Journal article
mTORC1 directly inhibits AMPK to promote cell proliferation under nutrient stress
NXY Ling, A Kaczmarek, A Hoque, E Davie, KRW Ngoei, KR Morrison, WJ Smiles, GM Forte, T Wang, S Lie, TA Dite, CG Langendorf, JW Scott, JS Oakhill, J Petersen
Nature Metabolism | NATURE RESEARCH | Published : 2020
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..
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Awarded by Worldwide Cancer Research
Funding Acknowledgements
We thank K. Gull (Oxford University, UK) and S. Lim (St. Vincent's Institute, Australia) for antibodies, M. Balasubramanian (Warwick University, UK), K. Shiozaki (Nara University, Japan) and S. Moreno (IBFG Salamanca, Spain) for yeast strains, M. Hall (University of Basel, Switzerland) for iRapKO MEFs, I. Hagan for stimulating discussions and C. Proud and J. Murphy for critical evaluation of the manuscript. C.G.L. was supported by an Early Career Fellowship from the National Health and Medical Research Council (NHMRC; 1143080). J.S.O. was supported by a Future Fellowship from the Australian Research Council (ARC; FT130100988), the NHMRC (1098459), St Vincent's Institute of Medical Research (Australia) and in part by the Victorian Government's Operational Infrastructure Support Program. J.P. was supported by a Cancer Research UK senior fellowship (C10888/A11178), Cancer Council Australia (1125662), Worldwide Cancer Research (16-0052), the NHMRC (1161262), the ARC (DP180101682), a Flinders Foundation seeding grant, Manchester (UK), and Flinders University (Australia).