.E13-02-0098 |
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