LKB1 and AMP-activated protein kinase control of mTOR signalling and growth.
LKB1 and AMP-activated protein kinase control of mTOR signalling and growth.
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LKB1和AMP激活的蛋白激酶对MTOR信号传导和生长的控制。
DOI：
10.1111/j.1748-1716.2009.01972.x
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发表时间：
2009-05
期刊：
影响因子：
--
通讯作者：
Shaw RJ
中科院分区：
文献类型：
--
作者：
Shaw RJ
AMP激活的丝氨酸/苏氨酸蛋白激酶（AMPK）是在所有真核生物中发现的细胞能量状态的传感器，其在诸如营养剥夺或缺氧的应激后在低细胞内ATP的条件下被激活。在过去的五年中，来自大量实验室的工作已经揭示了AMPK调节的主要下游信号通路之一是哺乳动物雷帕霉素靶蛋白（mTOR通路）。有趣的是，像AMPK一样，mTOR丝氨酸/苏氨酸激酶不仅在生长控制和细胞增殖中起关键作用，而且在代谢中也起关键作用。最近的研究表明，在真核生物中，mTOR直向同源物存在于两种生物化学上不同的复合物中，其中只有一种复合物（哺乳动物中的mTORC 1）对雷帕霉素非常敏感，并受营养素和AMPK的调节。AMPK抑制mTORC 1信号传导的分子机制的许多细节也在过去5年中被解码。AMPK直接磷酸化至少两种蛋白质以诱导mTORC 1活性的快速抑制，所述mTORC 1活性是TSC 2肿瘤抑制因子和关键的mTORC 1结合亚基raptor。在这里，我们探索AMPK和mTOR信号通路之间的分子连接，并检查AMPK调节mTOR的生理过程中，生长或代谢控制是至关重要的。AMPK和TOR在所有真核生物中的功能保守性，以及AMPK磷酸化位点周围的序列保守性在所有真核生物中的猛禽研究表明，这代表了一个基本的细胞生长模块连接营养状态的细胞生长机制。这些发现对许多细胞和生物体环境中营养素对细胞生长的控制具有广泛的意义。
The AMP-activated serine/threonine protein kinase (AMPK) is a sensor of cellular energy status found in all eukaryotes that is activated under conditions of low intracellular ATP following stresses such as nutrient deprivation or hypoxia. In the past five years, work from a large number of laboratories has revealed that one of the major downstream signaling pathways regulated by AMPK is the mammalian target-of-rapamycin (mTOR pathway). Interestingly, like AMPK, the mTOR serine/threonine kinase plays key roles not only in growth control and cell proliferation but also in metabolism. Recent work has revealed that across eukaryotes mTOR orthologs are found in two biochemically distinct complexes and only one of those complexes (mTORC1 in mammals) is acutely sensitive to rapamycin and regulated by nutrients and AMPK. Many details of the molecular mechanism by which AMPK inhibits mTORC1 signaling have also been decoded in the past 5 years. AMPK directly phosphorylates at least two proteins to induce rapid suppression of mTORC1 activity, the TSC2 tumor suppressor and the critical mTORC1 binding subunit raptor. Here we explore the molecular connections between AMPK and mTOR signaling pathways and examine the physiological processes in which AMPK regulation of mTOR is critical for growth or metabolic control. The functional conservation of AMPK and TOR in all eukaryotes, and the sequence conservation around the AMPK phosphorylation sites in raptor across all eukaryotes examined suggest that this represents a fundamental cell growth module connecting nutrient status to the cell growth machinery. These findings have broad implications for the control of cell growth by nutrients in a number of cellular and organismal contexts.
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