Phosphorylation of tau by glycogen synthase kinase-3β in intact mammalian cells: The effects on the organization and stability of microtubules
Abstract
The phosphorylation state of tau changes during neurodevelopment and highly phosphorylated tau accumulates in the paired helical filaments found in Alzheimer's disease. In non-neuronal mammalian cells transiently expressed tau is predominantly not phosphorylated at sites known to be phosphorylated in paired helical filaments. However this pattern of phosphorylation is induced by both glycogen synthase kinase-3 alpha and -3 beta and here we show that this results in a change in the intracellular properties of tau. Within cells tau is bound to cytoskeletal structures and causes changes in cellular cytoarchitecture with the induction of thick and stable microtubule bundles. This morphology is lost when tau is co-expressed with glycogen synthase kinase-3 beta; microtubules become less stable and are not bound by tau. Independently of any direct or indirect effects on tau, glycogen synthase kinase-3 beta induces some but relatively slight changes in microtubule organization with the loss of a prominent centrosomal microtubular origin. The cytoskeleton is critical to cell function and within post-mitotic neurons has a highly specialized structure induced, in part, by the neuronal-specific microtubule-associated proteins such as tau. In vitro studies have suggested that the properties of tau are regulated by phosphorylation as highly phosphorylated tau does not promote tubulin polymer assembly. We have demonstrated, in intact cells, that tau highly phosphorylated in the presence of…
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Tau phosphorylation at Ser262/356 decreases tau's affinity toward microtubules in vitro, in cultured cells, transgenic Drosophila, and transgenic mice.
“Tau phosphorylation at these sites decreases the protein’s affinity toward microtubules in vitro, in cultured cells, transgenic Drosophila, and transgenic mice [18, 19, 25–27, 50–52].”
Phosphorylation of tau negatively influences its ability to bind microtubules.
“Phosphorylation of tau negatively influences its ability to bind microtubules [25–27, 51, 52].”
Cites
Goedert, M., & Jakes, R. (1990) · The EMBO Journal · doi:10.1002/j.1460-2075.1990.tb07870.x · Cited by 929 · see citing works
Phosphorylation affects the ability of tau protein to promote microtubule assembly.
Lindwall, G., & Cole, R. D. (1984) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)42989-9 · Cited by 901 · see citing works
Glycogen synthase kinase-3β phosphorylates tau protein at multiple sites in intact cells
Sperbera, B. R., Leight, S., Goedert, M., & Lee, V. M.-Y. (1995) · Neuroscience Letters · doi:10.1016/0304-3940(95)11902-9 · Cited by 204 · see citing works
Latimer, D. A., Gallo, J.-M., Lovestone, S., Miller, C. C. J., Hugh Reynolds, C., Marquardt, B., Stabel, S., Woodgett, J. R., & Anderton, B. H. (1995) · FEBS Letters · doi:10.1016/0014-5793(95)00434-b · Cited by 48 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
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 · see citing works
Tau pathology in Alzheimer disease and other tauopathies
Iqbal, K., del C. Alonso, A., Chen, S., Chohan, M. O., El-Akkad, E., Gong, C.-X., Khatoon, S., Li, B., Liu, F., Rahman, A., et al. (2005) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2004.09.008 · Cited by 1,037 · see citing works
Mechanisms of tau-induced neurodegeneration
Iqbal, K., Liu, F., Gong, C.-X., Alonso, A. D. C., & Grundke-Iqbal, I. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0486-3 · Cited by 628 · see citing works
Tau phosphorylation in neuronal cell function and dysfunction
Johnson, G. V. W., & Stoothoff, W. H. (2004) · Journal of Cell Science · doi:10.1242/jcs.01558 · Cited by 624 · see citing works
Linking Aβ and Tau in Late-Onset Alzheimer's Disease: A Dual Pathway Hypothesis
Small, S. A., & Duff, K. (2008) · Neuron · doi:10.1016/j.neuron.2008.11.007 · Cited by 546 · see citing works
The importance of tau phosphorylation for neurodegenerative diseases
Noble, W., Hanger, D. P., Miller, C. C. J., & Lovestone, S. (2013) · Frontiers in Neurology · doi:10.3389/fneur.2013.00083 · Cited by 475 · see citing works
Self-citationTau-based therapies in neurodegeneration: opportunities and challenges
Li, C., & Götz, J. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.155 · Cited by 272 · see citing works
GSK‐3 in Neurodegenerative Diseases
Lei, P., Ayton, S., Bush, A. I., & Adlard, P. A. (2011) · International Journal of Alzheimer’s Disease · doi:10.4061/2011/189246 · Cited by 177 · see citing works
Cowan, C. M., Bossing, T., Page, A., Shepherd, D., & Mudher, A. (2010) · Acta Neuropathologica · doi:10.1007/s00401-010-0716-8 · Cited by 156 · see citing works
Basheer, N., Smolek, T., Hassan, I., Liu, F., Iqbal, K., Zilka, N., & Novak, P. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02113-z · Cited by 159 · see citing works
Hartigan, J. A., & Johnson, G. V. W. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.30.21395 · Cited by 141 · see citing works
Ando, K., Maruko-Otake, A., Ohtake, Y., Hayashishita, M., Sekiya, M., & Iijima, K. M. (2016) · PLOS Genetics · doi:10.1371/journal.pgen.1005917 · Cited by 105 · see citing works
Wnt/β-Catenin Signaling in Alzheimer’s Disease
Ferrari, G., Avila, M., Medina, M., Perez-Palma, E., Bustos, B., & Alarcon, M. (2014) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527312666131223113900 · Cited by 95 · see citing works
Hu, Z., Chen, P.-H., Li, W., Douglas, T., Hines, J., Liu, Y., & Crews, C. M. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.2c11706 · Cited by 98 · see citing works
Yin, X., Jin, N., Shi, J., Zhang, Y., Wu, Y., Gong, C.-X., Iqbal, K., & Liu, F. (2017) · Scientific Reports · doi:10.1038/s41598-017-00682-y · Cited by 93 · see citing works
- Authors
- Lovestone, S., Hartley, C. L., Pearce, J., & Anderton, B. H.
- Corresponding author
- Lovestone, S.
- ORCID
- Lovestone, S.
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 1996-08
- Volume
- 73
- Issue
- 4
- Pages
- 1145-1157
- ISSN
- 0306-4522 (ISSN-L)
- OpenAlex
- W1984453732
- Cited by
- 201
- References
- 4
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 2 · 2023: 5 · 2022: 3 · 2021: 3 · 2020: 3 · 2019: 5 · 2018: 1 · 2017: 3 · 2016: 4 · 2015: 4 · 2014: 5 · 2013: 7 · 2012: 6
- FWCI
- 5.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- 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 phosphorylation, glycogen synthase kinase-3β, microtubule stabilization, microtubule bundles, cytoskeleton, centrosome, paired helical filaments, Alzheimer's disease, brain development, neurodegeneration, microtubule assembly, microtubule-associated proteins
- MeSH terms
- Animals, Cytoskeleton, Microtubules, Phosphorylation, Polymers, Tubulin, Nocodazole, tau Proteins, Calcium-Calmodulin-Dependent Protein Kinases, COS Cells, Glycogen Synthase Kinases, Glycogen Synthase Kinase 3
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
