A novel and evolutionarily conserved PtdIns(3,4,5)P3-binding domain is necessary for DOCK180 signalling
A novel and evolutionarily conserved PtdIns(3,4,5)P3-binding domain is necessary for DOCK180 signalling
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DOI：
10.1038/ncb1280
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发表时间：
2005-08-01
影响因子：
21.3
通讯作者：
Vuori, K
中科院分区：
文献类型：
--
作者：
Côté, JF;Motoyama, AB;Vuori, K
进化上保守的DOCK 180蛋白通过其DOCK同源区（DHR）-2结构域作为Rac GT3的交换因子在细胞迁移中具有不可或缺的作用。我们在这里报告说，保守的DHR-1结构域也有一个重要的信号作用。缺乏DHR-1的DOCK 180的形式不能促进细胞迁移，尽管它能够诱导Rac GTP负载。DHR-1结构域在体外和体内与PtdIns（3，4，5）P-3相互作用，并介导DOCK 180信号传导复合物在细胞前缘PtdIns（3，4，5）P-3积累位点的定位。其中DHR-1结构域已被典型的PtdIns（3，4，5）P-3结合普列克底物蛋白同源结构域取代的DOCK 180形式在诱导细胞伸长和迁移方面具有完全功能，表明DHR-1的主要功能是结合PtdIns（3，4，5）P-3。这些结果表明，DOCK 180通过其DHR-1和DHR-2结构域将PtdIns（3，4，5）P-3信号传导偶联到Rac GTP-负载，这对于定向细胞运动是必需的。
The evolutionarily conserved DOCK180 protein has an indispensable role in cell migration by functioning as an exchange factor for Rac GTPase via its DOCK homology region (DHR)-2 domain. We report here that the conserved DHR-1 domain also has an important signalling role. A form of DOCK180 that lacks DHR-1 fails to promote cell migration, although it is capable of inducing Rac GTP-loading. The DHR-1 domain interacts with PtdIns(3,4,5)P-3 in vitro and in vivo, and mediates the DOCK180 signalling complex localization at sites of PtdIns(3,4,5)P-3 accumulation in the cell's leading edge. A form of DOCK180 in which the DHR-1 domain has been replaced by a canonical PtdIns(3,4,5)P-3-binding pleckstrin homology domain is fully functional at inducing cell elongation and migration, suggesting that the main function of DHR-1 is to bind PtdIns(3,4,5)P-3. These results demonstrate that DOCK180, via its DHR-1 and DHR-2 domains, couples PtdIns(3,4,5)P-3 signalling to Rac GTP-loading, which is essential for directional cell movement.