# Determining the mechanism of serine sensing by the mTOR pathway

> **NIH NIH F31** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2020 · $45,520

## Abstract

Project Summary/Abstract
 The mTORC1 kinase is a master regulator of cellular growth and metabolism. mTORC1 activity is
controlled by upstream environmental cues, including growth factors and nutrient availability; not surprisingly,
dysregulation of the mTORC1 pathway has been implicated in a diverse set of diseases, including cancers,
diabetes, obesity, neurodegeneration, and the aging process. In order to guide new therapeutic approaches
toward these diseases, we must understand how mTORC1 is regulated by specific upstream nutritional inputs
on a molecular level.
 By demonstrating that mTORC1 activity is inhibited by acute serine deprivation, we have identified a
new input into the mTORC1 pathway. This result is especially striking because deprivation of serine, a non-
essential amino acid, can induce metabolic rewiring in cancer cells and disrupt one-carbon metabolism;
moreover, exogenous serine is conditionally essential in many tumors. Our preliminary data show that
mTORC1 detects the presence of serine, or a serine-derived metabolite, through the nutrient-sensing pathway
upstream of the Rag-GTPases; however, we do not know the identity of the serine sensor, nor do we know
how it regulates mTORC1 signaling. To elucidate the mechanism of serine sensing by the mTORC1
pathway, we propose the following specific aims:
1) Establish the pathway upstream of the Rag-GTPases which signals serine sufficiency to mTORC1.
2) Determine the metabolite that signals serine sufficiency to mTORC1.
3) Identify the protein that negatively regulates mTORC1 activity when serine levels are insufficient.
We will employ a multidisciplinary approach that incorporates metabolite profiling, unbiased proteomics, and
functional genomics to determine how serine promotes activation of the mTORC1 pathway. Through these
studies, we may be able to establish a link between altered serine metabolism and mTORC1-dependent
growth and proliferation in cancer cells. In addition, our work may uncover new serine-dependent metabolic
vulnerabilities in cancers and lead to the identification of novel drug targets in the mTORC1 pathway.

## Key facts

- **NIH application ID:** 9969360
- **Project number:** 5F31CA232340-03
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Grace Yun Liu
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2018-07-06 → 2022-07-05

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9969360

## Citation

> US National Institutes of Health, RePORTER application 9969360, Determining the mechanism of serine sensing by the mTOR pathway (5F31CA232340-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9969360. Licensed CC0.

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