Decoding the PI3K/Akt/mTOR-AMPK signalling nexus: molecular crosstalk, metabolic reprogramming and therapeutic targeting in human disease

The dysregulation of the PI3K/Akt/mTOR and AMPK pathways are emerging as a major underlying cause of cancer, metabolic disorders, neurodegenerative diseases and immune dysfunction. Both pathways have been well investigated separately but the molecular interaction between the two and the therapeutic significance are not fully understood. While the PI3K/Akt/mTOR pathway promotes anabolic functions including protein synthesis and cell growth, the AMPK pathway serves as an energy sensor under metabolic stress through inhibiting anabolic pathways and activating catabolic activities, such as autophagy and fatty acid oxidation. Recent findings suggest that these signaling pathways interact through regulatory mechanisms, including TSC2, Raptor, ULK1, Rag GTPases, and lysosomal signaling complex. Their interaction regulates the metabolic response of cells under metabolic stress and directs the outcome of the response in cancer, metabolic diseases, neurodegenerative disease, immunodeficiency. This review summarizes the molecular crosstalk between the PI3K/Akt/mTOR and AMPK pathways, focusing on phosphorylation-dependent regulations, lysosomal nutrient sensing, autophagy, systems biology approaches, computational modeling, and network-based drug discovery. Overall, the integrated knowledge of the PI3K/Akt/mTOR and AMPK signaling pathways gives valuable information on the regulation of cellular metabolism and offers promising opportunities for the development of precision-based therapeutic interventions.