mTORC1 directly inhibits AMPK to promote cell proliferation under nutrient stress

Journal article


Ling, Naomi X. Y., Kaczmarek, Adrian, Hoque, Ashfaqul, Davie, Elizabeth, Ngoei, Kevin R. W., Morrison, Kaitlin R., Smiles, William J., Forte, Gabriella M., Wang, Tingting, Lie, Shervi, Dite, Toby A., Langendorf, Christopher G., Scott, John W., Oakhill, Jonathan S. and Petersen, Janni. (2020). mTORC1 directly inhibits AMPK to promote cell proliferation under nutrient stress. Nature Metabolism. 2, pp. 41-49. https://doi.org/10.1038/s42255-019-0157-1
AuthorsLing, Naomi X. Y., Kaczmarek, Adrian, Hoque, Ashfaqul, Davie, Elizabeth, Ngoei, Kevin R. W., Morrison, Kaitlin R., Smiles, William J., Forte, Gabriella M., Wang, Tingting, Lie, Shervi, Dite, Toby A., Langendorf, Christopher G., Scott, John W., Oakhill, Jonathan S. and Petersen, Janni
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.

Year2020
JournalNature Metabolism
Journal citation2, pp. 41-49
PublisherNature Publishing Group
ISSN2522-5812
Digital Object Identifier (DOI)https://doi.org/10.1038/s42255-019-0157-1
PubMed ID31993556
Scopus EID2-s2.0-85078318076
PubMed Central IDPMC6986917
Open accessPublished as green open access
Page range41-49
FunderAustralian Research Council (ARC)
National Health and Medical Research Council (NHMRC)
Author's accepted manuscript
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Open
Publisher's version
License
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File Access Level
Controlled
Output statusPublished
Publication dates
Online20 Jan 2020
Publication process dates
Accepted10 Dec 2019
Deposited30 Apr 2021
ARC Funded ResearchThis output has been funded, wholly or partially, under the Australian Research Council Act 2001
Grant IDARC/FT130100988
ARC/DP180101682
NHMRC/1143080
NHMRC/1098459
NHMRC/1161262
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O'Brien, Matthew, Oakhill, Jonathan S., Ling, Naomi, Langendorf, Christopher G., Hoque, Ashfaqul, Dite, Toby A., Means, Anthony R., Kemp, Bruce and Scott, John W.. (2017). Impact of genetic variation on human CaMKK2 regulation by Ca2+ -calmodulin and multisite phosphorylation. Scientific Reports. 7, pp. 1 - 11. https://doi.org/10.1038/srep43264
The sweet side of AMPK signaling: Regulation of GFAT1
Scott, John W. and Oakhill, Jonathan S.. (2017). The sweet side of AMPK signaling: Regulation of GFAT1. Biochemical Journal. 474(7), pp. 1289 - 1292. https://doi.org/10.1042/BCJ20170006
The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs
Dite, Toby A., Ling, Naomi, Scott, John W., Hoque, Ashfaqul, Galic, Sandra, Parker, Benjamin L., Ngoei, Kevin R.W., Langendorf, Christopher G., O'Brien, Matthew, Kundu, Mondira, Viollet, Benoit, Steinberg, Gregory R., Sakamoto, Kei, Kemp, Bruce and Oakhill, Jonathan S.. (2017). The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs. Nature Communications. 8(571), pp. 1 - 14. https://doi.org/10.1038/s41467-017-00628-y
Fake inhibitors: AMPK activation trumps inhibition
Langendorf, Christopher G., Scott, John W. and Kemp, Bruce E.. (2017). Fake inhibitors: AMPK activation trumps inhibition. Cell Chemical Biology. 24(7), pp. 775 - 777. https://doi.org/10.1016/j.chembiol.2017.07.005
Dynamic proteome profiling of individual proteins in human skeletal muscle after a high-fat diet and resistance exercise
Camera, Donny M., Burniston, Jatin G., Pogson, Mark A., Smiles, William J. and Hawley, John A.. (2017). Dynamic proteome profiling of individual proteins in human skeletal muscle after a high-fat diet and resistance exercise. The FASEB Journal. 31(12), pp. 5478-5494. https://doi.org/10.1096/fj.201700531R
