An AMPKα2-specific phospho-switch controls lysosomal targeting for activation

Kaitlin R. Morrison, William J. Smiles, Naomi X.Y. Ling, Ashfaqul Hoque, Gabrielle Shea, Kevin R.W. Ngoei, Dingyi Yu, Lisa Murray-Segal, John W. Scott, Sandra Galic, Bruce E. Kemp, Janni Petersen, Jonathan S. Oakhill

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8 Citations (Scopus)
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AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin complex 1 (mTORC1) are metabolic kinases that co-ordinate nutrient supply with cell growth. AMPK negatively regulates mTORC1, and mTORC1 reciprocally phosphorylates S345/7 in both AMPK α-isoforms. We report that genetic or torin1-induced loss of α2-S345 phosphorylation relieves suppression of AMPK signaling; however, the regulatory effect does not translate to α1-S347 in HEK293T or MEF cells. Dephosphorylation of α2-S345, but not α1-S347, transiently targets AMPK to lysosomes, a cellular site for activation by LKB1. By mass spectrometry, we find that α2-S345 is basally phosphorylated at 2.5-fold higher stoichiometry than α1-S347 in HEK293T cells and, unlike α1, phosphorylation is partially retained after prolonged mTORC1 inhibition. Loss of α2-S345 phosphorylation in endogenous AMPK fails to sustain growth of MEFs under amino acid starvation conditions. These findings uncover an α2-specific mechanism by which AMPK can be activated at lysosomes in the absence of changes in cellular energy.

Original languageEnglish
Article number110365
Number of pages28
JournalCell Reports
Issue number7
Publication statusPublished - 15 Feb 2022


  • AMPK
  • energy homeostasis
  • kinase
  • lysosome
  • metabolic signaling
  • mTORC1
  • phosphorylation


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