# Regulation of the mTOR Pathway by Nutrients

> **NIH NIH R01** · WHITEHEAD INSTITUTE FOR BIOMEDICAL RES · 2020 · $416,813

## Abstract

The mTOR pathway is a signaling network that controls growth (mass accumulation) and
metabolism in response to the nutritional state of organisms. The pathway is commonly deregulated in
cancer, neurological disorders like epilepsy, and diabetes, and also modulates the aging process.
Indeed, pharmacological or genetic inhibition of mTOR is amongst the best validated approaches for
increasing the lifespan of animals. The mTOR protein kinase is the target of the drug rapamycin and the
catalytic subunit of two multi-protein complexes, mTOR Complex 1 (mTORC1) and 2 (mTORC2), that
nucleate distinct branches of the pathway and respond to different stimuli. mTORC1 responds to a
variety of signals, including diverse types of growth factors, nutrients, and stresses, and regulates many
anabolic and catabolic processes, including protein, nucleotide, and lipid synthesis as well as
autophagy, respectively. Recently, we discovered that mTORC1 senses nutrients in two compartments,
the lysosome and the cytosol, and uncovered many of the molecular components involved. While we
have made progress in understanding the functions of many of these components, one in particular,
GATOR2, has been frustratingly mysterious. We know this protein complex is very important as it binds
several nutrient sensors and its loss inhibits mTORC1 activity. However, we still do not understand its
biochemical function or structure or function in vivo. We have recently made progress on all of these
fronts and now have assays to detect its activity and approaches to isolate its regulation by the amino
acid leucine in vivo.
 The goals of our proposed work are to understand the function and structure of GATOR2 (Aim 1);
the role of the GATOR2-interacting leucine sensor Sestrin2 in the adaptation of mice to a leucine-free
diet (Aim 2); and the mechanism through which mTORC1 senses glucose in AMPK-independent fashion
(Aim 3). We will accomplish these goals with a multi-disciplinary approach that uses the tools of
biochemistry, structural and molecular biology, and mouse engineering and analyses. Our results will
substantially increase our understanding of a central growth regulator and reveal the function of a
component (GATOR2) that may be of value to target in certain disease states.

## Key facts

- **NIH application ID:** 9872131
- **Project number:** 5R01CA103866-17
- **Recipient organization:** WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
- **Principal Investigator:** David M. Sabatini
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $416,813
- **Award type:** 5
- **Project period:** 2004-03-23 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9872131

## Citation

> US National Institutes of Health, RePORTER application 9872131, Regulation of the mTOR Pathway by Nutrients (5R01CA103866-17). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9872131. Licensed CC0.

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