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RagC phosphorylation autoregulates mTOR complex 1

Guang Yang1, Sean J Humphrey1, Danielle S Murashige2

  • 1School of Life and Environmental Sciences, Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia.

The EMBO Journal
|December 16, 2018
PubMed

Insights

Scientists discovered that phosphorylating RagC, a protein involved in nutrient sensing, is crucial for activating mTORC1 signaling. This finding reveals a new feedback loop controlling cell growth and metabolism.

Area of Science:

  • Cellular Biology
  • Molecular Signaling
  • Metabolism Regulation

Background:

  • Mammalian target of rapamycin complex 1 (mTORC1) is a central regulator of cell growth, proliferation, and metabolism.
  • mTORC1 is activated by growth factors (via TSC2/Rheb) and amino acids (via Rag GTPases), suggesting complex regulatory networks.

Purpose of the Study:

  • To investigate the cross-talk between growth factor and amino acid signaling pathways in mTORC1 regulation.
  • To identify and characterize novel regulatory mechanisms of mTORC1 activity.

Main Methods:

  • Identification and characterization of phosphorylation sites on RagC.
  • Biochemical assays to assess mTORC1 activity and RagC stability.
  • Genetic studies in *Drosophila* to evaluate the functional role of RagC phosphorylation.

Main Results:

  • Three conserved growth factor-responsive phosphorylation sites were identified on RagC.
  • RagC phosphorylation destabilizes mTORC1 and is essential for both growth factor and amino acid-induced mTORC1 activation.
  • RagC phosphorylation suppresses starvation-induced autophagy and is critical for cell growth regulation in *Drosophila*.

Conclusions:

  • RagC phosphorylation is a key regulatory event linking growth factor and amino acid pathways to mTORC1.
  • mTORC1 phosphorylates RagC (at S21), revealing a novel auto-regulatory feedback mechanism.
  • These findings elucidate a previously unappreciated mechanism controlling mTORC1 activity and cellular homeostasis.
Keywords:
RagCautophagycell growthmTORC1phosphorylation

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