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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Background
Direct AMP-activated protein kinase activators: a review of evidence from the patent literature
Giordanetto, F., & Karis, D. (2012) · Expert Opinion on Therapeutic Patents · doi:10.1517/13543776.2012.743994 · Cited by 66
“AMP (and ADP) binding to these sites on the g subunit can activate AMPK via at least two allosteric mechanisms: promotion of initial phosphorylation at Thr-172 on the catalytic a subunit and inhibition of dephosphorylation of the same residue [9-12].”
Background
Oxygen, pH, and mitochondrial oxidative phosphorylation
Wilson, D. F., Harrison, D. K., & Vinogradov, S. A. (2012) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01160.2012 · Cited by 68
Palbociclib induces activation of AMPK and inhibits hepatocellular carcinoma in a CDK 4/6‐independent manner
Hsieh, F., Chen, Y., Hung, M., Chu, P., Tsai, M., Chen, L., Hsiao, Y., Shih, C., Chang, M.-J., Chao, T., et al. (2017) · Molecular Oncology · doi:10.1002/1878-0261.12072 · Cited by 66
“AMPK phosphorylation at Thr172 can be negatively regulated by Ser/Thr protein phosphatases such as PP2A, PP2C, PP1, and PPM1E (Davies et al., 1995; Garcia-Haro et al., 2010; Voss et al., 2011; Wu et al., 2007).”
Background
Caffeine activates preferentially α1-isoform of 5′AMP-activated protein kinase in rat skeletal muscle
Egawa, T., Hamada, T., Ma, X., Karaike, K., Kameda, N., Masuda, S., Iwanaka, N., & Hayashi, T. (2010) · Acta Physiologica · doi:10.1111/j.1748-1716.2010.02169.x · Cited by 63
Selective Expression in Carotid Body Type I Cells of a Single Splice Variant of the Large Conductance Calcium- and Voltage-activated Potassium Channel Confers Regulation by AMP-activated Protein Kinase
Ross, F. A., Rafferty, J. N., Dallas, M. L., Ogunbayo, O. A., Ikematsu, N., McClafferty, H., Tian, L., Widmer, H., Rowe, I. C. M., Wyatt, C. N., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.189779 · Cited by 60
C-terminal Phosphorylation of LKB1 Is Not Required for Regulation of AMP-activated Protein Kinase, BRSK1, BRSK2, or Cell Cycle Arrest
Fogarty, S., & Hardie, D. G. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m806152200 · Cited by 63
Small Molecule Adenosine 5′-Monophosphate Activated Protein Kinase (AMPK) Modulators and Human Diseases
Rana, S., Blowers, E. C., & Natarajan, A. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm401994c · Cited by 63
Effect of different γ-subunit isoforms on the regulation of AMPK
Willows, R., Navaratnam, N., Lima, A., Read, J. A., & Carling, D. (2017) · Biochemical Journal · doi:10.1042/bcj20170046 · Cited by 64
AMP-activated protein kinase rescues the angiogenic functions of endothelial progenitor cells via manganese superoxide dismutase induction in type 1 diabetes
Wang, X., Zhang, M., Chen, D.-D., Zhang, Y., & Chen, A. F. (2011) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00001.2011 · Cited by 59
Nutrient Excess in AMPK Downregulation and Insulin Resistance.
