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
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Evolving Lessons on the Complex Role of AMPK in Normal Physiology and Cancer
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Hypothalamic AMPK and energy balance
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“These different subunits are encoded by different genes.1,4,10,13,14 The activation of AMPK by phosphorylation of Thr172 in the α subunit is a process that can be allosterically regulated by AMP (but not ADP)15 and mediated by several upstream kinases, such as the liver kinase B1 (LKB1),16,17 the scaffold protein mous…”
Background
Upregulation of 5′-AMP–Activated Protein Kinase Is Responsible for the Increase in Myocardial Fatty Acid Oxidation Rates Following Birth in the Newborn Rabbit
Makinde, A.-O., Gamble, J., & Lopaschuk, G. D. (1997) · Circulation Research · doi:10.1161/01.res.80.4.482 · Cited by 116
Three spinach leaf nitrate reductase-3-hydroxy-3-methylglutaryl-CoA reductase kinases that are regulated by reversible phosphorylation and/or Ca2+ ions
DOUGLAS, P., Pigaglio, E., Ferrer, A., Halford, N. G., & MacKintosh, C. (1997) · Biochemical Journal · doi:10.1042/bj3250101 · Cited by 116
Uncoupling of the LKB1-AMPKα Energy Sensor Pathway by Growth Factors and Oncogenic BRAFV600E
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“dephosphorylation [37,38,39], slightly increased the p-AMPK”
AMPK-mediated GSK3β inhibition by isoliquiritigenin contributes to protecting mitochondria against iron-catalyzed oxidative stress
Choi, S. H., Kim, Y. W., & Kim, S. G. (2009) · Biochemical Pharmacology · doi:10.1016/j.bcp.2009.12.011 · Cited by 118
“Protein phosphatase 2C is a negative regulator of AMPK [51].”
AMP-Activated Protein Kinase: A Master Switch in Glucose and Lipid Metabolism
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“Binding of AMP to AMPK also inhibits dephosphorylation at this site by protein phosphatases [10].”
Background
AMP‐ACTIVATED PROTEIN KINASE ACTIVATION AS A STRATEGY FOR PROTECTING VASCULAR ENDOTHELIAL FUNCTION
Zou, M., & Wu, Y. (2007) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/j.1440-1681.2007.04851.x · Cited by 116
“Using the inactivation assay as the criterion, Davies et al.(71) found that dephosphorylation of AMPK by PP2Ca is inhibited by 5¢-AMP.”
BackgroundMethodInfluential
Structure of an AMPK complex in an inactive, ATP-bound state
Yan, Y., Mukherjee, S., Harikumar, K. G., Strutzenberg, T. S., Zhou, X. E., Suino-Powell, K. M., Xu, T.-H., Sheldon, R. D., Lamp, J. A., Brunzelle, J. S., et al. (2021) · Science · doi:10.1126/science.abe7565 · Cited by 114
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“…been identified that are responsible for the phosphorylation and dephosphorylation of this residue: LKB1, calcium/ calmodulin-dependent kinase kinase 2 (CAMKK2), and protein phosphatase 2C and 2A (PP2C and PP2A) (Woods et al. 2003; Hawley et al. 2003, 2005; Woods et al. 2005; Davies et al. 1995).”
Osteoblast differentiation is functionally associated with decreased AMP kinase activity
Kasai, T., Bandow, K., Suzuki, H., Chiba, N., Kakimoto, K., Ohnishi, T., Kawamoto, S., Nagaoka, E., & Matsuguchi, T. (2009) · Journal of Cellular Physiology · doi:10.1002/jcp.21917 · Cited by 112
“ZMP then activates AMPK by inducing phosphorylation of the catalytic AMPKa subunit (Corton et al., 1995; Davies et al., 1995).”
Background
Exercise-induced metabolic fluctuations influence AMPK, p38-MAPK and CaMKII phosphorylation in human skeletal muscle
Combes, A., Dekerle, J., Webborn, N., Watt, P., Bougault, V., & Daussin, F. (2015) · Physiological Reports · doi:10.14814/phy2.12462 · Cited by 120
“9 | e12462 Page 5 (CBS) domain of the c subunit, to activate AMPK (Davies et al. 1995; Suter et al. 2006).”
Background
Regulation of fatty acid uptake and metabolism in L6 skeletal muscle cells by resistin
Palanivel, R., & Sweeney, G. (2005) · FEBS Letters · doi:10.1016/j.febslet.2005.08.011 · Cited by 111
“Similarly, the ability of resistin to promote desphosphorylation of AMPK by PP2Ca, or the less potent PP2Ac [34] remains to be determined.”
