mTORC1 directly inhibits AMPK to promote cell proliferation under nutrient stress

Naomi X.Y. Ling, Adrian Kaczmarek, Ashfaqul Hoque, Elizabeth Davie, Kevin R. W. Ngoei, Kaitlin R. Morrison, William J. Smiles, Gabriella M. Forte, Tingting Wang, Shervi Lie, Toby A. Dite, Christopher G. Langendorf, John W. Scott, Jonathan S. Oakhill (Lead / Corresponding author), Janni Petersen (Lead / Corresponding author)

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Abstract

Highly conserved signalling pathways controlled by mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) are central to cellular metabolism and cell proliferation1,2, and their dysregulation is implicated in the pathogenesis of major human diseases such as cancer and type 2 diabetes. AMPK pathways leading to reduced cell proliferation are well established and, in part, act through inhibition of TOR complex 1 (TORC1) activity. Here we demonstrate reciprocal regulation, specifically that TORC1 directly downregulates AMPK signalling by phosphorylating the evolutionarily conserved residue S367 in the fission yeast AMPK catalytic subunit Ssp2 and AMPK α1 S347 and α2 S345 in the mammalian homologs, which is associated with reduced phosphorylation of activation loop T172. Genetic or pharmacological inhibition of TORC1 signalling led to AMPK activation in the absence of increased AMP/ATP ratios, which under nutrient stress conditions was associated with growth limitation in both yeast and human cell cultures. Our findings reveal fundamental bidirectional regulation between two major metabolic signalling networks and uncover new opportunities for cancer treatment strategies aimed at suppressing cell proliferation in the nutrient-poor tumour microenvironment.

Original languageEnglish
Pages (from-to)41-49
Number of pages9
JournalNature Metabolism
Volume2
Issue number1
Early online date20 Jan 2020
DOIs
Publication statusPublished - Jan 2020

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Ling, N. X. Y., Kaczmarek, A., Hoque, A., Davie, E., Ngoei, K. R. W., Morrison, K. R., Smiles, W. J., Forte, G. M., Wang, T., Lie, S., Dite, T. A., Langendorf, C. G., Scott, J. W., Oakhill, J. S., & Petersen, J. (2020). mTORC1 directly inhibits AMPK to promote cell proliferation under nutrient stress. Nature Metabolism, 2(1), 41-49. https://doi.org/10.1038/s42255-019-0157-1