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Stimulation of the AMP-activated Protein Kinase Leads to Activation of Eukaryotic Elongation Factor 2 Kinase and to Its Phosphorylation at a Novel Site, Serine 398
Open accessAbstract
Protein synthesis consumes a high proportion of the metabolic energy of mammalian cells, and most of this is used by peptide chain elongation. An important regulator of energy supply and demand in eukaryotic cells is the AMP-activated protein kinase (AMPK). The rate of peptide chain elongation can be modulated through the phosphorylation of eukaryotic elongation factor (eEF) 2, which inhibits its activity and is catalyzed by a specific calcium/calmodulin-dependent protein kinase termed eEF2 kinase. Here we show that AMPK directly phosphorylates eEF2 kinase, and we identify the major site of phosphorylation as Ser-398 in a regulatory domain of eEF2 kinase. AMPK also phosphorylates two other sites (Ser-78 and Ser-366) in eEF2 kinase in vitro. We develop appropriate phosphospecific antisera and show that phosphorylation of Ser-398 in eEF2 kinase is enhanced in intact cells under a range of conditions that activate AMPK and increase the phosphorylation of eEF2. Ser-78 and Ser-366 do not appear to be phosphorylated by AMPK within cells. Although cardiomyocytes appear to contain a distinct isoform of eEF2 kinase, it also contains a site corresponding to Ser-398 that is phosphorylated by AMPK in vitro. Stimuli that activate AMPK and increase eEF2 phosphorylation within cells increase the activity of eEF2 kinase. Thus, AMPK and eEF2 kinase may provide a key link between cellular energy status and the inhibition of protein synthesis, a major consumer of metabolic energy.
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“The loss of AMPK activity is believed to be pro-hypertrophic because lines of molecular signaling pathways that control cell growth are attenuated by AMPK activation [197,198,199].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [199]
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Cites
Bradford, M. M. (1976) · Analytical Biochemistry · doi:10.1016/0003-2697(76)90527-3 · Cited by 255,302
THE AMP-ACTIVATED/SNF1 PROTEIN KINASE SUBFAMILY: Metabolic Sensors of the Eukaryotic Cell?
Hardie, D. G., Carling, D., & Carlson, M. (1998) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.67.1.821 · Cited by 1,440
Boyle, W. J., van der Geer, P., & Hunter, T. R. (1991) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/0076-6879(91)01013-r · Cited by 1,421
Translational control of gene expression
Sonenberg, N., Hershey, J. W. B., & Mathews, M. B. (2000) · Cold Spring Harbor Laboratory eBooks · Cited by 1,379
Corton, J. M., Gillespie, J. G., Hawley, S. A., & Hardie, D. G. (1995) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1995.tb20498.x · Cited by 1,232
Translational control of gene expression
Hannig, E. M. (2001) · BioEssays · doi:10.1002/bies.1108 · Cited by 1,194
Mammalian TOR: a homeostatic ATP sensor
Dennis, P. B., Jaeschke, A., Saitoh, M., Fowler, B., Kozma, S. C., & Thomas, G. (2001) · Science · doi:10.1126/science.1063518 · Cited by 962
Management of cellular energy by the AMP‐activated protein kinase system
Hardie, D. G., Scott, J. W., Pan, D. A., & Hudson, E. R. (2003) · FEBS Letters · doi:10.1016/s0014-5793(03)00560-x · Cited by 868
Regulation of elongation factor 2 kinase by p90RSK1 and p70 S6 kinase
Wang, X.-M., Li, W., Williams, M. R., Terada, N., Alessi, D., & Proud, C. G. (2001) · EMBO Journal · doi:10.1093/emboj/20.16.4370 · Cited by 862
Stokoe, D., Engel, K., Campbell, D. G., Cohen, P., & Gaestel, M. (1992) · FEBS Letters · doi:10.1016/0014-5793(92)81216-9 · Cited by 569
Regulation of peptide‐chain elongation in mammalian cells
Browne, G. J., & Proud, C. G. (2002) · European Journal of Biochemistry · doi:10.1046/j.1432-1033.2002.03290.x · Cited by 473
Horman, S., Browne, G. J., Krause, U., Patel, J. V., Vertommen, D., Bertrand, L., Lavoinne, A., Hue, L., Proud, C. G., & Rider, M. H. (2002) · Current Biology · doi:10.1016/s0960-9822(02)01077-1 · Cited by 467
Phosphorylation of elongation factor 2 by EF-2 kinase affects rate of translation
Ryazanov, A. G., Shestakova, E. A., & Natapov, P. G. (1988) · Nature · doi:10.1038/334170a0 · Cited by 459
Purification and characterization of the AMP‐activated protein kinase
Carling, D., Clarke, P. R., Zammit, V. A., & Hardie, D. G. (1989) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1989.tb15186.x · Cited by 418
Regulation of mammalian translation factors by nutrients
Proud, C. G. (2002) · European Journal of Biochemistry · doi:10.1046/j.1432-1033.2002.03292.x · Cited by 388
Nairn, A. C., & Palfrey, H. C. (1987) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)45377-x · Cited by 338
Functional properties of phosphorylated elongation factor 2
CARLBERG, U., NILSSON, A., & Nygârd, O. (1990) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1990.tb19169.x · Cited by 278
Redpath, N. T., Foulstone, E. J., & Proud, C. G. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00582.x · Cited by 265
Browne, G. J., & Proud, C. G. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.7.2986-2997.2004 · Cited by 256
