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Updated: Aug 11, 2025

Isolation of Primary Mouse Hepatocytes for Nascent Protein Synthesis Analysis by Non-radioactive L-azidohomoalanine Labeling Method
08:04

Isolation of Primary Mouse Hepatocytes for Nascent Protein Synthesis Analysis by Non-radioactive L-azidohomoalanine Labeling Method

Published on: October 23, 2018

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AMPK-dependent phosphorylation of the GATOR2 component WDR24 suppresses glucose-mediated mTORC1 activation

Xiaoming Dai1, Cong Jiang1, Qiwei Jiang2

  • 1Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

Nature Metabolism
|February 2, 2023
PubMed

Insights

AMP-activated protein kinase (AMPK) phosphorylates WDR24, a GATOR2 component, to regulate how the mechanistic target of rapamycin complex 1 (mTORC1) senses glucose. This discovery offers new therapeutic targets for diseases involving abnormal mTORC1 signaling.

Area of Science:

  • Cellular signaling
  • Metabolic regulation
  • Molecular mechanisms

Background:

  • The mechanistic target of rapamycin complex 1 (mTORC1) is a key regulator of cell growth, influenced by nutrient availability.
  • The precise mechanisms by which mTORC1 senses glucose levels to control downstream pathways are not fully understood.

Purpose of the Study:

  • To elucidate the role of AMP-activated protein kinase (AMPK) in glucose sensing by mTORC1.
  • To identify novel components involved in the mTORC1 glucose-sensing pathway.

Main Methods:

  • Investigated the phosphorylation of WDR24 by AMPK in response to glucose deprivation.
  • Utilized phosphomimetic (S155D) and phospho-deficient (S155A) Wdr24 knock-in mouse models.
  • Assessed mTORC1 activity and physiological responses in these models.

Main Results:

  • AMPK-mediated phosphorylation of WDR24 on S155 disrupts the GATOR2 complex, suppressing mTORC1 activation during glucose deprivation.
  • Wdr24S155D mice showed early embryonic lethality and reduced mTORC1 activity.
  • Wdr24S155A mice exhibited enhanced resistance to fasting and elevated mTORC1 activity.

Conclusions:

  • AMPK-dependent WDR24 phosphorylation is a critical mediator of glucose-induced mTORC1 activation.
  • Targeting the AMPK-WDR24 signaling axis presents a potential therapeutic strategy for diseases characterized by aberrant mTORC1 signaling, such as cancer.

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