Site-specific effects of tau phosphorylation on its microtubule assembly activity and self-aggregation
Open accessAbstract
Microtubule‐associated protein tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles in brains with Alzheimer's disease. The phosphorylation sites of tau are mainly localized in the proline‐rich (residues 172–251) and C‐terminal tail (residues 368–441) regions, which flank the microtubule‐binding repeats. Here, we investigated the effects of tau phosphorylation at these distinct sites/regions on its activity of stimulating microtubule assembly and its self‐aggregation. We found that tau phosphorylation at the proline‐rich region by dual‐specificity tyrosine‐phosphorylated and ‐regulated kinase 1A inhibited its microtubule assembly activity moderately and promoted its self‐aggregation slightly. Tau phosphorylation at the C‐terminal tail region by glycogen synthase kinase‐3β increased its activity and promoted its self‐aggregation markedly. Tau phosphorylation at both regions plus the microtubule‐binding region by cAMP‐dependent protein kinase diminished its activity (∼70% inhibition) and disrupted microtubules. These studies reveal the differential regulation of tau's biological activity and self‐aggregation by phosphorylation at various sites/regions.
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Phosphorylation at major Ser-Pro/Thr-Pro sites reduces but does not abolish Tau binding to MTs, leading to more dynamic MTs.
“Phosphorylation at these sites reduces, but does not abolish, Tau binding to MTs, leading to more dynamic MTs (Wada et al., 1998;Liu et al., 2007).”
From Regulation of Mitochondrial Transport and Inter-Microtubule Spacing by Tau Phosphorylation at the Sites Hyperphosphorylated in Alzheimer's Disease (2012) · cites this paper as Liu et al., 2007
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Self-citationO-GlcNAcylation regulates phosphorylation of tau: A mechanism involved in Alzheimer's disease
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Roles of tau protein in health and disease
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Acetylated tau, a novel pathological signature in Alzheimer's disease and other tauopathies
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High-fat diet-induced activation of SGK1 promotes Alzheimer’s disease-associated tau pathology
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DYRK1A Regulates the Bidirectional Axonal Transport of APP in Human-Derived Neurons
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- Authors
- Liu, F., Li, B., Tung, E., Grundke‐Iqbal, I., Iqbal, K., & Gong, C.
- Affiliations
- Nantong University (CN)
- New York State Office for People With Developmental Disabilities (US)
- Venue
- European Journal of Neuroscience
- Publisher
- Wiley
- Published
- 2007-12
- Volume
- 26
- Issue
- 12
- Pages
- 3429-3436
- ISSN
- 0953-816X (ISSN-L)
- 1460-9568
- PMC
- PMC2262108
- OpenAlex
- W1927347955
- Cited by
- 208
- References
- 3
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 9 · 2023: 7 · 2022: 14 · 2021: 16 · 2020: 15 · 2019: 16 · 2018: 18 · 2017: 12 · 2016: 9 · 2015: 8 · 2014: 9 · 2013: 7 · 2012: 13
- FWCI
- 4.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- European Journal of Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (AG 019158, R01AG019158, AG027429, R01AG027429)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tau protein, tau phosphorylation, microtubule assembly, self-aggregation, neurofibrillary tangles, Alzheimer's disease, proline-rich region, C-terminal tail, DAPK1, glycogen synthase kinase-3β, protein kinase A, microtubule-binding region
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Dyrk Kinases, Animals, Humans, Microtubules, Phosphorylation, Proline, Protein-Tyrosine Kinases, Recombinant Proteins, 3T3 Cells, tau Proteins, Protein Serine-Threonine Kinases, Cyclic AMP-Dependent Protein Kinases, Glycogen Synthase Kinase 3, Mice, Rats
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