Journal article

mTORC1 directly inhibits AMPK to promote cell proliferation under nutrient stress

Naomi XY Ling, Adrian Kaczmarek, Ashfaqul Hoque, Elizabeth Davie, Kevin RW 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, Janni Petersen

Nature Metabolism | NATURE RESEARCH | Published : 2020

Abstract

Central to cellular metabolism and cell proliferation are highly conserved signalling pathways controlled by mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK)1,2, dysregulation of which are implicated in 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 down-regulates AMPK signalling by phosphorylating the evolutionarily conserved residue Ser367 in the fission yeast AMPK catalytic subunit Ssp2, and AMPK α1Ser347/α2Ser345 in t..

View full abstract

Grants

Awarded by Early Career Fellowship from the National Health and Medical Research Council (NHMRC)


Awarded by Australian Research Council (ARC)


Awarded by NHMRC


Awarded by Cancer Research UK senior fellowship


Awarded by Cancer Council Australia


Awarded by Worldwide Cancer Research


Awarded by ARC


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).