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AKT-mediated phosphorylation of TSC2 controls stimulus- and tissue-specific mTORC1 signaling and organ growth

Yann Cormerais1,2, Samuel C Lapp1,2,3, Krystle C Kalafut1,2,3

  • 1Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.

Biorxiv : the Preprint Server for Biology
|October 10, 2024
PubMed

Insights

The mechanistic target of rapamycin complex 1 (mTORC1) pathway regulates cell growth. A new mouse model shows that tuberous sclerosis complex 2 (TSC2) phosphorylation is key for mTORC1 activation in specific tissues.

Area of Science:

  • Cellular Biology
  • Physiology
  • Biochemistry

Background:

  • Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates growth signals to control cell and tissue growth.
  • The precise physiological function of molecular mechanisms regulating mTORC1 signaling in mammalian tissues remains unclear.
  • Previous studies established mTORC1 regulation through biochemical and cell biological methods, but in vivo validation is limited.

Purpose of the Study:

  • To investigate the physiological role of tuberous sclerosis complex 2 (TSC2) phosphorylation in mTORC1 signaling using a genetic mouse model.
  • To characterize the impact of abrogated AKT-mediated TSC2 phosphorylation on mTORC1 activity and organismal growth.
  • To establish a valuable genetic tool for studying mTORC1 regulation in vivo.

Main Methods:

  • Development and characterization of a genetic mouse model (TSC2-5A) lacking five key AKT phosphorylation sites on TSC2.
  • Assessment of body weight, organ weight (brain, skeletal muscle), and mTORC1 signaling activity in TSC2-5A mice.
  • Utilized biochemical and cell biological approaches to analyze mTORC1 pathway regulation.

Main Results:

  • TSC2-5A mice were developmentally normal but exhibited reduced body weight and organ weights.
  • Cell-intrinsic growth factor-stimulated mTORC1 signaling was decreased in TSC2-5A mice.
  • TSC2 phosphorylation by AKT was identified as a critical regulator of mTORC1 in specific tissues.

Conclusions:

  • TSC2 phosphorylation is a significant mechanism for activating mTORC1 signaling in certain mammalian tissues.
  • The TSC2-5A mouse model provides crucial insights into the physiological regulation of mTORC1.
  • This genetic model serves as a powerful tool for future research on mTORC1 pathway dynamics.

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