Cited by 606Metabolism, Diabetes, and CancerBiochemical and Molecular ResearchProtein Kinase Regulation and GTPase Signaling

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5′‐AMP inhibits dephosphorylation, as well as promoting phosphorylation, of the AMP‐activated protein kinase. Studies using bacterially expressed human protein phosphatase‐2C α and native bovine protein phosphatase‐2A c

S P Davies, Nicholas R. Helps, Philip Cohen, David Grahame Hardie·1995·FEBS Letters

DOI 10.1016/0014-5793(95)01368-7

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Abstract

Human protein phosphatase-2C alpha (PP2C alpha) was purified to homogeneity after expression in Escherichia coli. AMP inhibited the dephosphorylation of AMP-activated protein kinase (AMPK), but not phosphocasein, by PP2C alpha. The concentration dependence and the effects of other nucleotides (ATP and formycin A-5'-monophosphate) suggest that AMP acts by binding to the same site which causes direct allosteric activation of AMPK. A similar, although less pronounced, effect was observed with another protein phosphatase (PP2AC). We have now shown that AMPK activates the AMPK cascade by four mechanisms, which should make the system exquisitely sensitive to changes in AMP concentration.

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10.1111/j.1432-1033.1995.0558k.x · DOI
Clarke P.R., 1991, Adv. Protein Phosphatases, 6, 187
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“AMP and ADP binding also inhibits AMPK dephosphorylation mediated by phosphatases (Davies et al., 1995; Xiao et al., 2011), and the binding of AMPK complexes to ADP or AMP also leads to conformational changes, thus promoting phosphorylation of a threonine residue (Thr-172) and inhibiting its dephosphorylation.”
Background
Methyl Cinnamate (MC) Alleviates Free Fatty Acids (FFAs) Induced Lipid Accumulation Through the AMPK Pathway in HepG2 Cells
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Methods to Study Lysosomal AMPK Activation
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Endocannabinoid biosynthetic enzymes regulate pain response via LKB1–AMPK signaling
Chen, M., Shin, M., Ware, T. B., Donvito, G., Muchhala, K. H., Mischel, R. A., Mustafa, M. A., Serbulea, V., Upchurch, C. M., Leitinger, N., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2304900120 · Cited by 9
AMPK links cellular bioenergy status to the decision making of axon initiation in neurons
Amato, S., & Man, H. (2011) · Cellular Logistics · doi:10.4161/cl.1.3.16815 · Cited by 9
The mammalian AMP‐activated protein kinase complex mediates glucose regulation of gene expression in the yeast Saccharomyces cerevisiae
Tian, Y., Bendrioua, L., Carmena, D., García‐Salcedo, R., Dahl, P. J., Carling, D., & Hohmann, S. (2014) · FEBS Letters · doi:10.1016/j.febslet.2014.04.039 · Cited by 8
New Regulator for Energy Signaling Pathway in Plants Highlights Conservation Among Species
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Stress signaling in the heart by AMP-activated protein kinase
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The CRISPR-Cas9 crATIC HeLa transcriptome: Characterization of a novel cellular model of ATIC deficiency and ZMP accumulation
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Analysis of the aging-related biomarker in a nonhuman primate model using multilayer omics
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Absence of ULK1 decreases AMPK activity in the kidney, leading to chronic kidney disease progression
Yanagi, T., Kikuchi, H., Susa, K., Takahashi, N., Bamba, H., Suzuki, T., Nakano, Y., Fujiki, T., Mori, Y., Ando, F., et al. (2022) · Genes to Cells · doi:10.1111/gtc.12989 · Cited by 6
“We used anti-β-actin (1:1000, AAN01, Cytoskeleton, Inc., Denver, CO, USA), anti-AMPKα (1:1000, #2532, Cell Signaling Technology, Danvers, MA, USA), anti-phospho-AMPKα (pThr172) (1:1000, #2535, Cell Signaling Technology), anti-ULK1 (1:1000, #8054, Cell Signaling Technology), anti-phospho-ULK1 (pSer555) (1:1000, #5869,…”
BackgroundInfluential
Protein phosphatase PP2Cα S-glutathionylation regulates cell migration
