Rap-afadin axis in control of Rho signaling and endothelial barrier recovery
Year: 2013
Type: article
Abstract: 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.
Source: Molecular Biology of the Cell
Institution: University of Chicago
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: G1002600088, Protective role of ANP in the models of acute lung injury, Molecular control of lung endothelial barrier function in ALI, G364505434, G4254869134, G4377192008, Microtubule-associated regulation of acute lung injury, Microtubule-associated regulation of acute lung injury, Control of lung permeability by oxidized phospholipids
OpenAlex ID: W1965660329