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Role of protein phosphatase-2A and -1 in the regulation of GSK-3, cdk5 and cdc2 and the phosphorylation of tau in rat forebrain
Open accessAbstract
In Alzheimer disease brain the activities of protein phosphatase (PP)-2A and PP-1 are decreased and the microtubule-associated protein tau is abnormally hyperphosphorylated at several sites at serine/threonine. Employing rat forebrain slices kept metabolically active in oxygenated artificial CSF as a model system, we investigated the role of PP-2A/PP-1 in the regulation of some of the major abnormally hyperphosphorylated sites of tau and the protein kinases involved. Treatment of the brain slices with 1.0 microM okadaic acid inhibited approximately 65% of PP-2A and produced hyperphosphorylation of tau at Ser 198/199/202, Ser 396/404 and Ser 422. No significant changes in the activities of glycogen synthase kinase-3 (GSK-3) and cyclin dependent protein kinases cdk5 and cdc2 were observed. Calyculin A (0.1 microM) inhibited approximately 50% PP-1, approximately 20% PP-2A, 50% GSK-3 and approximately 30% cdk5 but neither inhibited the activity of cyclin AMP dependent protein kinase A (PKA) nor resulted in the hyperphosphorylation of tau at any of the above sites. Treatment of brain slices with 1 microM okadaic acid plus 0.1 microM calyculin A inhibited approximately 100% of both PP-2A and PP-1, approximately 80% of GSK-3, approximately 50% of cdk5 and approximately 30% of cdc2 but neither inhibited PKA nor resulted in the hyperphosphorylation of tau at any of the above sites. These studies suggest (i) that PP-1 upregulates the phosphorylation of tau at Ser 198/199/202 and Ser 396/404 indirectly by regulating the activities of GSK-3, cdk5 and cdc2 whereas PP-2A regulates the phosphorylation of tau directly by dephosphorylation at the above sites, and (ii) that a decrease in the PP-2A activity leads to abnormal hyperphosphorylation of tau at Ser 198/199/202, Ser 396/404 and Ser 422.
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“PP2A has been shown to regulate GSK3 b activity by removing phosphorylation at serine 9 and other regulatory residues (Bennecib et al., 2000; Mitra et al., 2012).”
From Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis (2019) · cites this paper as Bennecib et al., 2000
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Tau and neurodegenerative disease: the story so far
Iqbal, K., Liu, F., & Gong, C.-X. (2016) · Nature Reviews Neurology · doi:10.1038/nrneurol.2015.225 · Cited by 806
Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration
Wang, J., Grundke, I., & Iqbal, K. (2007) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2006.05226.x · Cited by 569
Wang, J., Xia, Y., Grundke, I., & Iqbal, K. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-129031 · Cited by 547
GSK-3 as potential target for therapeutic intervention in cancer
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Metadata
- Authors
- Bennecib, M., Gong, C.-X., Grundke-Iqbal, I., & Iqbal, K.
- Affiliations
- New York State Office for People With Developmental Disabilities (US)
- Corresponding author
- Iqbal, Khalid
- Venue
- FEBS Letters
- Publisher
- Wiley
- Published
- 2000-11-14
- Volume
- 485
- Issue
- 1
- Pages
- 87-93
- ISSN
- 0014-5793 (ISSN-L)
- 1873-3468
- OpenAlex
- W1977560589
- Cited by
- 184
- References
- 54
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 4 · 2023: 7 · 2022: 6 · 2021: 6 · 2020: 4 · 2019: 2 · 2018: 8 · 2017: 9 · 2016: 5 · 2015: 5 · 2014: 10 · 2013: 9 · 2012: 4
- FWCI
- 5.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- FEBS Letters (publishedVersion)
- PubMed (publishedVersion)
- Funders
- City University of New York
- Northwestern University
- University of Tokyo
- National Institutes of Health (5r01ag008076-09, 5r01ag005892-16, 1r03ag014875-01)
- National Institute on Aging (AG-05892, AG 08076, AG14875)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- protein phosphatase 2A, protein phosphatase 1, tau hyperphosphorylation, glycogen synthase kinase-3, cyclin-dependent kinase 5, cdc2, okadaic acid, calyculin A, Alzheimer's disease, tau dephosphorylation, kinase regulation, rat brain, tau phosphorylation sites, protein phosphatase inhibition
- MeSH terms
- Animals, Enzyme Inhibitors, Female, Marine Toxins, Oxazoles, Phosphoprotein Phosphatases, Phosphorylation, CDC2 Protein Kinase, Prosencephalon, tau Proteins, Rats, Wistar, Calcium-Calmodulin-Dependent Protein Kinases, Cyclin-Dependent Kinases, Okadaic Acid, Glycogen Synthase Kinases, Glycogen Synthase Kinase 3, Cyclin-Dependent Kinase 5, Rats, Protein Phosphatase 2
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