# Unexpected role for AMPK and mTORC1 in cellular adaptation to nutrient stress

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $344,295

## Abstract

Project Summary
 Signaling networks centered on the conserved protein kinases AMPK (AMP-activated protein kinase)
and mTOR (mechanistic target of rapamycin) enable cells to sense and respond appropriately to dynamic
fluctuations in a variety of systemic and local cues. Energetic stress activates AMPK to promote catabolic and
suppress anabolic pathways to balance energy supply and demand. AMPK also promotes glucose and lipid
homeostasis. In fact, the AMPK-activating drug metformin (aka, GlucoPhage) represents the most widely
prescribed treatment for type II diabetes. Curiously, AMPK paradoxically functions as a tumor suppressor or
tumor promoter depending on cellular context. Nutrients (i.e. amino acids) and growth factors (i.e. IGF/insulin)
cooperate to activate mTOR complex 1 (mTORC1), which drives anabolic cell metabolism (i.e. protein and lipid
synthesis) and suppresses autophagy. Physiologically, aberrant mTORC1 signaling contributes to diverse
disorders including cancer and type II diabetes, and mTOR inhibitors are FDA-approved for renal cell carcinoma,
tuberous sclerosis complex (TSC), and stent restenosis following angioplasty. Despite the physiologic and
therapeutic importance of AMPK and mTORC1, major gaps exist in our molecular-level understanding of these
cell signaling networks. In prior work we showed that phosphorylation of mTOR (on S1261) promotes mTORC1
signaling and cell growth/size. Unexpectedly, a kinome screen identified AMPK as an mTOR S1261 kinase.
Finding that AMPK phosphorylates mTOR on an mTORC1-activating site presented an apparent paradox,
however, as AMPK canonically inhibits mTORC1 in response to severe energetic stress. Our preliminary results
reconcile this paradoxical finding and expose a major gap in our understanding of AMPK and its relationship with
mTORC1. We find that after induction of nutrient stress, specifically amino acid starvation, amino acids provided
either by re-feeding or autophagy activate AMPK and increase mTOR S1261 phosphorylation, which re-activates
mTORC1 signaling and promotes cell survival in an AMPK dependent manner. Moreover, mTOR S1261
phosphorylation requires Rheb, an upstream mTORC1 activator under negative control by TSC. In this proposal
we investigate an unexpected role for AMPK and mTORC1 in cellular adaptation to nutrient stress. We
hypothesize that the AMPK-mTORC1 axis functions to maintain a survival level of metabolism during prolonged
nutrient stress or facilitates metabolic recovery when the stress subsides. This research, which employs cultured
cells and a CRISPR-engineered mouse model lacking mTOR S1261 phosphorylation, will provide conceptual
advance as it will shift how we think about AMPK in metabolic control and its relationship with mTORC1.
Elucidating paradoxical activation of mTORC1 by AMPK will advance our understanding of mTOR and AMPK in
health and disease and may identify new therapeutic strategies for treatment of linked disorders, such as cancer
and metabolic di...

## Key facts

- **NIH application ID:** 10321301
- **Project number:** 5R01GM137577-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Diane C. Fingar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $344,295
- **Award type:** 5
- **Project period:** 2020-12-22 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10321301

## Citation

> US National Institutes of Health, RePORTER application 10321301, Unexpected role for AMPK and mTORC1 in cellular adaptation to nutrient stress (5R01GM137577-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10321301. Licensed CC0.

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