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
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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Activation loop phosphorylation increases AMPK activity by about 100-fold, while allosteric regulation changes AMPK activity up to tenfold in mammalian cells and about twofold in recombinant, bacterially produced AMPK.
“Activation loop phosphorylation increases AMPK activity by about 100-fold, while allosteric regulation changes AMPK activity up to tenfold in mammalian cells and about twofold in recombinant, bacterially produced AMPK [26,28,38,39].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [39]
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“Finally, binding of AMP to AMPK makes it a better substrate for phosphorylation by AMPKK and a worse substrate for dephosphorylation by protein phosphatases (Davies et al., 1995; Hawley et al., 1995).”
BackgroundPost‐transcriptional regulation of gene expression by degradation of messenger RNAs
Bevilacqua, A., Ceriani, M. C., Capaccioli, S., & Nicolin, A. (2003) · Journal of Cellular Physiology · doi:10.1002/jcp.10272 · Cited by 316 · see citing works
Hypothalamic AMPK: a canonical regulator of whole-body energy balance
López, M., Nogueiras, R., Tena‐Sempere, M., & Diéguez, C. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2016.67 · Cited by 312 · see citing works
Kim, E.-K., Miller, I., Aja, S., Landree, L. E., Pinn, M., Mcfadden, J., Kuhajda, F., Moran, T., & Ronnett, G. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m402165200 · Cited by 302 · see citing works
LKB1 and AMPK and the cancer-metabolism link - ten years after
Hardie, D. G., & Alessi, D. R. (2013) · BMC Biology · doi:10.1186/1741-7007-11-36 · Cited by 298 · see citing works
The Regulation of AMP-Activated Protein Kinase by H2O2
Choi, S.-L., Kim, S.-J., Lee, K.-T., Kim, J., Mu, J., Birnbaum, M. J., Soo Kim, S., & Ha, J. (2001) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2001.5544 · Cited by 294 · see citing works
Srivastava, R. A. K., Pinkosky, S. L., Filippov, S. I., Hanselman, J. C., Cramer, C. T., & Newton, R. S. (2012) · Journal of Lipid Research · doi:10.1194/jlr.r025882 · Cited by 297 · see citing works
AMPK: energy sensor and survival mechanism in the ischemic heart
Qi, D., & Young, L. H. (2015) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2015.05.010 · Cited by 285 · see citing works
“Deactivation of AMPK is mediated by protein phosphatase 2A and 2C, which dephosphorylate the Thr172 site [31], although the specific role of these phosphatases is not well understood in the heart.”
BackgroundThe regulation of AMP-activated protein kinase by upstream kinases
Carling, D., Sanders, M. J., & Woods, A. (2008) · International Journal of Obesity · doi:10.1038/ijo.2008.124 · Cited by 286 · see citing works
Sugden, C., Donaghy, P. G., Halford, N. G., & Hardie, D. G. (1999) · PLANT PHYSIOLOGY · doi:10.1104/pp.120.1.257 · Cited by 288 · see citing works
“AMPK is activated by increased AMP and decreased ATP via a complex mechanism involving allosteric regulation (Corton et al., 1995), promotion of phosphorylation by an upstream protein kinase (AMPKK) (Hawley et al., 1995), and inhibition of dephosphorylation (Davies et al., 1995).”
BackgroundMethodEnergy-sensing and signaling by AMP-activated protein kinase in skeletal muscle
Winder, W. W. (2001) · Journal of Applied Physiology · doi:10.1152/jappl.2001.91.3.1017 · Cited by 375 · see citing works
AMPK, Mitochondrial Function, and Cardiovascular Disease
Wu, S., & Zou, M.-H. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21144987 · Cited by 286 · see citing works
“Activation loop phosphorylation increases AMPK activity by about 100-fold, while allosteric regulation changes AMPK activity up to tenfold in mammalian cells and about twofold in recombinant, bacterially produced AMPK [26,28,38,39].”
BackgroundMolecular mechanisms for mitochondrial adaptation to exercise training in skeletal muscle
Drake, J. C., Wilson, R. J., & Yan, Z. (2016) · The FASEB Journal · doi:10.1096/fj.15-276337 · Cited by 263 · see citing works
“Thea subunit can then be phosphorylated at Thr172 by activating kinases, such asCaMKkinase (CaMKK) and liver kinaseB (LKB)-1, resulting in AMPK activation (39, 40).”
BackgroundAMP-activated protein kinase regulation and biological actions in the heart
Zaha, V. G., & Young, L. H. (2012) · Circulation Research · doi:10.1161/circresaha.111.255505 · Cited by 279 · see citing works
Activation of Protein Phosphatase 2A by Palmitate Inhibits AMP-activated Protein Kinase
Wu, Y., Song, P., Xu, J., Zhang, M., & Zou, M. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m608310200 · Cited by 272 · see citing works
RetractedZhang, Y., Guo, H., Zhang, C., Lin, S., Yin, Z., Peng, Y., Luo, H., Shi, Y., Lian, G., Zhang, C., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.09.005 · Cited by 266 · see citing works
“However, although early studies employing crude AMPK and its upstream kinase reported a direct promoting effect of AMP on Thr172 phosphorylation (Davies et al., 1995; Moore et al., 1991), follow-up experiments demonstrated that recombinant AMPK expressed in E. coli was not stimulated by AMP…”
BackgroundBroeckx, T., Hulsmans, S., & Rolland, F. (2016) · Journal of Experimental Botany · doi:10.1093/jxb/erw416 · Cited by 268 · see citing works
AMP-activated protein kinase: maintaining energy homeostasis at the cellular and whole-body levels
Hardie, D. G. (2014) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071812-161148 · Cited by 281 · see citing works
Turnley, A. M., Stapleton, D., Mann, R. J., Witters, L. A., Kemp, B. E., & Bartlett, P. F. (1999) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1999.721707.x · Cited by 262 · see citing works
“Activation of AMPK is due to the rise in concentration of AMP, as well as phosphorylation by a kinase kinase (Davies et al., 1995).”
