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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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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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