Kukulage, D. S. K., Samarasinghe, K. T. G., Don, N. N. J. M., Shivamadhu, M. C., Shishikura, K., Schiff, W., Ramezani, F. M., Padmavathi, R., Matthews, M. L., & Ahn, Y. (2024) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2024.107784 · Cited by 7
“For example, PP2C a negatively regulates cell proliferation, migration, and mitogen-signaling (MAPK, including c-Jun N-terminal kinase (JNK) and p38) (33, 34), metabolism ( e.g. , AMPK) (35), cell cycle (CDK2 and CDK6), TGF-b signaling (SMAD2 and SMAD3) (36), in ﬂ ammation (IKK b and p65) (37, 38), and innate immunity…”
Inositol, Glycogen, Insulin, and Six Nobelists
Larner, J. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.x113.471177 · Cited by 7
Sucrose nonfermenting AMPK‐related kinase (SNARK) regulates exercise‐stimulated and ischemia‐stimulated glucose transport in the heart
Sun, X., Lessard, S. J., An, D., Koh, H., Esumi, H., Hirshman, M. F., & Goodyear, L. J. (2018) · Journal of Cellular Biochemistry · doi:10.1002/jcb.27425 · Cited by 7
Signaling by AMP‐activated Protein Kinase
Neumann, D., Wallimann, T., Rider, M. H., Tokarska-Schlattner, M., Hardie, D. G., & Schlattner, U. (2007) · Wiley eBooks · doi:10.1002/9783527621095.ch9 · Cited by 7
Cross-tissue MiRNA profiling of extracellular vesicles and PBMCs from amyotrophic lateral sclerosis patients
Dragoni, F., Gerlando, R. D., Diamanti, L., Rizzo, B., Bordoni, M., Scarian, E., Viola, C., Cerchia, G., Zucca, S., Pansarasa, O., et al. (2025) · Scientific Reports · doi:10.1038/s41598-025-99206-2 · Cited by 6
“Also it has been found that AMPK pathway activation delayed disease progression of ALS in SOD1 mice 37, 38 .”
Diet control to achieve euglycaemia induces tau hyperphosphorylation via AMPK activation in the hippocampus of diabetic rats
Sung, D. J., Noh, Y., Lee, J., Jin, M., Kim, J.-S., & Han, S.-D. (2019) · Food & Function · doi:10.1039/c9fo00709a · Cited by 6
AMPK
Karabiyik, C., Vicinanza, M., & Rubinsztein, D. C. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-820538-9.00004-1 · Cited by 6
Nutrient Digestion, Absorption, and Sensing
Bishu, S., & Quigley, E. M. M. (2015) · Wiley eBooks · doi:10.1002/9781118512074.ch29 · Cited by 6
Common and distinct roles of AMPKγ isoforms in small-molecule activator-stimulated glucose uptake in mouse skeletal muscle
Biswas, D., Espino-González, E., Ahwazi, D., Freemantle, J. B., Ehrlich, A. M., Jomard, C., Brorson, J., Schou, A. N., Farup, J., Gondin, J., et al. (2025) · Molecular Metabolism · doi:10.1016/j.molmet.2025.102294 · Cited by 5
“Similar to AMP, binding of ZMP to the γ -subunit activates AMPK by three distinct mechanisms: (i) increased Thr172 phosphorylation by LKB1; (ii) decreased Thr172 dephosphorylation by protein phosphatases; (iii) allosteric activation [1,15 — 17].”
Influential
AMPK–NLRP3 Inflammasome Crosstalk: Structural Insights, Molecular Mechanisms, and Therapeutic Implications for Inflammation and Neuroinflammation
Kodi, T., Nandakumar, K., & Kishore, A. (2026) · Molecular Neurobiology · doi:10.1007/s12035-026-05932-7 · Cited by 6
“This enhances the accessibility of Thr172 for phosphorylation by upstream kinases and protects it from dephosphorylation by protein phosphatases [28, 39].”
Charting protein dephosphorylation triggered by Toll-like receptor (TLR) signaling in macrophages and its role in health and disease
Silva, A. M., & Postler, T. S. (2021) · International review of cytology · doi:10.1016/bs.ircmb.2021.02.003 · Cited by 5
A multimodal Darwinian strategy for alleviating the atherosclerosis pandemic
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Array-based Western-blotting reveals spatial differences in hepatic signaling and metabolism following CAR activation
Treindl, F., Zabinsky, E., Kling, S., Schwarz, M., Braeuning, A., & Templin, M. F. (2020) · Archives of Toxicology · doi:10.1007/s00204-020-02680-y · Cited by 5
Dephosphorylation of endogenous GABAB receptor R2 subunit and AMPK α subunits which were measured by in vitro method using transfer membrane
Kuramoto, N., Ito, M., Saito, Y., Niihara, H., Tanaka, N., Yamada, K., Yamamura, Y., Iwasaki, K., Onishi, Y., & Ogita, K. (2012) · Neurochemistry International · doi:10.1016/j.neuint.2012.12.003 · Cited by 5
