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Epac1 和 PDZ-GEF 在 Rap1 介导的内皮细胞连接控制中协同作用。

Epac1 and PDZ-GEF cooperate in Rap1 mediated endothelial junction control.

机构信息

Molecular Cancer Research, Centre of Biomedical Genetics and Cancer Genomics Centre, University Medical Center Utrecht, Utrecht, The Netherlands.

出版信息

Cell Signal. 2011 Dec;23(12):2056-64. doi: 10.1016/j.cellsig.2011.07.022. Epub 2011 Aug 4.

Abstract

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.

摘要

Epac1 和其效应因子 Rap1 是 cAMP 诱导的内皮细胞紧密连接和随后增加的屏障功能的重要介质。我们使用实时电细胞-基质阻抗传感技术研究了 Rap1 信号通路在人脐静脉内皮细胞(HUVEC)单层细胞紧密连接和基础屏障功能中的作用。Rap1 的耗竭导致屏障功能明显下降,但 Epac1 的耗竭则不会。当细胞耗尽 cAMP 独立的 Rap 交换因子 PDZ-GEF1 和 2 时,也观察到这种下降,这表明 PDZ-GEFs 负责控制基础屏障功能的 Rap1 活性。耗尽 PDZ-GEF 或 Rap1 的细胞单层表现出 VE-钙粘蛋白的不规则、拉链样组织,活细胞成像显示 VE-钙粘蛋白-GFP 的连接运动在 PDZ-GEF 或 Rap1 耗尽时增强。重要的是,Epac1 的激活增加了细胞连接处皮质肌动蛋白束的形成,抑制了连接运动,并恢复了 PDZ-GEF 耗尽但不消耗 Rap1 耗尽的细胞的屏障功能。我们得出结论,PDZ-GEF 在静息状态下激活 Rap1 以稳定细胞-细胞连接并维持基础完整性。cAMP/Epac1 激活 Rap1 诱导细胞连接处的肌动蛋白进一步收紧细胞-细胞接触。

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