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Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome

Suchithra Menon1, Christian C Dibble2, George Talbott1

  • 1Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.

Cell
|February 18, 2014
PubMed

Insights

Insulin signaling controls cell growth by regulating the TSC complex

Area of Science:

  • Cellular biology
  • Molecular signaling
  • Metabolic regulation

Background:

  • The mechanistic target of rapamycin complex 1 (mTORC1) pathway regulates cell growth.
  • Insulin activates mTORC1 via the PI3K-Akt pathway, inhibiting the TSC complex to activate Rheb.
  • Integration of nutrient-sensing and growth factor pathways with mTORC1 regulation remains unclear.

Purpose of the Study:

  • To elucidate the mechanism by which insulin signaling integrates with nutrient-sensing pathways to control mTORC1.
  • To investigate the role of the TSC complex localization in mTORC1 activation.

Main Methods:

  • Cellular localization studies of the TSC complex, Rheb, and mTORC1.
  • Analysis of Akt-mediated phosphorylation of TSC2.
  • Investigation of PTEN loss-of-function effects on mTORC1 signaling.

Main Results:

  • Insulin induces acute dissociation of the TSC complex from the lysosomal surface.
  • The TSC complex associates with lysosomes in a Rheb-dependent manner.
  • Akt-mediated TSC2 phosphorylation is required for TSC complex dissociation upon insulin stimulation.
  • Loss of PTEN leads to constitutive mTORC1 activation via Akt-dependent TSC complex dissociation.

Conclusions:

  • Spatial recruitment of the TSC complex and mTORC1 to Rheb at the lysosome integrates diverse growth signals.
  • This provides a unifying mechanism for mTORC1 regulation by insulin and nutrient availability.

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