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Decoding the PI3K/Akt/mTOR-AMPK signalling nexus: molecular crosstalk, metabolic reprogramming and therapeutic
Josef Yakin1, Faruk Alam1, Jose Fernando G Elpa2
1Faculty of Pharmaceutical Science, Assam Down Town University, Guwahati, India.
Abstract:
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.
Insights
The PI3K/Akt/mTOR and AMPK pathways are key in diseases. Understanding their crosstalk offers new precision medicine strategies for cancer and metabolic disorders.
Area of Science:
- Cellular Metabolism
- Molecular Signaling Pathways
- Disease Pathogenesis
Background:
- Dysregulation of PI3K/Akt/mTOR and AMPK pathways is implicated in cancer, metabolic, neurodegenerative, and immune disorders.
- While individually studied, the molecular interplay and therapeutic potential between these pathways remain incompletely understood.
- PI3K/Akt/mTOR promotes anabolism, while AMPK senses energy status, inhibiting anabolism and activating catabolism like autophagy.
Purpose of the Study:
- To review the molecular crosstalk between the PI3K/Akt/mTOR and AMPK signaling pathways.
- To highlight the regulatory mechanisms and therapeutic significance of their interaction.
- To explore applications in precision medicine for related diseases.
Main Methods:
- Literature review focusing on molecular interactions, phosphorylation-dependent regulations, and lysosomal nutrient sensing.
- Discussion of autophagy, systems biology, computational modeling, and network-based drug discovery.
- Synthesis of current findings on pathway crosstalk and its role in cellular metabolism.
Main Results:
- Identified key regulatory mechanisms including TSC2, Raptor, ULK1, Rag GTPases, and lysosomal signaling.
- Demonstrated that pathway interaction governs cellular metabolic responses to stress.
- Highlighted the role of this crosstalk in directing disease outcomes in cancer, metabolic, and neurodegenerative conditions.
Conclusions:
- Integrated knowledge of PI3K/Akt/mTOR and AMPK pathways provides crucial insights into cellular metabolism regulation.
- Understanding pathway crosstalk opens avenues for developing precision-based therapeutic interventions.
- Further research into these interactions promises novel strategies for treating complex diseases.
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