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Rapid mitogenic regulation of the mTORC1 inhibitor, DEPTOR, by phosphatidic acid

Mee-Sup Yoon1, Christina L Rosenberger2, Cong Wu3

  • 1Department of Cell and Developmental Biology, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA; Department of Molecular Medicine, Graduate School of Medicine, Gachon University, Incheon 406-840, Republic of Korea.

Molecular Cell
|May 5, 2015
PubMed

Insights

Mitogenic stimulation rapidly activates mTORC1 by temporarily dissociating DEPTOR, an inhibitor. Phospholipase D (PLD) and its product phosphatidic acid (PA) are key regulators of this acute mTORC1 activation mechanism.

Area of Science:

  • Cellular signaling
  • Molecular biology
  • Biochemistry

Background:

  • The mammalian target of rapamycin complex 1 (mTORC1) is a crucial regulator of cell growth and metabolism.
  • DEPTOR acts as an endogenous inhibitor of mTORC1, but its rapid regulatory mechanisms are not fully understood.

Purpose of the Study:

  • To elucidate the mechanism by which DEPTOR regulates rapid mTORC1 activation upon mitogenic stimulation.
  • To identify the specific molecular players involved in DEPTOR-mTORC1 dynamics.

Main Methods:

  • Mitogenic stimulation assays
  • Inhibition and depletion of phospholipase D (PLD)
  • Mass spectrometry analysis
  • Analysis of phosphatidic acid (PA) species

Main Results:

  • DEPTOR rapidly and transiently dissociates from mTORC1 following mitogenic stimulation.
  • PLD inhibition or depletion blocks this dissociation, while addition of PA recapitulates it.
  • Mass spectrometry confirmed DEPTOR as an mTOR binding partner displaced by PA.
  • Unsaturated fatty acid-containing PA species, produced by PLD, exhibit high affinity for the mTOR FRB domain and effectively displace DEPTOR.

Conclusions:

  • Mitogen-stimulated DEPTOR dissociation from mTORC1 is a key mechanism for acute mTORC1 activation.
  • Phospholipase D and its product phosphatidic acid play critical roles in this regulatory process.
  • Specific unsaturated PA species mediate mTORC1 activation by displacing DEPTOR, highlighting the specificity of PA function in mTOR regulation.

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