Inhibition of AMP kinase by the protein phosphatase 2a heterotrimer, PP2APpp2r2d
Open accessAbstract
AMP kinase is a heterotrimeric serine/threonine protein kinase that regulates a number of metabolic processes, including lipid biosynthesis and metabolism. AMP kinase activity is regulated by phosphorylation, and the kinases involved have been uncovered. The particular phosphatases counteracting these kinases remain elusive. Here we discovered that the protein phosphatase 2A heterotrimer, PP2A(Ppp2r2d), regulates the phosphorylation state of AMP kinase by dephosphorylating Thr-172, a residue that activates kinase activity when phosphorylated. Co-immunoprecipitation and co-localization studies indicated that PP2A(Ppp2r2d) directly interacted with AMP kinase. PP2A(Ppp2r2d) dephosphorylated Thr-172 in rat aortic and human vascular smooth muscle cells. A positive correlation existed between decreased phosphorylation, decreased acetyl-CoA carboxylase Acc1 phosphorylation, and sterol response element-binding protein 1c-dependent gene expression. PP2A(Ppp2r2d) protein expression was up-regulated in the aortas of mice fed a high fat diet, and the increased expression correlated with increased blood lipid levels. Finally, we found that the aortas of mice fed a high fat diet had decreased AMP kinase Thr-172 phosphorylation, and contained an Ampk-PP2A(Ppp2r2d) complex. Thus, PP2A(Ppp2r2d) may antagonize the aortic AMP kinase activity necessary for maintaining normal aortic lipid metabolism. Inhibiting PP2A(Ppp2r2d) or activating AMP kinase represents a potential pharmacological treatment for many lipid-related diseases.
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AMP protects Thr172 against dephosphorylation by phosphatases.
“Second, AMP protects Thr172 against dephosphorylation by phosphatases [28,35,36,37].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [37]
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- Authors
- Joseph, B. K., Liu, H.-Y., Francisco, J., Pandya, D., Donigan, M., Gallo-Ebert, C., Giordano, C., Bata, A., & Nickels, J. T.
- Corresponding author
- Nickels, Joseph T.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2015-04
- Volume
- 290
- Issue
- 17
- Pages
- 10588-10598
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4409226
- OpenAlex
- W2028670385
- Cited by
- 91
- References
- 60
- Citations by year
- 2026: 9 · 2025: 8 · 2024: 6 · 2023: 9 · 2022: 8 · 2021: 12 · 2020: 12 · 2019: 10 · 2018: 9 · 2017: 2 · 2016: 4 · 2015: 2
- FWCI
- 2.46
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- AMP kinase, protein phosphatase 2A, kinase regulation, acetyl-CoA carboxylase 1, SREBP-1c, high-fat diet, serum lipids, vascular smooth muscle cells
- MeSH terms
- AMP-Activated Protein Kinase Kinases, Animals, Aorta, Cell Line, Cholesterol, Enzyme Inhibitors, Humans, Male, Mice, Inbred C57BL, Phosphorylation, Protein Serine-Threonine Kinases, Okadaic Acid, Protein Structure, Quaternary, Protein Subunits, RNA, Small Interfering, Lipogenesis, Lipid Metabolism, Mice, Rats, Sterol Regulatory Element Binding Protein 1, Protein Phosphatase 2, Calcium-Calmodulin-Dependent Protein Kinase Kinase, AMP-Activated Protein Kinases, Diet, High-Fat
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