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Reactivating Kinase/p38 Phosphorylates τ Protein In Vitro
Abstract
Neurofibrillary tangles, one of the major pathological hallmarks of Alzheimer-diseased brains, consist primarily of aggregated paired helical filaments (PHFs) of hyperphosphorylated tau protein. Tau from normal brain and especially from foetal brain is also phosphorylated on some of the sites phosphorylated in PHFs, mainly at serines or threonines followed by prolines. A number of protein kinases can phosphorylate tau in vitro; those that require or accept prolines include GSK3 and members of the mitogen-activated protein (MAP) kinase family, ERK1, ERK2, and SAP kinase-beta/JNK. In this report, we show that another member of the MAP kinase family, the stress-activated kinase p38/RK, can phosphorylate tau in vitro. Western blots with phosphorylation-sensitive antibodies showed that p38, like ERK2 and SAP kinase-beta/JNK, phosphorylated tau at sites found phosphorylated physiologically (Thr181, Ser202, Thr205, and Ser396) and also at Ser422, which is phosphorylated in neurofibrillary tangles but not in normal adult or foetal brain. These findings support the possibility that cellular stress might contribute to tau hyperphosphorylation during the formation of PHFs, and hence, to the development of tau pathology.
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“Furthermore, tau can be phosphorylated by p38, which can induce microtubule assembly in vitro (33,39).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [33]
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Lee, V. M.-Y., Goedert, M., & Trojanowski, J. Q. (2001) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.24.1.1121 · Cited by 2,480
Activation and signaling of the p38 MAP kinase pathway
Zarubin, T., & Han, J. (2005) · Cell Research · doi:10.1038/sj.cr.7290257 · Cited by 1,711
Tau phosphorylation: the therapeutic challenge for neurodegenerative disease
Hanger, D. P., Anderton, B. H., & Noble, W. (2009) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2009.01.003 · Cited by 965
Self-citationChen, Z., Gibson, T. B., Robinson, F. L., Silvestro, L., Pearson, G. W., Xu, B.-E., Wright, A., Vanderbilt, C. A., & Cobb, M. H. (2001) · Chemical Reviews · doi:10.1021/cr000241p · Cited by 809
Tau protein kinases: Involvement in Alzheimer's disease
Martin, L., Latypova, X., Wilson, C. M., Magnaudeix, A., Perrin, M.-L., Yardin, C., & Terro, F. (2013) · Ageing Research Reviews · doi:10.1016/j.arr.2012.06.003 · Cited by 631
Metadata
- Authors
- Reynolds, C. H., Nebreda, A. R., Gibb, G. M., Utton, M. A., & Anderton, B. H.
- Affiliations
- Guy's Hospital (GB)
- Corresponding author
- Reynolds, C. Hugh
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 1997-07
- Volume
- 69
- Issue
- 1
- Pages
- 191-198
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W2013149569
- Cited by
- 161
- References
- 0
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 5 · 2023: 13 · 2022: 7 · 2021: 2 · 2020: 2 · 2019: 1 · 2016: 3 · 2015: 3 · 2014: 6 · 2013: 6 · 2012: 5
- FWCI
- 3.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- 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
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- tau phosphorylation, p38 MAPK, neurofibrillary tangles, paired helical filaments, Alzheimer's disease, ERK2, glycogen synthase kinase-3, stress-activated kinases, cellular stress, tau hyperphosphorylation
- MeSH terms
- Alzheimer Disease, Amino Acids, Antibody Specificity, Brain Chemistry, Humans, Neurons, Phosphorylation, Stress, Physiological, tau Proteins, Calcium-Calmodulin-Dependent Protein Kinases, Mitogen-Activated Protein Kinases, p38 Mitogen-Activated Protein Kinases
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