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Regulation of mTORC1 and mTORC2 complex assembly by phosphatidic acid: competition with rapamycin

Alfredo Toschi1, Evan Lee, Limei Xu

  • 1Department of Biological Sciences, Hunter College of the City University of New York, New York, NY 10065, USA.

Molecular and Cellular Biology
|December 31, 2008
PubMed

Insights

Phosphatidic acid (PA), produced by Phospholipase D (PLD), is essential for stabilizing both mTORC1 and mTORC2 complexes. Suppressing PLD enhances mTORC2 sensitivity to rapamycin, suggesting a therapeutic strategy.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Cancer Research

Background:

  • The mammalian target of rapamycin (mTOR) pathway is crucial for cell growth and survival, and is often dysregulated in cancer.
  • mTOR functions in two distinct complexes, mTORC1 and mTORC2, with their regulation by Phospholipase D (PLD) and phosphatidic acid (PA) remaining controversial.

Purpose of the Study:

  • To investigate the role of PLD and PA in the regulation and complex formation of mTORC1 and mTORC2.
  • To elucidate the mechanism by which PA influences mTOR complex stability and rapamycin sensitivity.

Main Methods:

  • Utilized suppression of PLD activity to assess its impact on mTORC1 and mTORC2 substrate phosphorylation.
  • Investigated the effect of PA on the association of mTOR with its regulatory partners Raptor (mTORC1) and Rictor (mTORC2).
  • Examined the competitive interaction between PA and rapamycin on mTOR complex formation and activity.

Main Results:

  • Suppression of PLD inhibited phosphorylation of mTORC1 (S6K at Thr389) and mTORC2 (Akt at Ser473, PRAS40) substrates.
  • Demonstrated that PA is required for the formation of both mTORC1 (mTOR-Raptor) and mTORC2 (mTOR-Rictor) complexes.
  • Showed that PA competes with rapamycin, and its suppression increases mTORC2 sensitivity to rapamycin.

Conclusions:

  • PA is essential for the stabilization of both mTORC1 and mTORC2 complexes.
  • Revealed a mechanism for rapamycin's inhibitory action on mTOR.
  • Suggests targeting mTORC2 therapeutically by suppressing PLD activity to enhance rapamycin efficacy.

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