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Multi-mechanisms are involved in reactive oxygen species regulation of mTORC1 signaling

Ming Li1, Li Zhao, Jun Liu

  • 1Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.

Cellular Signalling
|July 20, 2010
PubMed

Insights

Reactive oxygen species (ROS) have a dual effect on the mTORC1 pathway, stimulating it at low doses and inhibiting it at high doses. This modulation involves AMP-activated kinase (AMPK) and protein phosphatase 2A (PP2A).

Area of Science:

  • Cellular Biology
  • Biochemistry
  • Signaling Pathways

Background:

  • The mammalian target of rapamycin complex 1 (mTORC1) is a central regulator of cell growth, proliferation, survival, and metabolism.
  • The precise role and mechanisms of reactive oxygen species (ROS) in modulating mTORC1 signaling remain largely unknown.

Purpose of the Study:

  • To investigate the dose- and time-dependent effects of ROS on mTORC1 activity.
  • To elucidate the molecular mechanisms by which ROS influence mTORC1 signaling.

Main Methods:

  • Exposure of various cell lines and in vivo models to different concentrations and durations of hydrogen peroxide (H2O2).
  • Assessment of mTORC1 activity through phosphorylation of key targets like Raptor, p70-S6K1, S6, and 4E-BP1.
  • Investigation of the involvement of AMP-activated kinase (AMPK) and protein phosphatase 2A (PP2A) using specific inhibitors and co-immunoprecipitation assays.

Main Results:

  • Low doses of ROS stimulate mTORC1 activity, while high doses or prolonged exposure inhibit it in a cell type-dependent manner.
  • Hydrogen peroxide (H2O2) activates AMPK, leading to Raptor phosphorylation and subsequent mTORC1 inhibition.
  • H2O2 also promotes the association of PP2A with p70-S6K1, contributing to mTORC1 substrate dephosphorylation.
  • Inhibition of both AMPK and PP2A partially protected cells from H2O2-induced cell death.

Conclusions:

  • ROS exert a dual role in regulating mTORC1 signaling, with low concentrations activating and high concentrations inhibiting the pathway.
  • AMPK and PP2A-mediated phosphorylation of Raptor are key mechanisms underlying ROS-induced mTORC1 inhibition.
  • Targeting AMPK and PP2A may offer therapeutic strategies against ROS-induced cellular damage.

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