Glycogen Synthase Kinase 3β Phosphorylates Alzheimer's Disease-Specific Ser396 of Microtubule-Associated Protein Tau by a Sequential Mechanism

Li, Tong; Paudel, Hemant K.

doi:10.1021/bi051634r

Cited by 141Alzheimer's disease research and treatmentsProtein Kinase Regulation and GTPase SignalingDementia and Cognitive Impairment Research

Glycogen Synthase Kinase 3β Phosphorylates Alzheimer's Disease-Specific Ser396 of Microtubule-Associated Protein Tau by a Sequential Mechanism

Li, Tong, Paudel, Hemant K.·2006·Biochemistry

DOI 10.1021/bi051634r

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Abstract

Phosphorylation of tau on S(396) was suggested to be a key step in the development of neurofibrillary pathology in Alzheimer's disease brain [Bramblett, G. T., Goedert, M., Jacks, R., Merrick, S. E., Trojanowski, J. Q., and Lee, V. M.-Y. (1993) Neuron 10, 1089-1099]. GSK3beta phosphorylates Ser(396) of tau in the brain by a mechanism which is not clear. In this study, when HEK-293 cells were cotransfected with tau and GSK3beta, GSK3beta co-immunoprecipitated with tau and phosphorylated tau on S(202), T(231), S(396), and S(400) but not on S(262), S(235), and S(404). Blocking phosphorylation on T(231), S(235), S(396), S(400), or S(404) did not prevent the subsequent phosphorylation on S(202) by GSK3beta. These data suggest that GSK3beta directly phosphorylates tau on S(202) (without requiring prephosphorylation). However, preventing phosphorylation on S(235), S(400), and S(404) prevented GSK3beta-dependent phosphorylation of T(231), S(396), and S(400), respectively. This indicates that phosphorylation of T(231), S(396), and S(400) by GSK3beta depends on a previous phosphorylation of S(235), S(400), and S(404), respectively. To examine S(396) phosphorylation, we analyzed phosphorylation of S(396), S(400), and S(404). Blocking phosphorylation of S(404) prevented the subsequent GSK3beta-dependent phosphorylation of both S(400) and S(396). When phosphorylation of S(404) was allowed but S(400) blocked, GSK3beta failed to phosphorylate S(396). Thus, GSK3beta phosphorylates S(396) by a two-step mechanism. In the first step, GSK3beta phosphorylates S(400) of previously S(404)-phosphorylated tau. This event primes tau for second-step phosphorylation of S(396) by GSK3beta. We conclude that GSK3beta phosphorylates tau directly at S(202) but requires the previous phosphorylation on S(235) to phosphorylate T(231). Phosphorylation of S(396), on the other hand, occurs sequentially. Once a priming kinase phosphorylates S(404), GSK3beta sequentially phosphorylates S(400) and then S(396).

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GSK3β phosphorylates tau at the early pathology site S396 and is a vital component of the β-catenin destruction complex.
“Indeed, GSK3β is known to phosphorylate tau at the early pathology site S396 (Li and Paudel, 2006), and GSK3β is also a vital component of the β-catenin destruction complex.”
From APOE3 Christchurch modulates β-catenin/Wnt signaling in iPS cell-derived cerebral organoids from Alzheimer’s cases (2024) · cites this paper as Li and Paudel, 2006

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Authors: Li, T., & Paudel, H. K.
Affiliations: Jewish General Hospital (CA)
Corresponding author: Paudel, Hemant K.
ORCID: Li, Tong
Venue: Biochemistry
Publisher: American Chemical Society (ACS)
Published: 2006-02-14
Volume: 45
Issue: 10
Pages: 3125-3133
ISSN: 0006-2960 (ISSN-L)
1520-4995
DOI: 10.1021/bi051634r
OpenAlex: W2094263795
Cited by: 140
References: 14
Citations by year: 2026: 7 · 2025: 6 · 2024: 6 · 2023: 11 · 2022: 7 · 2021: 10 · 2020: 7 · 2019: 10 · 2018: 8 · 2017: 4 · 2016: 8 · 2015: 4 · 2014: 9 · 2013: 5 · 2012: 5
FWCI: 3.99
Type: journal article
Language: en
Open access: closed
Locations: Biochemistry (publishedVersion)
PubMed (publishedVersion)
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
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: glycogen synthase kinase-3β, tau protein, tau phosphorylation, sequential phosphorylation, Alzheimer's disease, neurofibrillary tangles, tau isoforms
MeSH terms: Glycogen Synthase Kinase 3 beta, Alanine, Alzheimer Disease, Animals, Brain, Cattle, Cells, Cultured, Humans, Mutation, Phosphorylation, Serine, Transfection, Tyrosine, tau Proteins, Glycogen Synthase Kinase 3

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Glycogen Synthase Kinase 3β Phosphorylates Alzheimer's Disease-Specific Ser396 of Microtubule-Associated Protein Tau by a Sequential Mechanism

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