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Re-evaluating the roles of proposed modulators of mammalian target of rapamycin complex 1 (mTORC1) signaling

Xuemin Wang1, Bruno D Fonseca, Hua Tang

  • 1Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver V6T 1Z3, Canada.

The Journal of Biological Chemistry
|August 5, 2008
PubMed

Insights

Amino acids and insulin regulate mammalian target of rapamycin complex 1 (mTORC1) signaling. This study found that neither FKBP38 nor TCTP regulates mTORC1, and uncharged tRNA does not inhibit signaling.

Area of Science:

  • Cellular signaling
  • Molecular biology
  • Biochemistry

Background:

  • Mammalian target of rapamycin complex 1 (mTORC1) signaling is crucial for cell growth and is regulated by nutrients and growth factors.
  • The precise mechanisms by which amino acids control mTORC1 are not fully understood.
  • Previous studies suggested roles for FKBP38, TCTP, and uncharged tRNA in mTORC1 regulation.

Purpose of the Study:

  • To investigate the roles of FKBP38, TCTP, and uncharged tRNA in amino acid-mediated mTORC1 signaling.
  • To elucidate the molecular mechanisms underlying mTORC1 regulation by amino acids.

Main Methods:

  • Utilized mammalian cell lines and genetic manipulation (e.g., altering TCTP levels).
  • Performed co-immunoprecipitation assays to assess protein interactions (Rheb, FKBP38, TCTP, mTORC1).
  • Employed a Chinese hamster ovary cell line with a temperature-sensitive mutation in leucyl-tRNA synthetase to study the effect of leucine deprivation and uncharged tRNA.

Main Results:

  • FKBP38 binds Rheb, but its interaction with mTORC1 is not regulated by amino acids or insulin.
  • FKBP38 does not inhibit mTORC1 signaling.
  • TCTP does not appear to be involved in mammalian mTORC1 signaling or its regulation by amino acids.
  • Accumulation of uncharged tRNA(Leu) does not inhibit mTORC1 signaling, challenging previous hypotheses.

Conclusions:

  • Neither FKBP38 nor TCTP plays a significant role in regulating mTORC1 signaling in the tested mammalian cell lines.
  • Uncharged tRNA is not the signal that inhibits mTORC1 during amino acid starvation.
  • mTORC1 signaling is likely controlled by a distinct pathway that senses amino acid availability.

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