Coughlan, K. A., Valentine, R. J., Ruderman, N. B., & Saha, A. K. (2013) · PubMed · Cited by 59
Creatine kinase regulation by reversible phosphorylation in frog muscle
Dieni, C. A., & Storey, K. B. (2009) · Comparative Biochemistry and Physiology Part B Biochemistry and Molecular Biology · doi:10.1016/j.cbpb.2009.01.012 · Cited by 58
Deconvoluting AMP-activated protein kinase (AMPK) adenine nucleotide binding and sensing
Gu, X., Yan, Y., Novick, S. J., Kovach, A., Goswami, D., Ke, J., Tan, M. H., Wang, L., Li, X., de Waal, P. W., et al. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.793018 · Cited by 61
AMP-activated protein kinase kinase: detection with recombinant AMPK α1 subunit
Hamilton, S. R., O’Donnell, J. B., Hammet, A., Stapleton, D., Habinowski, S. A., Means, A. R., Kemp, B. E., & Witters, L. A. (2002) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(02)00312-1 · Cited by 58
Long-chain acyl-CoA esters inhibit phosphorylation of AMP-activated protein kinase at threonine-172 by LKB1/STRAD/MO25
Taylor, E. B., Ellingson, W. J., Lamb, J. D., Chesser, D. G., & Winder, W. W. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00516.2004 · Cited by 58
AMP-Activated Protein Kinase: Do We Need Activators or Inhibitors to Treat or Prevent Cancer?
Russell, F. M., & Hardie, D. G. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms22010186 · Cited by 57
“, the protein phosphatase) [24], the identity of the latter ay not be critical.”
Background
AMP kinase (PRKAA1)
Krishan, S., Richardson, D. R., & Sahni, S. (2014) · Journal of Clinical Pathology · doi:10.1136/jclinpath-2014-202422 · Cited by 57
A-769662 potentiates the effect of other AMP-activated protein kinase activators on cardiac glucose uptake
Timmermans, A. D., Balteau, M., Gélinas, R., Renguet, E., Ginion, A., de Meester, C., Sakamoto, K., Balligand, J., Bontemps, F., Vanoverschelde, J., et al. (2014) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00965.2013 · Cited by 57
The AMPKα1 Pathway Positively Regulates the Developmental Transition from Proliferation to Quiescence in Trypanosoma brucei
Saldivia, M., Ceballos-Pérez, G., Bart, J.-M., & Navarro, M. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.09.041 · Cited by 54
“Furthermore, AMP binding to AMPK leads to a conformational change, making AMPK a poorer substrate for phosphatases , and hence increasing its phosphorylation (Davies et al., 1995).”
Background
Regulation of SNARK activity in response to cellular stresses
Lefebvre, D. L., & Rosen, C. F. (2005) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2005.03.015 · Cited by 57
Contraction-mediated phosphorylation of AMPK is lower in skeletal muscle of adenylate kinase-deficient mice
Hancock, C. R., Janssen, E., & Terjung, R. L. (2005) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00885.2005 · Cited by 55
Adenosine Monophosphate-Activated Protein Kinase: A Central Regulator of Metabolism with Roles in Diabetes, Cancer, and Viral InfectionPreprint
Hardie, D. G. (2011) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2011.76.010819 · Cited by 55
“We subsequently reported that AMP both promoted phosphorylation (Hawley et al. 1995) and inhibited dephosphorylation (Davies et al. 1995), so that (combined with the allosteric effect) AMP activates AMPK by a three-pronged mechanism.”
