Overexpression of the catalytic subunit of protein phosphatase 2A impairs cardiac function
Open accessAbstract
Reversible protein phosphorylation is an essential regulatory mechanism in many cellular functions. In contrast to protein kinases, the role and regulation of protein phosphatases has remained ambiguous. To address this issue, we generated transgenic mice that overexpress the catalytic subunit alpha of protein phosphatase 2A (PP2A) (PP2Acalpha) in the heart driven by the alpha-myosin heavy chain promoter. Overexpression of the PP2Acalpha gene in the heart led to increased levels of the transgene both at RNA and protein levels. This was accompanied by a significant increase of PP2A enzyme activity in the myocardium. Morphological analysis revealed isles of necrosis and fibrosis. The phosphorylation state of phospholamban, troponin inhibitor, and eukaryotic elongation factor 2 was reduced significantly. The expression of junctional (calsequestrin) and free SR proteins (SERCA and phospholamban) was not altered. Whereas no increase in morbidity or mortality was noted, transgenic mice developed cardiac hypertrophy and reduced contractility of the heart, as well as cardiac dilatation as shown by biplane echocardiography. Taken together, these findings are indicative of the fundamental role of PP2A in cardiac function and imply that disturbances in protein phosphatases expression and activity may cause or aggravate the course of cardiac diseases.
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In the Ppp2ca knockout, Cα expression was reduced by 80% at P11.5, while in the transgene total PP2A activity was increased 1.7-fold.
“In the KO, an 80% reduction in Cα expression was observed at P11.5 [62], while in the transgene, total PP2A activity was 1.7-fold increased [61].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [61]
Cα knockout mice had increased phospholamban Ser16 phosphorylation in the heart, while Cα transgenic mice had decreased phospholamban Ser16/Ser17 phosphorylation.
“the Cα KO mice showed increased phosphorylation of phospholamban (PLB) (Ser16) in the heart [62], while in the Cα transgenes, PLB phosphorylation (Ser16, Ser17) was found decreased [61].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [61]
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References 39 · Cited by 125
Research works printed but not linked: 2
- Gotz, J., Probst, A., Ehler, E., Hemmings, B., and Kues, W. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 12370 -12375
- Murata, K., Wu, J., and Brautigan, D. L. (1997) Proc. Natl. Acad. Sci. U. S. A. 94, 10624 -10629
- Authors
- Gergs, U., Boknik, P., Buchwalow, I., Fabritz, L., Matus, M., Justus, I., Hanske, G., Schmitz, W., & Neumann, J.
- Affiliations
- University of Münster (DE)
- Corresponding author
- Neumann, Joachim
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-09
- Volume
- 279
- Issue
- 39
- Pages
- 40827-40834
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1969715546
- Cited by
- 125
- References
- 39
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 5 · 2023: 3 · 2022: 1 · 2021: 9 · 2020: 4 · 2019: 8 · 2018: 7 · 2017: 9 · 2016: 4 · 2015: 5 · 2014: 4 · 2013: 3 · 2012: 7
- FWCI
- 2.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (SFB 556)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Keywords
- protein phosphatase 2A, cardiac function, transgenic mice, alpha-myosin heavy chain promoter, protein dephosphorylation, phospholamban, cardiac hypertrophy, cardiac dilatation, cardiac contractility, myocardial necrosis, myocardial fibrosis, reversible protein phosphorylation
- MeSH terms
- Actins, Animals, Calcium, Cells, Cultured, Dobutamine, Dose-Response Relationship, Drug, Echocardiography, Fibrosis, Heart, Heart Diseases, Image Processing, Computer-Assisted, Immunohistochemistry, Mice, Transgenic, Myocardium, Phosphoprotein Phosphatases, Phosphorylation, Promoter Regions, Genetic, Receptors, Adrenergic, beta, RNA, Blotting, Northern, Blotting, Western, DNA, Complementary, Transgenes, Catalytic Domain, Mice, Protein Phosphatase 2
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