Autophagy and Protein Turnover Responses to Exercise-Nutrient Interactions in Human Skeletal Muscle
Smiles, William J.. (2017). Autophagy and Protein Turnover Responses to Exercise-Nutrient Interactions in Human Skeletal Muscle [Thesis]. https://doi.org/10.4226/66/59f29efd01e38
Transcriptomic and epigenetic responses to short-term nutrient-exercise stress in humans
Laker, R. C., Garde, C., Camera, Donny, Smiles, William, Zierath, J. R., Hawley, John and Barrès, R.. (2017). Transcriptomic and epigenetic responses to short-term nutrient-exercise stress in humans. Scientific Reports. 7(1), pp. 1 - 12. https://doi.org/10.1038/s41598-017-15420-7
Cyclin-dependent kinase-mediated phosphorylation of breast cancer metastasis suppressor 1 (BRMS1) affects cell migration
Roesley, Siti Nur Ain, Suryadinata, Randy, Morrish, Emma, Tan, Anthonius Ricardo, Issa, Samah M. A., Oakhill, Jon, Bernard, Ora, Welch, Danny R. and Sarcevic, Boris. (2016). Cyclin-dependent kinase-mediated phosphorylation of breast cancer metastasis suppressor 1 (BRMS1) affects cell migration. Cell Cycle. 15(1), pp. 137 - 151. https://doi.org/10.1080/15384101.2015.1121328
Acute endurance exercise induces nuclear p53 abundance in human skeletal muscle
Tachtsis, Bill, Smiles, William, Lane, Steven C., Hawley, John Alan and Camera, Donny Michael. (2016). Acute endurance exercise induces nuclear p53 abundance in human skeletal muscle. Frontiers in Physiology. 7(144), pp. 1 - 10. https://doi.org/10.3389/fphys.2016.00144
Structural basis of allosteric and synergistic activation of AMPK by furan-2-phosphonic derivative C2 binding
Langendorf, Christopher G., Ngoei, Kevin R. W., Scott, John W., Ling, Naomi X. Y., Issa, Sam M. A., Gorman, Michael A., Parker, Michael W., Sakamoto, Kei, Oakhill, Jonathan S. and Kemp, Bruce Ernest. (2016). Structural basis of allosteric and synergistic activation of AMPK by furan-2-phosphonic derivative C2 binding. Nature Communications. 7, pp. 1 - 8. https://doi.org/10.1038/ncomms10912
Exercise-induced skeletal muscle signaling pathways and human athletic performance
Camera, Donny Michael, Smiles, William J. and Hawley, John Alan. (2016). Exercise-induced skeletal muscle signaling pathways and human athletic performance. Free Radical Biology & Medicine. 98, pp. 131 - 143. https://doi.org/10.1016/j.freeradbiomed.2016.02.007
Effects of skeletal muscle energy availability on protein turnover responses to exercise
Smiles, William J., Hawley, John Alan and Camera, Donny Michael. (2016). Effects of skeletal muscle energy availability on protein turnover responses to exercise. Journal of Experimental Biology. 219(Pt 2), pp. 214 - 225. https://doi.org/10.1242/jeb.125104
Protein coingestion with alcohol following strenuous exercise attenuates alcohol-induced intramyocellular apoptosis and inhibition of autophagy
Smiles, William J., Parr, Evelyn B., Coffey, Vernon G., Lacham-Kaplan, Orly, Hawley, John Alan and Camera, Donny Michael. (2016). Protein coingestion with alcohol following strenuous exercise attenuates alcohol-induced intramyocellular apoptosis and inhibition of autophagy. American Journal of Physiology - Endocrinology and Metabolism. 311(5), pp. E836 - E849. https://doi.org/10.1152/ajpendo.00303.2016
The social supply of cannabis among young people in Australia
Lenton, Simon, Grigg, Jodie, Scott, John, Barratt, Monica and Eleftheriadis, Dina. (2015). The social supply of cannabis among young people in Australia. Trends and Issues in Crime and Criminal Justice. (503), pp. 1-6.
