Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling
Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling
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DOI：
10.1101/gad.1110003
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发表时间：
2003-08-01
影响因子：
10.5
通讯作者：
Guan, KL
中科院分区：
文献类型：
--
作者：
Inoki, K;Li, Y;Guan, KL
多发性硬化症（TSC）是一种由TSC 1或TSC 2突变引起的遗传性疾病。TSC 1和TSC 2基因产物形成功能复合物并抑制S6 K和4 EBP 1的磷酸化。TSC 1/TSC 2的这些功能可能由mTOR介导。在这里，我们报告，TSC 2是一个GTP酶激活蛋白（GAP）对Rheb，Ras家族GTP酶。Rheb刺激S6 K和4 EBP 1的磷酸化。Rheb的这种功能被雷帕霉素和显性阴性mTOR阻断。Rheb刺激mTOR的磷酸化，并在响应营养和细胞能量状态的S6 K和4 EBP 1的调节中起重要作用。我们的数据表明Rheb作用于TSC 1/TSC 2下游和mTOR上游以调节细胞生长。
Tuberous sclerosis complex (TSC) is a genetic disease caused by mutation in either TSC1 or TSC2. The TSC1 and TSC2 gene products form a functional complex and inhibit phosphorylation of S6K and 4EBP1. These functions of TSC1/TSC2 are likely mediated by mTOR. Here we report that TSC2 is a GTPase-activating protein (GAP) toward Rheb, a Ras family GTPase. Rheb stimulates phosphorylation of S6K and 4EBP1. This function of Rheb is blocked by rapamycin and dominant-negative mTOR. Rheb stimulates the phosphorylation of mTOR and plays an essential role in regulation of S6K and 4EBP1 in response to nutrients and cellular energy status. Our data demonstrate that Rheb acts downstream of TSC1/TSC2 and upstream of mTOR to regulate cell growth.