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Role of paxillin isoforms and their tyrosine phosphorylation in cell migration.

桩蛋白亚型及其酪氨酸磷酸化在细胞迁移中的作用。

基本信息

批准号：
10480199
负责人：
SABE Hisataka
金额：
$ 8.45万
依托单位：
OSAKA BIOSCIENCE INSTITUTE(OBI)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

Temporal and spatial regulation of actin-based cytoskeletal organization and focal adhesion formation play an essential role in cell migration. We found that tyrosine phosphorylation of paxillin and pi3OCas was a prominent event upon integrin activation during epithelial-mesenchymal transdifferentiation and cell migration. Tyrosine phosphorylation of p130^<Cas> has been demonstrated to facilitate cell migration. We showed that tyrosine phosphorylation of paxillin cc acts to reduce haptotactic cell migration as well as transcellular invasive activities in several different experimental cell systems, whereas tyrosine phosphorylation of p130^<Cas> exerts opposing effects to those of paxillina. Each of the phosphorylation-null mutant acted as dominant-negatives for each phenotype. Moreover, we found that overexpression of paxillin a reduced the cell saturation density of NMuMG cells while overexpression of pi30^<Cas> increased it. These effects also seemed to be dependent on the tyrosine phosphorylation events. Cell growth rates and morphologies at growing phases were not significantly altered, nor were cells transformed. Addition of epidermal growth factor increased saturation density of the paxillin α-overexpressing cells, while no further increment was observed in p130^<Cas>-overexpressing cells. We propose that tyrosine phosphorylation of paxillin a and p130^<Cas> exert opposing effects on several integrin-mediated cellular events, possibly through different signaling pathways. We also found that paxillin binds to several ARFGAPs. ARFGAPs are regulators of intracellular membrane trafficking. We currently analysing role of paxillin from aspects of its tyrosine phosphorylation and its interaction with ARFGAPs, in regulation of cell migratory activity.

基于肌动蛋白的细胞骨架组织和粘着斑形成的时空调节在细胞迁移中起重要作用。我们发现桩蛋白和pi 3 OCas的酪氨酸磷酸化是上皮-间充质转分化和细胞迁移过程中整合素活化的突出事件。已经证明p130的酪氨酸磷酸化<Cas>促进细胞迁移。我们发现，在几种不同的实验细胞系统中，桩蛋白α的酪氨酸磷酸化作用于减少趋触细胞迁移以及跨细胞侵袭活性，而p130 α的酪氨酸磷酸化作用<Cas>与桩蛋白α相反。每个磷酸化无效突变体作为显性阴性的每一个表型。此外，我们发现paxillin a过表达降低了NMuMG细胞的细胞饱和密度，而pi 30 α过表达<Cas>增加了细胞饱和密度，这些作用似乎也依赖于酪氨酸磷酸化事件。细胞生长速率和生长阶段的形态没有显著改变，也没有细胞转化。加入表皮生长因子可增加桩蛋白α过表达细胞的饱和密度，而在p130^ -过表达细胞中没有观察到进一步的增加<Cas>。我们认为桩蛋白a和p130的酪氨酸磷酸化可能<Cas>通过不同的信号通路对几种整合素介导的细胞事件产生相反的作用。我们还发现桩蛋白与几种ARFGAP结合。ARFGAP是细胞内膜运输的调节剂。目前，我们从其酪氨酸磷酸化及其与ARFGAP的相互作用方面分析桩蛋白在细胞迁移活动中的调节作用。