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首页> 外文期刊>American Journal of Physiology >Role of VASP in reestablishment of epithelial tight junction assembly after Ca2+ switch.
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Role of VASP in reestablishment of epithelial tight junction assembly after Ca2+ switch.

机译：VASP在Ca2 +转换后重建上皮紧密连接组件中的作用。

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摘要

Epithelial permeability is tightly regulated by intracellular messengers. Critical to maintaining barrier integrity is the formation of tight junction complexes. A number of signaling pathways have been implicated in tight junction biogenesis; however, the precise molecular mechanisms are not fully understood. A growing body of evidence suggests a role for intracellular cAMP in tight junction assembly. Using an epithelial model, we investigated the role of cAMP signal transduction in barrier recovery after Ca2+ switch. Our data demonstrate that elevation of intracellular cAMP levels significantly enhanced barrier recovery after Ca2+ switch. Parallel experiments revealed that epithelial barrier recovery is diminished by H-89, a specific and potent inhibitor of cAMP-dependent protein kinase (protein kinase A) activity. Of the possible PKA effector proteins, the vasodilator-stimulated phosphoprotein (VASP) is an attractive candidate, since it has been implicated in actin-binding and cross-linking functions. We therefore hypothesized that VASP may play a role in the cAMP-mediated regulation of epithelial junctional reassembly after Ca2+ switch. We demonstrate here that VASP is phosphorylated via a PKA-dependent process under conditions that enhance barrier recovery. Confocal laser scanning microscopy studies revealed that VASP localizes with ZO-1 at the tight junction and at cell-cell borders and that phospho-VASP appears at the junction after Ca2+ switch. Subsequent transfection studies utilizing epithelial cells expressing truncated forms of VASP abnormal in oligomerization or actin-binding activity revealed a functional diminution of barrier recovery after Ca2+ chelation. Our present studies suggest that VASP may provide a link between cAMP signal transduction and epithelial permeability.
机译：上皮通透性由细胞内信使严格调节。保持势垒完整性的关键是紧密连接复合物的形成。紧密连接的生物发生涉及许多信号传导途径。但是，确切的分子机制尚未完全了解。越来越多的证据表明细胞内cAMP在紧密连接装配中的作用。使用上皮模型，我们研究了cAMP信号转导在Ca2 +转换后在屏障恢复中的作用。我们的数据表明细胞内cAMP水平的升高显着增强了Ca2 +转换后的屏障恢复。并行实验表明，H-89是一种特异性且有效的cAMP依赖性蛋白激酶（蛋白激酶A）活性抑制剂，可减少上皮屏障的恢复。在可能的PKA效应蛋白中，血管舒张剂刺激的磷蛋白（VASP）是诱人的候选物，因为它与肌动蛋白的结合和交联功能有关。因此，我们假设VASP可能在Ca2 +转换后在cAMP介导的上皮连接重组中发挥作用。我们在这里证明VASP通过PKA依赖过程在增强屏障恢复的条件下被磷酸化。共聚焦激光扫描显微镜研究表明，VASP在紧密连接处和细胞边界处定位于ZO-1，并且磷酸钙-VASP在Ca2 +转换后出现在连接处。随后的转染研究利用上皮细胞表达寡聚化或肌动蛋白结合活性异常的截短形式的VASP，揭示了Ca2 +螯合后屏障恢复的功能减弱。我们目前的研究表明VASP可能提供cAMP信号转导和上皮通透性之间的联系。

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