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mTORC1 directly inhibits AMPK to promote cell proliferation under nutrient stress

Naomi X Y Ling1, Adrian Kaczmarek2, Ashfaqul Hoque1

  • 1Metabolic Signalling Laboratory, St Vincent's Institute of Medical Research, School of Medicine, University of Melbourne, Melbourne, Victoria, Australia.

Nature Metabolism
|January 30, 2020
PubMed

Insights

Mammalian target of rapamycin (mTOR) complex 1 (TORC1) directly inhibits AMP-activated protein kinase (AMPK) signaling. This reciprocal regulation impacts cell proliferation and offers new cancer treatment strategies targeting nutrient-poor tumors.

Area of Science:

  • Cellular Metabolism
  • Molecular Biology
  • Signal Transduction

Background:

  • Mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) pathways are crucial for cellular metabolism and proliferation.
  • Dysregulation of these pathways is linked to diseases like cancer and type 2 diabetes.
  • AMPK signaling typically reduces cell proliferation, partly by inhibiting TOR complex-1 (TORC1).

Purpose of the Study:

  • To investigate the regulatory relationship between TORC1 and AMPK signaling.
  • To identify the molecular mechanisms underlying this interaction.
  • To explore therapeutic opportunities based on this bidirectional regulation.

Main Methods:

  • Investigated TORC1's effect on AMPK signaling in yeast and mammalian cells.
  • Utilized genetic and pharmacological inhibition of TORC1.
  • Analyzed phosphorylation sites, including Ser367 in yeast and Ser347/345 in mammalian AMPK, and Thr172 in the activation loop.

Main Results:

  • Demonstrated that TORC1 directly down-regulates AMPK signaling via phosphorylation of conserved residues.
  • Observed reduced AMPK activation loop phosphorylation (Thr172) upon TORC1 inhibition.
  • Showed TORC1 inhibition activates AMPK independently of AMP:ATP ratios, leading to growth limitation under nutrient stress.

Conclusions:

  • Revealed a fundamental, bidirectional regulatory mechanism between mTOR and AMPK signaling networks.
  • Identified a novel pathway for TORC1 to control AMPK activity.
  • Uncovered potential therapeutic strategies targeting the tumor microenvironment by modulating these pathways for cancer treatment.

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