The Rho exchange factor Net1 is regulated by nuclear sequestration
The Rho exchange factor Net1 is regulated by nuclear sequestration
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DOI：
10.1074/jbc.m111108200
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发表时间：
2002-04-26
影响因子：
4.8
通讯作者：
Hall, A
中科院分区：
文献类型：
--
作者：
Schmidt, A;Hall, A
Net1是小GTPase Rho特异性的鸟嘌呤核苷酸交换因子。Net1的致癌激活通过截断该蛋白的n端部分发生，该部分作为负调控结构域。在这里，我们研究了Net1通过其N端调控的机制。我们发现Net1定位于细胞核，而致癌的Net1则存在于细胞质中。Net1的核输入是由蛋白N端存在的两个核定位信号介导的，并且Net1的细胞质强制定位足以激活Rho。此外，Net1的pleckstrin同源（PH）结构域作为核输出信号。由于PH结构域中的氨基酸取代抑制鸟嘌呤核苷酸交换因子活性，但不抑制核输出，因此我们得出结论，该PH结构域至少具有两种功能。综上所述，我们的研究结果表明，Net1可以在细胞核内外穿梭，并且Net1对Rho的激活是由其亚细胞定位的变化控制的。
Net1 is a guanine nucleotide exchange factor specific for the small GTPase Rho. Oncogenic activation of Net1 occurs by truncation of the N-terminal part of the protein, which functions as a negative regulatory domain. Here, we have investigated the mechanism of Net1 regulation via its N terminus. We find that Net1 localizes to the nucleus, whereas oncogenic Net1 is found in the cytoplasm. Nuclear import of Net1 is mediated by two nuclear localization signals present in the N terminus of the protein, and forced cytoplasmic localization of Net1 is sufficient to activate Rho. In addition, the pleckstrin homology (PH) domain of Net1 acts as a nuclear export signal. Because an amino acid substitution in the PH domain that inhibits guanine nucleotide exchange factor activity does not inhibit nuclear export, we conclude that this PH domain has at least two functions. Together, our results suggest that Net1 can shuttle in and out of the nucleus, and that activation of Rho by Net1 is controlled by changes in its subcellular localization.