Cited by 184Alzheimer's disease research and treatmentsProtein Kinase Regulation and GTPase SignalingProtein Tyrosine Phosphatases

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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

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Bennecib, Malika, Gong, Cheng-Xin, Grundke-Iqbal, Inge, Iqbal, Khalid·2000·FEBS Letters

DOI 10.1016/s0014-5793(00)02203-1

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Abstract

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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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
ORCID: Gong, Cheng-Xin
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
DOI: 10.1016/s0014-5793(00)02203-1
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
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
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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Role of protein phosphatase-2A and -1 in the regulation of GSK-3, cdk5 and cdc2 and the phosphorylation of tau in rat forebrain

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