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Updated: Jun 17, 2025
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Published on: June 6, 2025
40
mTORC1 phosphorylates and stabilizes LST2 to negatively regulate EGFR
Stefania Battaglioni1, Louise-Marie Craigie1, Sofia Filippini1
1Biozentrum, University of Basel, Basel 4056, Switzerland.
Summary
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.
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