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mTORC1 phosphorylates and stabilizes LST2 to negatively regulate EGFR

Stefania Battaglioni1, Louise-Marie Craigie1, Sofia Filippini1

  • 1Biozentrum, University of Basel, Basel 4056, Switzerland.

Proceedings of the National Academy of Sciences of the United States of America
|August 14, 2024
PubMed

Insights

Target of rapamycin complex 1 (TORC1) directly phosphorylates LST2, a protein that regulates epidermal growth factor receptor (EGFR) signaling. This interaction reveals a novel negative feedback loop where mTORC1 inhibits EGFR signaling through LST2.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Target of rapamycin complex 1 (TORC1) is a crucial regulator of cell growth, metabolism, and disease.
  • Understanding downstream signaling and feedback mechanisms of mammalian TORC1 (mTORC1) is vital.
  • mTORC1 recognizes substrates via the TOR signaling (TOS) motif, facilitating phosphorylation at distal sites.

Purpose of the Study:

  • To investigate the interaction between mTORC1 and its substrates.
  • To identify novel downstream effectors of mTORC1 signaling.
  • To elucidate the role of LST2 in mTORC1-mediated cellular processes.

Main Methods:

  • Identification of the TOS motif in LST2 (amino acids 401-405).
  • In vitro phosphorylation assays to confirm mTORC1-mediated phosphorylation of LST2 at S670.
  • Analysis of LST2 ubiquitination and stability in response to mTORC1 activity.
  • Assessment of EGFR signaling in the presence and absence of LST2.

Main Results:

  • LST2 contains a functional TOS motif and is directly phosphorylated by mTORC1 at S670.
  • mTORC1-dependent S670 phosphorylation of LST2 promotes its monoubiquitination at K87, stabilizing the protein.
  • Monoubiquitinated LST2 exhibits a stable, reticular distribution.
  • Unphosphorylated LST2 is proteasomally degraded upon mTORC1 inactivation.
  • Loss of LST2 leads to enhanced epidermal growth factor receptor (EGFR) signaling.

Conclusions:

  • mTORC1 directly phosphorylates LST2, stabilizing it via monoubiquitination.
  • LST2 acts as a negative regulator of EGFR signaling.
  • mTORC1 negatively feeds back on upstream EGFR signaling through the LST2 protein.
Keywords:
LST2TOS motifmTOR signalingnegative feedbackphosphorylation substrate

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