Restraining PI3K: mTOR signalling goes back to the membrane

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Updated: Aug 20, 2026

Development and Application of Rapamycin-regulated Tyrosine Phosphatases
06:56

Development and Application of Rapamycin-regulated Tyrosine Phosphatases

Published on: September 6, 2024

Laura S Harrington1, Greg M Findlay, Richard F Lamb

  • 1Cancer Research UK Centre for Cell and Molecular Biology, The Institute of Cancer Research, London, UK.

Trends in Biochemical Sciences
|January 18, 2005
PubMed

Insights

Phosphoinositide 3-kinase (PI3K) signaling, crucial for insulin response, is negatively regulated by a feedback loop involving mTOR and S6K. This discovery offers new insights into type 2 diabetes and tuberous sclerosis complex.

Area of Science:

  • Biochemistry
  • Cellular Signaling
  • Molecular Biology

Background:

  • Phosphoinositide 3-kinase (PI3K) activation by growth factors like insulin is central to cellular processes.
  • PI3K generates phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P(3)], mediating glucose homeostasis, proliferation, survival, and cell growth.
  • PTEN (phosphatase and tensin homologue deleted on chromosome 10) has been considered the primary negative regulator by dephosphorylating PtdIns(3,4,5)P(3).

Purpose of the Study:

  • To identify and characterize novel regulatory pathways of PI3K signaling.
  • To investigate mechanisms of negative feedback inhibition of PI3K.
  • To explore the implications of PI3K regulation in metabolic and developmental diseases.

Main Methods:

  • The study likely involved biochemical assays to measure PI3K activity.
  • Investigated signaling pathways using cell-based experiments and molecular biology techniques.
  • Analyzed feedback inhibition mechanisms involving mTOR and S6K.

Main Results:

  • A novel pathway for PI3K regulation was identified, involving direct prevention of PI3K activation.
  • Evidence suggests a significant negative feedback loop where activated mammalian target of rapamycin (mTOR) and p70 S6 kinase (S6K) inhibit PI3K.
  • This feedback mechanism represents a major regulatory pathway for PI3K signaling.

Conclusions:

  • PI3K signaling is subject to negative feedback regulation beyond phosphatase activity.
  • The mTOR/S6K-mediated inhibition of PI3K provides a new perspective on controlling PI3K pathway activity.
  • Understanding this regulatory loop is critical for potential therapeutic strategies targeting type 2 diabetes and tuberous sclerosis complex.

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