“…S783) can be activated by phosphorylation of its catalytic a1/2 subunit at threonine 172 (T172) and was suggested to be dephosphorylated by PP2C (Davies et al., 1995; Hardie et al., 1998) and by OA-sensitive phosphatases, presumably PP1, PP2A, or both (Terunuma et al., 2010; Samari et al.,…”
Background
Analyzing AMPK Function in the Hypothalamus
Seoane‐Collazo, P., & López, M. (2018) · Methods in molecular biology · doi:10.1007/978-1-4939-7598-3_27 · Cited by 5
Systems modeling and uncertainty quantification of AMP-activated protein kinase signaling
Linden-Santangeli, N. J., Zhang, J., Krämer, B., & Rangamani, P. (2025) · npj Systems Biology and Applications · doi:10.1038/s41540-025-00588-w · Cited by 4
AMP-Activated Protein Kinase: A Metabolic Stress Sensor in the Heart
Pelosse, M., Tokarska-Schlattner, M., & Schlattner, U. (2015) · Springer eBooks · doi:10.1007/978-3-319-15263-9_10 · Cited by 4
AMPK – A pivotal rheostat in the control of cardiac metabolism
Miller, E. J., Russell, R. R., Li, J., & Young, L. H. (2005) · Drug Discovery Today Disease Mechanisms · doi:10.1016/j.ddmec.2005.05.008 · Cited by 4
Reduction behavior induced by HL010183, a metformin derivative against the growth of cutaneous squamous cell carcinoma.
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The Role of Mammalian Target of Rapamycin (mTOR) and Adenosine Monophosphate-Activated Protein Kinase (AMPK) Signaling in Skeletal Muscle Hypertrophy: A Literature Review With Implications for Health and Disease
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“More importantly, this conformational change enhances the phosphorylation of the α -subunit at threonine-172 (Thr-172) by upstream kinases [80,81] and protects it from dephosphorylation by protein phosphatases like PP1, PP2A, and PP2C [82].”
Adenylate kinase 4 promotes radioresistance by suppressing radiation-induced ferroptosis through metabolic regulation in glioblastoma
Kim, B., Kang, H., Park, J., 박, 수., Youn, H., & Youn, B. (2026) · APOPTOSIS · doi:10.1007/s10495-026-02314-1 · Cited by 3
Regulation and Role of AMP-Activated Protein Kinase at the Cellular Level and Relevance to Diabetes Mellitus
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Trivalent Chromium Modulates Hexosamine Biosynthesis Pathway Transcriptional Activation of Cholesterol Synthesis and Insulin Resistance
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Authors: Davies, S. P., Helps, N. R., Cohen, P., & Hardie, D. G.
Affiliations: University of Dundee (GB)
ORCID: Philip Cohen
David Grahame Hardie
Venue: FEBS Letters
Publisher: Wiley
Published: 1995-12-27
Volume: 377
Issue: 3
Pages: 421-425
ISSN: 0014-5793 (ISSN-L)
1873-3468
DOI: 10.1016/0014-5793(95)01368-7
OpenAlex: W2030636484
Cited by: 595
References: 19
Citations by year: 2026: 7 · 2025: 6 · 2024: 18 · 2023: 11 · 2022: 16 · 2021: 25 · 2020: 23 · 2019: 17 · 2018: 21 · 2017: 28 · 2016: 25 · 2015: 30 · 2014: 36 · 2013: 32 · 2012: 35
FWCI: 3.22
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor, 1532 d)
Locations: FEBS Letters (publishedVersion)
PubMed (publishedVersion)
Funders: Wellcome Trust
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords: AMPK, AMP, dephosphorylation, phosphorylation, allosteric activation, nucleotide binding, formycin A, energy homeostasis
MeSH terms: Protein Phosphatase 2C, Adenosine Monophosphate, Allosteric Regulation, Animals, Base Sequence, Cattle, Dose-Response Relationship, Drug, Enzyme Activation, Escherichia coli, Humans, Isoenzymes, Models, Biological, Molecular Sequence Data, Multienzyme Complexes, Nucleotides, Phosphoprotein Phosphatases, Phosphorylation, Protein Kinases, Recombinant Proteins, Signal Transduction, Protein Serine-Threonine Kinases, Saccharomyces cerevisiae Proteins, Protein Phosphatase 2, AMP-Activated Protein Kinases

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5′‐AMP inhibits dephosphorylation, as well as promoting phosphorylation, of the AMP‐activated protein kinase. Studies using bacterially expressed human protein phosphatase‐2C α and native bovine protein phosphatase‐2A c

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