Real Talk: The Inter-play Between the mTOR, AMPK, and Hexosamine Biosynthetic Pathways in Cell Signaling.
Real Talk: The Inter-play Between the mTOR, AMPK, and Hexosamine Biosynthetic Pathways in Cell Signaling.
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DOI：
10.3389/fendo.2018.00522
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发表时间：
2018
影响因子：
5.2
通讯作者：
Slawson C
中科院分区：
文献类型：
--
作者：
Cork GK;Thompson J;Slawson C
O-连接的N-乙酰葡糖胺，更好地称为O-GlcNAc，是参与多种细胞功能的糖翻译后修饰。分别由O-GlcNAc转移酶（OGT）和O-GlcNAc酶（OGA）介导的O-GlcNAc循环的破坏是疾病病理学（例如糖尿病、肥胖症、阿尔茨海默病和癌症）中异常细胞信号传导的驱动力。通过己糖胺生物合成途径（HBP）生产OGT的代谢底物UDP-GlcNAc受氨基酸、脂肪和核酸的输入控制，使O-GlcNAc成为这些大分子波动的关键营养素传感器。哺乳动物雷帕霉素靶蛋白（mTOR）和AMP活化蛋白激酶（AMPK）通路也参与营养感应，作为控制细胞活性的一种手段，是多种病理学中的重要因素。对HBP、AMPK和mTOR通路的个体营养敏感性的研究揭示了一种复杂的调节动态，它们对大分子水平的独特反应协调了细胞行为。重要的是，这些途径之间的相互作用可以微调细胞对营养物质的反应。强有力的证据表明，AMPK负调节mTOR通路，但AMPK的O-GlcNAc酰化降低酶活性并促进生长。另一方面，AMPK可以磷酸化OGT，导致OGT功能的改变。HBP、AMPK和mTOR通路之间复杂的相互作用集合整合了营养信号以响应环境的变化。特别是，使用系统生物学方法检查这些关系可能证明是探索细胞信号传导复杂性的有用方法。总的来说，了解这些营养物质途径的复杂相互作用将为营养物质如何影响健康和疾病提供新的机制信息。
O-linked N-acetylglucosamine, better known as O-GlcNAc, is a sugar post-translational modification participating in a diverse range of cell functions. Disruptions in the cycling of O-GlcNAc mediated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively, is a driving force for aberrant cell signaling in disease pathologies, such as diabetes, obesity, Alzheimer's disease, and cancer. Production of UDP-GlcNAc, the metabolic substrate for OGT, by the Hexosamine Biosynthetic Pathway (HBP) is controlled by the input of amino acids, fats, and nucleic acids, making O-GlcNAc a key nutrient-sensor for fluctuations in these macromolecules. The mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) pathways also participate in nutrient-sensing as a means of controlling cell activity and are significant factors in a variety of pathologies. Research into the individual nutrient-sensitivities of the HBP, AMPK, and mTOR pathways has revealed a complex regulatory dynamic, where their unique responses to macromolecule levels coordinate cell behavior. Importantly, cross-talk between these pathways fine-tunes the cellular response to nutrients. Strong evidence demonstrates that AMPK negatively regulates the mTOR pathway, but O-GlcNAcylation of AMPK lowers enzymatic activity and promotes growth. On the other hand, AMPK can phosphorylate OGT leading to changes in OGT function. Complex sets of interactions between the HBP, AMPK, and mTOR pathways integrate nutritional signals to respond to changes in the environment. In particular, examining these relationships using systems biology approaches might prove a useful method of exploring the complex nature of cell signaling. Overall, understanding the complex interactions of these nutrient pathways will provide novel mechanistic information into how nutrients influence health and disease.