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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
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 [26,28,38,39].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [39]
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Wu, S., & Zou, M.-H. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21144987 · Cited by 286
“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
“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
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 283
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 278
“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 279
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
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 270
“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
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
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
“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…”
BackgroundInfluentialAMPK 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 265
Witczak, C. A., Sharoff, C. G., & Goodyear, L. J. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-8244-6 · Cited by 253
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 251
AMP-activated protein kinase, stress responses and cardiovascular diseases
Wang, S., Song, P., & Zou, M. (2012) · Clinical Science · doi:10.1042/cs20110625 · Cited by 251
Emerging Role of cAMP/AMPK Signaling
Aslam, M., & Ladilov, Y. (2022) · Cells · doi:10.3390/cells11020308 · Cited by 241
“, 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
“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 241
“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
“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 231
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
“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 224
Metadata
- 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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