Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation

Liu, Fei; Grundke‐Iqbal, Inge; Iqbal, Khalid; Gong, Cheng‐Xin

doi:10.1111/j.1460-9568.2005.04391.x

Cited by 759Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchProtein Tyrosine Phosphatases

Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation

Liu, Fei, Grundke‐Iqbal, Inge, Iqbal, Khalid, Gong, Cheng‐Xin·2005·European Journal of Neuroscience

DOI 10.1111/j.1460-9568.2005.04391.x

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Abstract

Abnormal hyperphosphorylation of tau is believed to lead to neurofibrillary degeneration in Alzheimer's disease (AD) and other tauopathies. Recent studies have shown that protein phosphatases (PPs) PP1, PP2A, PP2B and PP5 dephosphorylate tau in vitro, but the exact role of each of these phosphatases in the regulation of site-specific phosphorylation of tau in the human brain was unknown. Hence, we investigated the contributions of these PPs to the regulation of tau phosphorylation quantitatively. We found that these four phosphatases all dephosphorylated tau at Ser199, Ser202, Thr205, Thr212, Ser214, Ser235, Ser262, Ser396, Ser404 and Ser409, but with different efficiencies toward different sites. The K(m) values of tau dephosphorylation catalysed by PP1, PP2A and PP5 were 8-12 microm, similar to the intraneuronal tau concentration of human brain, whereas the K(m) of PP2B was fivefold higher. PP2A, PP1, PP5 and PP2B accounted for approximately 71%, approximately 11%, approximately 10% and approximately 7%, respectively, of the total tau phosphatase activity of human brain. The total phosphatase activity and the activities of PP2A and PP5 toward tau were significantly decreased, whereas that of PP2B was increased in AD brain. PP2A activity negatively correlated to the level of tau phosphorylation at the most phosphorylation sites in human brains. Our findings indicate that PP2A is the major tau phosphatase that regulates its phosphorylation at multiple sites in human brain. The abnormal hyperphosphorylation of tau is partially due to a downregulation of PP2A activity in AD brain.

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PP2A contributed 71% of the dephosphorylation of human hyperphosphorylated tau isolated from AD patient brains.
“In vitro analysis of the dephosphorylation ability of different phosphatases toward tau showed that PP2A contributed 71% of the dephosphorylation of human hyperphosphorylated tau isolated from AD patient brains (Liu et al., 2005).”
From CIP2A Causes Tau/APP Phosphorylation, Synaptopathy, and Memory Deficits in Alzheimer’s Disease (2018) · cites this paper as Liu et al., 2005
PP2A inhibition causes hyperphosphorylation of tau and APP in Alzheimer's disease.
“Protein phosphatase 2A (PP2A) inhibition causes hy-perphosphorylation of tau and APP in Alzheimer’s disease (AD).”
From CIP2A Causes Tau/APP Phosphorylation, Synaptopathy, and Memory Deficits in Alzheimer’s Disease (2018) · cites this paper as Liu et al., 2005
PP2A is responsible for over 70% of total tau phosphatase activity.
“Although many tau kinases have been identified, protein phosphatase 2A (PP2A) is one of only a few tau phosphatases, and is responsible for over 70% of the total tau phosphatase activity33.”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [33]

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Authors: Liu, F., Grundke‐Iqbal, I., Iqbal, K., & Gong, C.
Corresponding author: Liu, Fei
ORCID: Liu, Fei
Iqbal, Khalid
Gong, Cheng‐Xin
Venue: European Journal of Neuroscience
Publisher: Wiley
Published: 2005-10
Volume: 22
Issue: 8
Pages: 1942-1950
ISSN: 0953-816X (ISSN-L)
1460-9568
DOI: 10.1111/j.1460-9568.2005.04391.x
OpenAlex: W2036011584
Cited by: 759
References: 50
Citations by year: 2026: 27 · 2025: 35 · 2024: 27 · 2023: 35 · 2022: 45 · 2021: 50 · 2020: 42 · 2019: 36 · 2018: 44 · 2017: 41 · 2016: 40 · 2015: 38 · 2014: 47 · 2013: 48 · 2012: 37
FWCI: 14.19
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor, 20 d)
Locations: European Journal of Neuroscience (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute on Aging (AG16760, R01AG016760)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords: tau phosphorylation, protein phosphatase 2A, protein phosphatase 1, calcineurin, protein phosphatase 5, tau dephosphorylation, site-specific phosphorylation, Alzheimer's disease, tauopathy, neurofibrillary degeneration, phosphatase activity, human brain
MeSH terms: Aged, 80 and over, Alzheimer Disease, Dose-Response Relationship, Drug, Enzyme Activation, Female, Humans, Iodine Isotopes, Kinetics, Male, Phosphoprotein Phosphatases, Phosphorylation, Postmortem Changes, Serine, Threonine, Time Factors, tau Proteins, Catalytic Domain, Immunoprecipitation

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Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation

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