Phosphorylation of VE-cadherin controls endothelial phenotypes via p120-catenin coupling and Rac1 activation
Phosphorylation of VE-cadherin controls endothelial phenotypes via p120-catenin coupling and Rac1 activation
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DOI：
10.1152/ajpheart.00650.2010
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发表时间：
2011-01-01
影响因子：
4.8
通讯作者：
Murakami, Masahiro
中科院分区：
文献类型：
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作者：
Hatanaka, Kunihiko;Simons, Michael;Murakami, Masahiro
Hatanaka K、Simons M、Murakami M。VE-钙粘蛋白的磷酸化通过 p120-连环蛋白偶联和 Rac1 激活控制内皮表型。 Am J Physiol Heart Circ Physiol 300：H162-H172，2011。首次发表于 2010 年 10 月 29 日； doi:10.1152/ajpheart.00650.2010.-为了确定血管内皮 (VE)-钙粘蛋白在内皮细胞功能调节中的作用，我们研究了 VE-钙粘蛋白位点的磷酸化对血管通透性和内皮细胞迁移的影响，该位点试图参与 p120-连环蛋白的结合。为此，我们将野生型VE-钙粘蛋白或Y658磷酸模拟物（Y658E）或去磷模拟物（Y658F）VE-钙粘蛋白突变体构建体引入缺乏内源性VE-钙粘蛋白的内皮细胞系（大鼠脂肪垫内皮细胞）中。值得注意的是，由于p120-连环蛋白优先结合N-钙粘蛋白，野生型和Y658E VE-钙粘蛋白都没有保留在细胞-细胞接触处，导致N-钙粘蛋白靶向细胞-细胞连接并排除VE-钙粘蛋白。然而，Y658F VE-钙粘蛋白能够结合 p120-连环蛋白并定位在粘附连接处，取代 N-钙粘蛋白。这导致屏障功能增强并完全消除 Rac1 激活和片状伪足形成，从而抑制细胞迁移。这些发现表明，VE-钙粘蛋白通过调节 Y658 磷酸化，与 N-钙粘蛋白竞争连接定位，并控制血管通透性和内皮细胞迁移。
Hatanaka K, Simons M, Murakami M. Phosphorylation of VE-cadherin controls endothelial phenotypes via p120-catenin coupling and Rac1 activation. Am J Physiol Heart Circ Physiol 300: H162-H172, 2011. First published October 29, 2010; doi:10.1152/ajpheart.00650.2010.-To establish the role of vascular endothelial (VE)-cadherin in the regulation of endothelial cell functions, we investigated the effect of phosphorylation of a VE-cadherin site sought to be involved in p120-catenin binding on vascular permeability and endothelial cell migration. To this end, we introduced either wild-type VE-cadherin or Y658 phosphomimetic (Y658E) or dephosphomimetic (Y658F) VE-cadherin mutant constructs into an endothelial cell line (rat fat pad endothelial cells) lacking endogenous VE-cadherin. Remarkably, neither wild-type-nor Y658E VE-cadherin was retained at cell-cell contacts because of p120-catenin preferential binding to N-cadherin, resulting in the targeting of N-cadherin to cell-cell junctions and the exclusion of VE-cadherin. However, Y658F VE-cadherin was able to bind p120-catenin and to localize at adherence junctions displacing N-cadherin. This resulted in an enhanced barrier function and a complete abrogation of Rac1 activation and lamellipodia formation, thereby inhibiting cell migration. These findings demonstrate that VE-cadherin, through the regulation of Y658 phosphorylation, competes for junctional localization with N-cadherin and controls vascular permeability and endothelial cell migration.