BackgroundWoods, A., Salt, I. P., Scott, J., Hardie, D. G., & Carling, D. (1996) · FEBS Letters · doi:10.1016/s0014-5793(96)01209-4 · Cited by 261 · see citing works
Foretz, M., Carling, D., Guichard, C., Ferré, P., & Foufelle, F. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.24.14767 · Cited by 256 · see citing works
AMPK signaling and its targeting in cancer progression and treatment
Hsu, C.-C., Peng, D., Cai, Z., & Lin, H. (2021) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.04.006 · Cited by 257 · see citing works
Structure and Physiological Regulation of AMPK
Yan, Y., Zhou, X. E., Xu, H. E., & Melcher, K. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19113534 · Cited by 254 · see citing works
“Regulation of Activation Loop Accessib lity A majo regulatory mechanism for AMPK activation by AMP and ADP is the protection of activation loop p-T172 (human α1 T174) gainst dephosphorylation. p-T172 protection can be demonstrated in a cell-free, reconstituted system independent of the phosph tase used (e.g., P2C, P2A…”
BackgroundInfluentialWitczak, C. A., Sharoff, C. G., & Goodyear, L. J. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-8244-6 · Cited by 250 · see citing works
Metformin Activates AMP Kinase through Inhibition of AMP Deaminase
Ouyang, J., Parakhia, R. A., & Ochs, R. S. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.121806 · Cited by 246 · see citing works
AMP-activated protein kinase, stress responses and cardiovascular diseases
Wang, S., Song, P., & Zou, M. (2012) · Clinical Science · doi:10.1042/cs20110625 · Cited by 243 · see citing works
Emerging Role of cAMP/AMPK Signaling
Aslam, M., & Ladilov, Y. (2022) · Cells · doi:10.3390/cells11020308 · Cited by 241 · see citing works
“, LKB1) [33], and (iii) reduced dephosphorylation by protein phosphatases [47].”
BackgroundWinder, W. W., Wilson, H. A., Hardie, D. G., Rasmussen, B. B., Hutber, C. A., Call, G. B., Clayton, R. D., Conley, L. M., Yoon, S., & Zhou, B. (1997) · Journal of Applied Physiology · doi:10.1152/jappl.1997.82.1.219 · Cited by 237 · see citing works
“It has also been determined recently that 58-AMP decreases the rate of inactivation of AMPK by protein phosphatase-2C and by protein phosphatase-2A (6).”
BackgroundMechanisms of regulation of SNF1/AMPK/SnRK1 protein kinases
Crozet, P., Margalha, L., Confraria, A., Rodrigues, A., Martinho, C., Adamo, M., Elias, A., & Gonzalez, E. B. (2014) · Frontiers in Plant Science · doi:10.3389/fpls.2014.00190 · Cited by 234 · see citing works
“However, the exact interface of dimerization remains to be determined, as there are conflicting reports amongst the known structures (Amodeo et al., 2007; Townley and Shapiro, 2007; Xiao et al., 2007).”
BackgroundInfluentialGeminivirus AL2 and L2 Proteins Interact with and Inactivate SNF1 Kinase
Hao, L., Wang, H., Sunter, G., & Bisaro, D. M. (2003) · The Plant Cell · doi:10.1105/tpc.009530 · Cited by 233 · see citing works
“In the case of plant SNF1 and mammalian AMPK, it is known that the kinases are directly bound and activated by 5 -AMP (Davies et al., 1995; Hawley et al., 1995; Sugden et al., 1999a).”
BackgroundHutber, C. A., Hardie, D. G., & Winder, W. W. (1997) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1997.272.2.e262 · Cited by 229 · see citing works
Adenosine Kinase Is Inactivated by Geminivirus AL2 and L2 Proteins
Wang, H., Hao, L., Shung, C.-Y., Sunter, G., & Bisaro, D. M. (2003) · The Plant Cell · doi:10.1105/tpc.015180 · Cited by 226 · see citing works
“SNF1 (in plants and yeast) and its mammalian homolog, AMPK, play a central role in the regulation of metabolism in response to stresses that deplete ATP (the cellular stress response) (Halford and Hardie, 1998; Hardie et al., 1998; Johnston, 1999; Hardie and Hawley, 2001).”
BackgroundInfluentialAMP‐activated protein kinase: a potential player in Alzheimer’s disease
Salminen, A., Kaarniranta, K., Haapasalo, A., Soininen, H. S., & Hiltunen, M. O. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07331.x · Cited by 221 · see citing works
- Authors
- Davies, S. P., Helps, N. R., Cohen, P., & Hardie, D. G.
- Affiliations
- University of Dundee (GB)
- Venue
- FEBS Letters
- Publisher
- Wiley
- Published
- 1995-12-27
- Volume
- 377
- Issue
- 3
- Pages
- 421-425
- ISSN
- 0014-5793 (ISSN-L)
- 1873-3468
- 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
- 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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