# Elucidating the role of GATOR2 in nutrient sensing by mTORC1

> **NIH NIH F30** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2020 · $50,520

## Abstract

Project Summary/Abstract
 The mechanistic target of rapamycin complex 1 (mTORC1) kinase is a key regulator of cell growth and
proliferation that integrates mitogen cues, energy stress, and nutrient availability to coordinate central anabolic and
catabolic cellular processes1-4. Aberrant mTORC1 signaling has been implicated in a variety of human diseases
including cancer, diabetes, and epilepsy as well as normal physiological processes such as aging1,5-6. Accordingly,
the molecular basis for mTORC1 activation is of significant fundamental and pathophysiological interest.
 Coincident detection of growth factor signals and nutrients, including the amino acids leucine and arginine,
is required for mTORC1 activation1-4. Availability of these amino acids is conveyed to mTORC1 via the
heterodimeric Rag GTPases, which recruit mTORC1 to the lysosomal surface for activation by the mTOR kinase
activator Rheb11-12. The GATOR1 complex inhibits mTORC1 recruitment through its function as a GAP toward
RagA/B. The GATOR2 complex interacts with and inhibits GATOR118. In the absence of amino acids, the leucine
sensor Sestrin2 and arginine sensor CASTOR1 bind to and inhibit GATOR2 thereby repressing mTORC1
activation19-24.
 Despite identification of these components of the amino acid sensing machinery and their respective
functions, the mechanism by which the GATOR2 complex inhibits GATOR1 and leads to mTORC1 activation
remains elusive. As the node that integrates the availability of leucine and arginine, GATOR2 is a key component of
the nutrient sensing branch upstream of mTORC1. Our preliminary results suggest that GATOR2 functions as an
E3 ubiquitin ligase and that this activity is essential for mTORC1 to sense amino acids. Elucidation of the molecular
mechanism of GATOR2 will provide key insight into how mammalian cells sense and respond to essential nutrients
and may also provide novel targets for therapeutic agents designed to ameliorate deregulated mTORC1 signaling.
To characterize the molecular function of GATOR2, we propose the following aims:
1. Characterize the E3 ubiquitin ligase activity of GATOR2
2. Identify substrates of GATOR2
3. Determine how GATOR2 ubiquitin ligase activity regulates mTORC1 activation in vivo

## Key facts

- **NIH application ID:** 9968177
- **Project number:** 5F30CA228229-03
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Max Valenstein
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2018-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9968177

## Citation

> US National Institutes of Health, RePORTER application 9968177, Elucidating the role of GATOR2 in nutrient sensing by mTORC1 (5F30CA228229-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9968177. Licensed CC0.

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