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

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

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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  1. Grundke-Iqbal, I., Iqbal, K., Tung, Y.-C., Quinlan, M., Wis- niewski, H.M. and Binder, L.I. (1986) Proc. Natl. Acad. Sci. USA 83, 4913^4917.
  2. Iqbal, K., Grundke-Iqbal, I., Smith, A.J., George, L., Tung, Y-C. and Zaidi, T. (1989) Proc. Natl. Acad. Sci. USA 86, 5646^5650.
  3. Weingarten, M.D., Lockwood, A.H., Hwo, S.-Y. and Kirschner, M.W. (1975) Proc. Natl. Acad. Sci. USA 72, 1858^1862.
  4. Alonso, A.delC., Zaidi, T., Grundke-Iqbal, I. and Iqbal, K. (1994) Proc. Natl. Acad. Sci. USA 91, 5562^5566.
  5. Alonso, A. del C., Grundke-Iqbal, I., Barra, H.S. and Iqbal, K. (1997) Proc. Natl. Acad. Sci. USA 94, 298^303.
  6. Eldar-Finkelman, H., Argast, G.M., Foord, O., Fisher, E.H. and Krebs, E.G. (1996) Proc. Natl. Acad. Sci. USA 93, 10228^ 10233.

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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
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
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
  • Health Sciences › Medicine › Physiology › 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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