Metformin and salicylate synergistically activate liver AMPK, inhibit lipogenesis and improve insulin sensitivity
Ford, Rebecca, Fullerton, Morgan, Pinkosky, Stephen, Day, Emily, Scott, John, Oakhill, Jonathan, Bujak, Adam, Smith, Brennan, Crane, Justin, Blumer, Regje, Marcinko, Katarina, Kemp, Bruce, Gerstein, Hertzel and Steinberg, Gregory. (2015). Metformin and salicylate synergistically activate liver AMPK, inhibit lipogenesis and improve insulin sensitivity. Biochemical Journal. 468(1), pp. 125 - 132. https://doi.org/10.1042/BJ20150125
Inhibition of AMP-activated protein kinase at the allosteric drug-binding site promotes islet insulin release
Scott, John, Galic, Sandra, Graham, Kate, Foitzik, Richard, Ling, Naomi, Dite, Toby, Issa, Samah, Langendorf, Chris, Weng, Qing, Thomas, Helen, Kay, Thomas, Birnberg, Neal, Steinberg, Gregory, Kemp, Bruce and Oakhill, Jonathan. (2015). Inhibition of AMP-activated protein kinase at the allosteric drug-binding site promotes islet insulin release. Chemistry and Biology. 22(6), pp. 705 - 711. https://doi.org/10.1016/j.chembiol.2015.05.011
Autophosphorylation of CaMKK2 generates autonomous activity that is disrupted by a T85S mutation linked to anxiety and bipolar disorder
Scott, John, Park, Elizabeth, Rodriguiz, Ramona, Oakhill, Jonathan, Issa, Samah, O'Brien, Matthew, Dite, Toby, Langendorf, Christopher, Wetsel, William, Means, Anthony and Kemp, Bruce. (2015). Autophosphorylation of CaMKK2 generates autonomous activity that is disrupted by a T85S mutation linked to anxiety and bipolar disorder. Scientific Reports. 5, pp. 1 - 10. https://doi.org/10.1038/srep14436
SnRK1 from Arabidopsis thaliana is an atypical AMPK
Emanuelle, Shane, Hossain, Mohammed Iqbal, Moller, Isabel E., Pedersen, Henriette L., van de Meene, Allison M. L., Doblin, Monika S., Koay, Ann, Oakhill, Jonathan S., Scott, John W., Willats, William G. T., Kemp, Bruce Ernest, Bacic, Antony, Gooley, Paul R. and Stapleton, David I.. (2015). SnRK1 from Arabidopsis thaliana is an atypical AMPK. Plant Journal. 82(2), pp. 183 - 192. https://doi.org/10.1111/tpj.12813
Mutant TDP-43 deregulates AMPK activation by PP2A in ALS models
Perera, Nirma, Sheean, Rebecca, Scott, John, Kemp, Bruce, Horne, Malcolm and Turner, Bradley. (2014). Mutant TDP-43 deregulates AMPK activation by PP2A in ALS models. PLoS One (online). 9(3), pp. 1 - 11. https://doi.org/10.1371/journal.pone.0090449
The relationship between exercise, nutrition and type 2 diabetes
Stephenson, Erin J., Smiles, William and Hawley, John Alan. (2014). The relationship between exercise, nutrition and type 2 diabetes. Medicine and Sport Science. 60, pp. 1 - 10. https://doi.org/10.1159/000357331
ATP sensitive bi-quinoline activator of the AMP-activated protein kinase
Scott, John, Oakhill, Jonathan, Ling, Naomi, Langendorf, Christopher, Foitzik, Richard, Kemp, Bruce and Issinger, Olaf-Georg. (2014). ATP sensitive bi-quinoline activator of the AMP-activated protein kinase. Biochemical and Biophysical Research Communications. 443(2), pp. 435 - 440. https://doi.org/10.1016/j.bbrc.2013.11.130
Small molecule drug A-769662 and AMP synergistically activate naive AMPK independent of upstream kinase signaling
Scott, John, Ling, Naomi, Issa, Samah, Dite, Toby, O'Brien, Matthew, Chen, Zhi-Ping, Galic, Sandra, Langendorf, Christopher, Steinberg, Gregory, Kemp, Bruce and Oakhill, Jonathan. (2014). Small molecule drug A-769662 and AMP synergistically activate naive AMPK independent of upstream kinase signaling. Chemistry and Biology. 21(5), pp. 619 - 627. https://doi.org/10.1016/j.chembiol.2014.03.006
Differences between first episode schizophrenia and schizoaffective disorder
Cotton, Sue, Lambert, M, Schimmelmann, B, Mackinnon, Andrew, Gleeson, John, Berk, Michael, Hides, L, Chanen, Andrew, Scott, J and Schottle, D. (2013). Differences between first episode schizophrenia and schizoaffective disorder. Schizophrenia Research. https://doi.org/10.1016/j.schres.2013.02.036
Ca 2+/calmodulin-dependent protein kinase kinase beta is regulated by multisite phosphorylation
Green, Michelle, Scott, John, Steel, Rohan, Oakhill, Jonathan, Kemp, Bruce and Means, Anthony. (2011). Ca 2+/calmodulin-dependent protein kinase kinase beta is regulated by multisite phosphorylation. Journal of Biological Chemistry. 286(32), pp. 28066 - 28079. https://doi.org/10.1074/jbc.M111.251504
AMPK is a direct adenylate charge-regulated protein kinase
Oakhill, Jonathan S., Steel, Rohan, Chen, Zhi-Ping, Scott, John W., Ling, Naomi, Tam, Shanna and Kemp, Bruce Ernest. (2011). AMPK is a direct adenylate charge-regulated protein kinase. Science. 332(6036), pp. 1433 - 1435. https://doi.org/10.1126/science.1200094