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.

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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