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Regulation of mTORC1 by PI3K signaling

Christian C Dibble1, Lewis C Cantley2

  • 1Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

Trends in Cell Biology
|July 11, 2015
PubMed

Insights

The PI3K-mTORC1 pathway regulates cell growth and metabolism. Growth factors activate this pathway via Akt, controlling Rheb GTPase at the lysosome to enable mTORC1 activation.

Area of Science:

  • Cellular signaling
  • Molecular biology
  • Biochemistry

Background:

  • The phosphoinositide 3-kinase (PI3K)-mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) network is crucial for cellular metabolism and growth.
  • mTORC1 activation is influenced by nutrients, energy status, oxygen, and growth factors, involving key proteins like Ras-related GTPases (Rags) and Ras homolog enriched in brain (Rheb).

Purpose of the Study:

  • To elucidate the signal transduction mechanisms by which growth factor-responsive PI3K signaling activates mTORC1.
  • To detail the integration of PI3K and amino acid signals upstream of mTORC1 at the lysosome.

Main Methods:

  • Review of signal transduction pathways.
  • Focus on PI3K-dependent Akt activation.
  • Analysis of spatial regulation of the tuberous sclerosis complex (TSC) at the lysosome.

Main Results:

  • Growth factor signaling activates PI3K, leading to Akt activation.
  • PI3K-Akt signaling spatially regulates the TSC complex at the lysosome.
  • This regulation switches on Rheb GTPase, a prerequisite for mTORC1 activation at the lysosome.

Conclusions:

  • A model for PI3K-mTORC1 network integration at the lysosome is presented.
  • Dysregulation of the PI3K-mTORC1 pathway is linked to cancer, diabetes, autism, and aging.
  • Understanding this network is vital for addressing associated pathologies.
Keywords:
RagRaptorRhebTSC2insulinlysosome

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