Dual roles of tight junction-associated protein, Zonula Occludens-1, in sphingosine 1-phosphate-mediated endothelial chemotaxis and barrier integrity
Dual roles of tight junction-associated protein, Zonula Occludens-1, in sphingosine 1-phosphate-mediated endothelial chemotaxis and barrier integrity
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DOI：
10.1074/jbc.m604310200
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发表时间：
2006-09-29
影响因子：
4.8
通讯作者：
Lee, Menq-Jer
中科院分区：
文献类型：
--
作者：
Lee, Jen-Fu;Zeng, Qun;Lee, Menq-Jer
在本报告中，鞘氨醇-1-磷酸（S1P）是一种血清性生物活性脂质，被证明可以激活紧密连接相关蛋白Zonula occluden -1 (ZO-1)，这反过来在调节内皮趋化性和屏障完整性中起关键作用。S1P刺激后，ZO-1通过S1P1/G(i)/Akt/Rac通路重新分布到板足和细胞-细胞连接处。同样，通过G(i)/Akt/Rac通路，s1p处理的细胞内皮屏障完整性和细胞运动性均显著增强。重要的是，在ZO-1敲低的细胞中，sp1增强的屏障完整性和细胞迁移被取消，这表明ZO-1在这些过程中在功能上是不可或缺的。为了研究潜在的机制，我们证明了接触在s1p诱导的ZO-1再分配到板足中起关键作用。此外，S1P显著诱导内皮紧密连接的形成。ZO-1和α -连环蛋白多肽在s1p诱导的连接结构中共定位；然而，在这些区域未观察到接触。综上所述，这些结果表明S1P诱导形成两种不同的ZO-1复合物来调节两种不同的内皮功能：调节趋化反应的ZO-1/皮质复合物和调节内皮屏障完整性的ZO-1/ α -连环蛋白复合物。这两种ZO-1复合物的协同作用可能协调了血管内皮细胞中两种重要的s1p介导的功能，即迁移和屏障完整性。
In this report, sphingosine-1-phosphate (S1P), a serum-borne bioactive lipid, is shown to activate tight-junction-associated protein Zonula Occludens-1 (ZO-1), which in turn plays a critical role in regulating endothelial chemotaxis and barrier integrity. After S1P stimulation, ZO-1 was redistributed to the lamellipodia and cell-cell junctions via the S1P1/G(i)/Akt/Rac pathway. Similarly, both endothelial barrier integrity and cell motility were significantly enhanced in S1P-treated cells through the G(i)/Akt/Rac pathway. Importantly, S1P-enhanced barrier integrity and cell migration were abrogated in ZO-1 knockdown cells, indicating ZO-1 is functionally indispensable for these processes. To investigate the underlying mechanisms, we demonstrated that cortactin plays a critical role in S1P-induced ZO-1 redistribution to the lamellipodia. In addition, S1P significantly induced the formation of endothelial tight junctions. ZO-1 and alpha-catenin polypeptides were colocalized in S1P-induced junctional structures; whereas, cortactin was not observed in these regions. Together, these results suggest that S1P induces the formation of two distinct ZO-1 complexes to regulate two different endothelial functions: ZO-1/cortactin complexes to regulate chemotactic response and ZO-1/alpha-catenin complexes to regulate endothelial barrier integrity. The concerted operation of these two ZO-1 complexes may coordinate two important S1P-mediated functions, i.e. migration and barrier integrity, in vascular endothelial cells.