Background
Glutaredoxins concomitant with optimal ROS activate AMPK through S-glutathionylation to improve glucose metabolism in type 2 diabetes
Dong, K., Wu, M., Liu, X., Huang, Y., Zhang, D., Wang, Y., Yan, L., & Shi, D. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.10.007 · Cited by 54
Long-term exercise stimulates adenosine monophosphate–activated protein kinase activity and subunit expression in rat visceral adipose tissue and liver
Takekoshi, K., Fukuhara, M., Quin, Z., Nissato, S., Isobe, K., Kawakami, Y., & Ohmori, H. (2006) · Metabolism · doi:10.1016/j.metabol.2006.04.007 · Cited by 55
What we know about facilitative glucose transporters: Lessons from cultured cells, animal models, and human studies
Gorovits, N., & Charron, M. J. (2003) · Biochemistry and Molecular Biology Education · doi:10.1002/bmb.2003.494031030227 · Cited by 52
New dammarane-type glucosides as potential activators of AMP-activated protein kinase (AMPK) from Gynostemma pentaphyllum
Nguyễn, P. H., Rehman, G., Hwang, S.-L., Đào, T. T., Park, D. C., Kim, J. E., Song, H., Huh, T. L., & Oh, W. K. (2011) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2011.09.013 · Cited by 53
Protein phosphatase type 2C dephosphorylates BAD
Klumpp, S., Selke, D., & Krieglstein, J. (2003) · Neurochemistry International · doi:10.1016/s0197-0186(02)00174-2 · Cited by 52
Effect of ethanol on hydrogen peroxide-induced AMPK phosphorylation
Liangpunsakul, S., Wou, S.-E., Zeng, Y., Ross, R. A., Jayaram, H. N., & Crabb, D. W. (2008) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.90349.2008 · Cited by 52
N-Myristoylation is essential for protein phosphatases PPM1A and PPM1B to dephosphorylate their physiological substrates in cells
Chida, T., Ando, M., Matsuki, T., Masu, Y., Nagaura, Y., Takano‐Yamamoto, T., Tamura, S., & Kobayashi, T. (2012) · Biochemical Journal · doi:10.1042/bj20121201 · Cited by 52
The Regulatory Role of Key Metabolites in the Control of Cell Signaling
Milanesi, R., Coccetti, P., & Tripodi, F. (2020) · Biomolecules · doi:10.3390/biom10060862 · Cited by 52
“It was reported that AMP interacts with the γ regulatory subunit of AMPK, similarly to what was shown for ADP on yeast SNF1 complex (Figure 2) [65,76].”
Background
Ion Channel Regulation by AMPK
Evans, A. M., Hardie, D. G., Peers, C., Wyatt, C. N., Viollet, B., Kumar, P., Dallas, M. L., Ross, F. A., Ikematsu, N., Jordan, H. L., et al. (2009) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2009.05041.x · Cited by 51
The Calcium/CaMKKalpha/beta and the cAMP/PKA Pathways Are Essential Upstream Regulators of AMPK Activity in Boar Spermatozoa1
de Llera, A. H., Martín‐Hidalgo, D., Gil, M. C., Garcı́a, L. J., & Bragado, M. J. (2014) · Biology of Reproduction · doi:10.1095/biolreprod.113.112797 · Cited by 50
“Although AMP binding was previously thought both to induce phosphorylation [16] and to inhibit dephosphorylation [17] later studies suggest that the AMP effect is exclusively mediated by an inhibition of Thr172 dephosphorylation [18] by unknown mechanism.”
Background
The effects of age and muscle contraction on AMPK activity and heterotrimer composition
Hardman, S. E., Hall, D. E., Cabrera, A. J., Hancock, C. R., & Thomson, D. M. (2014) · Experimental Gerontology · doi:10.1016/j.exger.2014.04.007 · Cited by 51
“AMP binding leads to AMPK phosphorylation through a conformational shift that makes AMPK a better substrate for LKB1 (Gowans et al., 2013; Hawley et al., 1995, 1996; Scott et al., 2007) and a worse substrate for dephosphorylation by protein phosphatase 2C (Davies et al., 1995; Marley et al., 1996).”
Background
Physiological and Pathogenic Roles of Prolyl Isomerase Pin1 in Metabolic Regulations via Multiple Signal Transduction Pathway Modulations
Nakatsu, Y., Matsunaga, Y., Yamamotoya, T., Ueda, K., Inoue, Y., Mori, K., Sakoda, H., Fujishiro, M., Ono, H., Kushiyama, A., et al. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17091495 · Cited by 50
Kahweol inhibits lipid accumulation and induces Glucose-uptake through activation of AMP-activated protein kinase (AMPK)
Baek, J.-H., Kim, N.-J., Song, J., & Chun, K. (2017) · BMB Reports · doi:10.5483/bmbrep.2017.50.11.031 · Cited by 49
“Thr172 phosphorylation of the AMPK -subunit is regulated by three phosphatases: Mg2＋/Mn2＋ dependent protein phosphatase 1E (PPM1E), protein phosphatase 2A (PP2A), and protein phosphatase 2C (PP2C) (13, 32).”
Background

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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