Knebel, A., Morrice, N., & Cohen, P. (2001) · The EMBO Journal · doi:10.1093/emboj/20.16.4360 · Cited by 254
Nairn, A. C., Bhagat, B., & Palfrey, H. C. (1985) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.82.23.7939 · Cited by 218
Ryazanov, A. G., Ward, M. D., Mendola, C. E., Pavur, K. S., Dorovkov, M. V., Wiedmann, M., Erdjument‐Bromage, H., Tempst, P., Parmer, T. G., Prostko, C. R., et al. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.10.4884 · Cited by 208
The p70 S6 Kinase Integrates Nutrient and Growth Signals to Control Translational Capacity
Avruch, J., BELHAM, C. M., Weng, Q. P., Hara, K., & Yonezawa, K. (2001) · Progress in molecular and subcellular biology · doi:10.1007/978-3-642-56688-2_5 · Cited by 181
Control of protein synthesis by amino acid availability
Kimball, S. R., & Jefferson, L. S. (2002) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/00075197-200201000-00012 · Cited by 132
Horman, S., Beauloye, C., Vertommen, D., Vanoverschelde, J., Hue, L., & Rider, M. H. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m302403200 · Cited by 121
Stimulation of rat liver AMP-activated protein kinase by AMP analogues
Henin, N., Vincent, M. F., & Berghe, G. (1996) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/0304-4165(96)00021-9 · Cited by 100
Redpath, N. T., & Proud, C. G. (1993) · Biochemical Journal · doi:10.1042/bj2930031 · Cited by 87
Knebel, A., Haydon, C. E., MORRICE, N. A., & Cohen, P. (2002) · Biochemical Journal · doi:10.1042/bj20020916 · Cited by 80
Ryazanov, A. G., Natapov, P. G., Shestakova, E. A., Severin, F. F., & Spirin, A. S. (1988) · Biochimie · doi:10.1016/0300-9084(88)90245-3 · Cited by 72
Purification and phosphorylation of elongation factor‐2 kinase from rabbit reticulocytes
Redpath, N. T., & Proud, C. G. (1993) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1993.tb17688.x · Cited by 65
Mapping the Functional Domains of Elongation Factor-2 Kinase
Pavur, K. S., Petrov, A. N., & Ryazanov, A. G. (2000) · Biochemistry · doi:10.1021/bi0007270 · Cited by 61
Analysis of the domain structure of elongation factor‐2 kinase by mutagenesis
Diggle, T. A., Seehra, C. K., Hase, S., & Redpath, N. T. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)01034-0 · Cited by 53
McLeod, L. E., Wang, L., & Proud, C. G. (2001) · FEBS Letters · doi:10.1016/s0014-5793(01)02100-7 · Cited by 36
Protein synthesis during oxygen conformance and severe hypoxia in the mouse muscle cell line C2C12
Arthur, P. G., Giles, J. J., & Wakeford, C. M. (2000) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/s0304-4165(00)00046-5 · Cited by 33
Yan, L., Nairn, A. C., Palfrey, H. C., & Brady, M. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m301116200 · Cited by 32
Flagged first, then by citations
Research works printed but not linked: 2
- Beugnet, 2002, 372, 555
- Wang, 2000, Am. J. Physiol., 278, H1056
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Sorted by citations
Steinberg, G. R., & Kemp, B. E. (2009) · Physiological Reviews · doi:10.1152/physrev.00011.2008 · Cited by 1,672
AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function
Hardie, D. G. (2011) · Genes & Development · doi:10.1101/gad.17420111 · Cited by 1,638
The AMP-activated protein kinase pathway – new players upstream and downstream
Hardie, D. G. (2004) · Journal of Cell Science · doi:10.1242/jcs.01540 · Cited by 1,163
Tumor suppressors and cell metabolism: a recipe for cancer growth
Jones, R. G., & Thompson, C. B. (2009) · Genes & Development · doi:10.1101/gad.1756509 · Cited by 1,085
The mTOR pathway in the control of protein synthesis
Wang, X., & Proud, C. G. (2006) · Physiology · doi:10.1152/physiol.00024.2006 · Cited by 778
Metadata
- Authors
- Browne, G. J., Finn, S. G., & Proud, C. G.
- Affiliations
- University of Dundee (GB)
- Corresponding author
- Proud, Christopher G.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-03
- Volume
- 279
- Issue
- 13
- Pages
- 12220-12231
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1983195734
- Cited by
- 353
- References
- 35
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 7 · 2023: 11 · 2022: 7 · 2021: 15 · 2020: 16 · 2019: 9 · 2018: 11 · 2017: 16 · 2016: 18 · 2015: 20 · 2014: 19 · 2013: 20 · 2012: 25
- FWCI
- 7.82
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Funders
- British Heart Foundation
- Directorate for Biological Sciences
- Biotechnology and Biological Sciences Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- AMPK, eEF2K, eEF2 kinase, eEF2 phosphorylation, translation elongation, protein synthesis regulation, cellular energy status, cardiomyocytes
- MeSH terms
- Amino Acid Sequence, Animals, Binding Sites, Cells, Cultured, Enzyme Activation, Glutathione Transferase, Humans, Molecular Sequence Data, Multienzyme Complexes, Peptides, Phosphorylation, Precipitin Tests, Serine, Time Factors, Immunoblotting, Blotting, Western, Mutagenesis, Protein Serine-Threonine Kinases, Protein Structure, Tertiary, Calcium-Calmodulin-Dependent Protein Kinases, DNA, Complementary, Protein Isoforms, Myocytes, Cardiac, Rats, Elongation Factor 2 Kinase, AMP-Activated Protein Kinases
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