Tuberin activates and controls the distribution of Rac1 via association with p62 and ubiquitin through the mTORC1 signaling pathway
Tuberin activates and controls the distribution of Rac1 via association with p62 and ubiquitin through the mTORC1 signaling pathway
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DOI：
10.3892/ijo.2013.1984
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发表时间：
2013-08-01
影响因子：
5.2
通讯作者：
Hino, Okio
中科院分区：
文献类型：
--
作者：
Okura, Hidehiro;Kobayashi, Toshiyuki;Hino, Okio
最近的研究表明，结节性硬化症2（TSC 2）基因产物--结节素调节Rac 1活性。然而，迄今为止，块茎素调节Rac 1活性的潜在机制尚未明确阐明。为了更好地了解块茎蛋白功能和Rac 1之间的分子联系，我们使用野生型块茎蛋白的恢复实验来表征Rac 1在小鼠Tsc 2缺陷肾肿瘤细胞中的活性和分布。Rac 1活性显着高于tuberin表达细胞与对照Tsc 2缺陷细胞。此外，Rac 1激活诱导雷帕霉素治疗或敲低的raptor，但不是rictor，在Tsc 2缺陷细胞，表明mTORC 1是一个上游负调节Rac 1。有趣的是，Rac 1似乎在Tsc 2缺陷细胞中形成细胞质点，但在表达tuberin的细胞中不形成，并且由于雷帕霉素处理分散了这些点，因此怀疑点形成中涉及异常mTOR复合物1（mTORC 1）活化。此外，点与p62/螯合体-1和ubiquitin共定位。这些发现意味着Rac 1的分布和/或其降解可能是通过mTORC 1信号通路调控的块茎素。
Recent studies indicated that the tuberous sclerosis 2 (TSC2) gene product, tuberin, regulates Rac1 activity. However, the underlying mechanism by which tuberin regulates Rac1 activity has not been clearly elucidated to date. To better understand the molecular link between tuberin function and Rac1, we characterized the activity and distribution of Rac1 in mouse Tsc2-deficient renal tumor cells using restoration experiments with wild-type tuberin. Rac1 activity was significantly higher in tuberin-expressing cells compared with control Tsc2-deficient cells. Further, Rac1 activation was induced by rapamycin treatment or knockdown of raptor, but not rictor, in Tsc2-deficient cells, indicating that mTORC1 is an upstream negative regulator of Rac1. Intriguingly, Rac1 appeared to form cytoplasmic dots in Tsc2-deficient cells, but not in tuberin-expressing and since rapamycin treatment dispersed these dots, involvement of aberrant mTOR complex 1 (mTORC1) activation in the dot formation was suspected. Moreover, the dots were co-localized with p62/sequestosome-1 and ubiquitin. These findings imply that Rac1 distribution and/or its degradation may be regulated by tuberin through the mTORC1 signaling pathway.