Metabolic Signalling Laboratory, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia.
Research Program for Receptor Biochemistry and Tumour Metabolism, Department of Paediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria.
Essays Biochem. 2024 Nov 18;68(3):321-336. doi: 10.1042/EBC20240007.
Metabolic homeostasis and the ability to link energy supply to demand are essential requirements for all living cells to grow and proliferate. Key to metabolic homeostasis in all eukaryotes are AMPK and mTORC1, two kinases that sense nutrient levels and function as counteracting regulators of catabolism (AMPK) and anabolism (mTORC1) to control cell survival, growth and proliferation. Discoveries beginning in the early 2000s revealed that AMPK and mTORC1 communicate, or cross-talk, through direct and indirect phosphorylation events to regulate the activities of each other and their shared protein substrate ULK1, the master initiator of autophagy, thereby allowing cellular metabolism to rapidly adapt to energy and nutritional state. More recent reports describe divergent mechanisms of AMPK/mTORC1 cross-talk and the elaborate means by which AMPK and mTORC1 are activated at the lysosome. Here, we provide a comprehensive overview of current understanding in this exciting area and comment on new evidence showing mTORC1 feedback extends to the level of the AMPK isoform, which is particularly pertinent for some cancers where specific AMPK isoforms are implicated in disease pathogenesis.
代谢稳态和将能量供应与需求联系起来的能力是所有活细胞生长和增殖的基本要求。所有真核生物代谢稳态的关键是 AMPK 和 mTORC1，这两种激酶能够感知营养物质水平，并作为分解代谢（AMPK）和合成代谢（mTORC1）的拮抗调节剂，以控制细胞存活、生长和增殖。从 21 世纪初开始的发现揭示了 AMPK 和 mTORC1 通过直接和间接磷酸化事件进行通讯或串扰，以调节彼此的活性及其共同的蛋白质底物 ULK1（自噬的主要启动子）的活性，从而使细胞代谢能够快速适应能量和营养状态。最近的报告描述了 AMPK/mTORC1 串扰的不同机制，以及 AMPK 和 mTORC1 在溶酶体中被激活的精细方式。在这里，我们全面概述了这一令人兴奋的领域的现有认识，并评论了新的证据，表明 mTORC1 的反馈延伸到 AMPK 同工型的水平，这对于某些癌症尤其重要，因为某些 AMPK 同工型与疾病的发病机制有关。
