1. Academic Validation
  2. mTORC1 directly inhibits AMPK to promote cell proliferation under nutrient stress

mTORC1 directly inhibits AMPK to promote cell proliferation under nutrient stress

  • Nat Metab. 2020 Jan;2(1):41-49. doi: 10.1038/s42255-019-0157-1.
Naomi X Y Ling  # 1 Adrian Kaczmarek  # 2 Ashfaqul Hoque  # 1 Elizabeth Davie  # 3 Kevin R W Ngoei  # 4 Kaitlin R Morrison 2 William J Smiles 1 Gabriella M Forte 3 Tingting Wang 2 Shervi Lie 2 Toby A Dite 1 5 Christopher G Langendorf 4 John W Scott 4 6 7 Jonathan S Oakhill 8 9 Janni Petersen 10 11 12
Affiliations

Affiliations

  • 1 Metabolic Signalling Laboratory, St Vincent's Institute of Medical Research, School of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
  • 2 Flinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia.
  • 3 Faculty of Life Sciences, University of Manchester, Manchester, UK.
  • 4 Protein Chemistry and Metabolism Unit, St Vincent's Institute of Medical Research, School of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
  • 5 MRC Protein Phosphorylation and Ubiquitylation Unit, James Black Centre, University of Dundee, Dundee, UK.
  • 6 Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Victoria, Australia.
  • 7 Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.
  • 8 Metabolic Signalling Laboratory, St Vincent's Institute of Medical Research, School of Medicine, University of Melbourne, Melbourne, Victoria, Australia. [email protected].
  • 9 Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Victoria, Australia. [email protected].
  • 10 Flinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia. [email protected].
  • 11 Faculty of Life Sciences, University of Manchester, Manchester, UK. [email protected].
  • 12 Nutrition and Metabolism, South Australia Health and Medical Research Institute, Adelaide, South Australia, Australia. [email protected].
  • # Contributed equally.
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 the mammalian homologs, which is associated with reduced phosphorylation of activation loop Thr172. Genetic or pharmacological inhibition of TORC1 signalling led to AMPK activation in the absence of increased AMP:ATP ratios; under nutrient stress conditions this was associated with growth limitation in both yeast and human cell cultures. Our findings reveal fundamental, bi-directional regulation between two major metabolic signalling networks and uncover new opportunity for Cancer treatment strategies aimed at suppressing cell proliferation in the nutrient-poor tumor microenvironment.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-16297A
    99.96%, CDK4/6 Inhibitor
    CDK