Central to cellular metabolism and cell proliferation are highly conserved signalling pathways controlled by mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK)1,2, dysregulation of which are implicated in pathogenesis of major human diseases such as cancer and type 2 diabetes. AMPK pathways leading to reduced cell proliferation are well established and, in part, act through inhibition of TOR complex-1 (TORC1) activity. Here we demonstrate reciprocal regulation, specifically that TORC1 directly down-regulates AMPK signalling by phosphorylating the evolutionarily conserved residue Ser367 in the fission yeast AMPK catalytic subunit Ssp2, and AMPK α1Ser347/α2Ser345 in the mammalian homologs, which is associated with reduced phosphorylation of activation loop Thr172. Genetic or pharmacological inhibition of TORC1 signalling led to AMPK activation in the absence of increased AMP:ATP ratios; under nutrient stress conditions this was associated with growth limitation in both yeast and human cell cultures. Our findings reveal fundamental, bi-directional regulation between two major metabolic signalling networks and uncover new opportunity for cancer treatment strategies aimed at suppressing cell proliferation in the nutrient-poor tumor microenvironment.

中文翻译：

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在营养胁迫下，mTORC1直接抑制AMPK促进细胞增殖。

细胞代谢和细胞增殖的中心是高度保守的信号通路，受哺乳动物雷帕霉素靶标（mTOR）和AMP激活的蛋白激酶（AMPK）1,2的控制，它们的失调与主要人类疾病的发病机理有关，例如癌症和类型2糖尿病。导致细胞增殖减少的AMPK途径已经建立，并且部分通过抑制TOR complex-1（TORC1）活性发挥作用。在这里，我们证明了相互调节，特别是TORC1通过使裂变酵母AMPK催化亚基Ssp2中的进化保守残基Ser367和哺乳动物同源物中的AMPKα1Ser347/α2Ser345磷酸化来直接下调AMPK信号传导，这与激活环的磷酸化减少有关Thr172。在不增加AMP：ATP比的情况下，TORC1信号的遗传或药理抑制导致AMPK激活；在营养胁迫条件下，这与酵母和人类细胞培养物中的生长限制有关。我们的发现揭示了两个主要代谢信号网络之间的基本双向调控，并发现了旨在在营养不良的肿瘤微环境中抑制细胞增殖的癌症治疗策略的新机会。