Background
AMPK and vasculoprotection
Ewart, M., & Kennedy, S. (2010) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2010.11.002 · Cited by 112
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Ppm1E is an in cellulo AMP-activated protein kinase phosphatase
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Hepatic energy state is regulated by glucagon receptor signaling in mice
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Normal hypertrophy accompanied by phosphoryation and activation of AMP‐activated protein kinase α1 following overload in LKB1 knockout mice
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“This causes a conformational change that inhibits dephosphorylation of Thr172 on the α subunit (Davies et al. 1995; Sanders et al. 2007), causing a net increase in phosphorylation at this site and thus activation (Hawley et al. 1996).”
Background
The Relationship between AMP-activated Protein Kinase Activity and AMP Concentration in the Isolated Perfused Rat Heart
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HIGD1A Regulates Oxygen Consumption, ROS Production, and AMPK Activity during Glucose Deprivation to Modulate Cell Survival and Tumor Growth
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“…in human GBM. Multiple studies have previously linked ROS suppression and cell survival with AMPK activation, likely via phosphatase inhibition (Davies et al., 1995; Faubert et al., 2013; Han et al., 2010; Hofstetter et al., 2012; Indraccolo, 2013; Ingebritsen et al., 1983; Jeon et al., 2012;…”
Background
Nilotinib Induces Autophagy in Hepatocellular Carcinoma through AMPK Activation
Yu, H.-C., Lin, C., Tai, W., Liu, C., Shiau, C., & Chen, K. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.446385 · Cited by 103
Rapid alteration of protein phosphorylation during postmortem: implication in the study of protein phosphorylation
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Role of PP2C in cardiac lipid accumulation in obese rodents and its prevention by troglitazone
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The regulation of Acetyl-CoA carboxylase—a potential target for the action of hypolipidemic agents
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Dephosphorylation of Human Cyclin-dependent Kinases by Protein Phosphatase Type 2Cα and β2 Isoforms
Cheng, A., Kaldis, P., & Solomon, M. J. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m006210200 · Cited by 99
AMP‐activated protein kinase: a core signalling pathway in the heart
Kim, A. S., Miller, E. J., & Young, L. H. (2009) · Acta Physiologica · doi:10.1111/j.1748-1716.2009.01978.x · Cited by 99
“Both PP2A and PP2C have been shown to dephosphorylate AMPK in vitro (Davies et al. 1995, Kudo et al. 1996).”
Background
Extracellular adenosine activates AMP-dependent protein kinase (AMPK)
Aymerich, I., Foufelle, F., Ferré, P., Casado, F. J., & Pastor‐Anglada, M. (2006) · Journal of Cell Science · doi:10.1242/jcs.02865 · Cited by 97
“AMP interaction with AMPK also seems to turn this kinase into a poorer substrate for phosphatases (Davies et al., 1995).”
Background
The SNF1 kinase complex from Saccharomyces cerevisiae phosphorylates the transcriptional repressor protein Mig1p in vitro at four sites within or near regulatory domain 1
Smith, F. C., Davies, S. P., Wilson, W. A., Carling, D., & Hardie, D. G. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)00725-5 · Cited by 96
Inhibition of several protein phosphatases by a non-covalently interacting microcystin and a novel cyanobacterial peptide, nostocyclin
Hastie, C. J., Borthwick, E. B., Morrison, L. F., Codd, G., & COHEN, P. (2005) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2005.06.005 · Cited by 96
Regulation of AMPK by the Ubiquitin Proteasome System
Zungu, M., Schisler, J. C., Essop, M. F., McCudden, C. R., Patterson, C., & Willis, M. S. (2011) · American Journal Of Pathology · doi:10.1016/j.ajpath.2010.11.030 · Cited by 96
“Last, AMP binding inhibits Thr172 dephosphorylation by upstream phosphatases, thus promoting increased AMPK phosphorylation.(20) However, there is also AMP/ATP-independent activation of cardiac AMPK by upstream AMPKKs, such as the serine-threonine liver kinase B1 (LKB1) and Ca(2) /calmodulin-dependent protein kinase k…”
Background
Regulation of the renal-specific Na+–K+–2Cl− co-transporter NKCC2 by AMP-activated protein kinase (AMPK)
Fraser, S. A., Gimenez-Lopez, I., Cook, N., Jennings, I. G., Katerelos, M., Katsis, F., Levidiotis, V., Kemp, B. E., & Power, D. A. (2007) · Biochemical Journal · doi:10.1042/bj20061850 · Cited by 93

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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