Primed phosphorylation of tau at Thr231 by glycogen synthase kinase 3β (GSK3β) plays a critical role in regulating tau's ability to bind and stabilize microtubules
Abstract
Site‐specific phosphorylation of tau negatively regulates its ability to bind and stabilize microtubule structure. Although tau is a substrate of glycogen synthase kinase 3β (GSK3β), the exact sites on tau that are phosphorylated by this kinase in situ have not yet been established, and the effect of these phosphorylation events on tau–microtubule interactions have not been fully elucidated. GSK3β phosphorylates both primed and unprimed sites on tau, but only primed phosphorylation events significantly decrease the ability of tau to bind microtubules. The focus of the present study is on determining the importance of the GSK3β‐mediated phosphorylation of a specific primed site, Thr231, in regulating tau's function. Pre‐phosphorylation of Ser235 primes tau for phosphorylation by GSK3β at Thr231. Phosphorylation by GSK3β of wild‐type tau or tau with Ser235 mutated to Ala decreases tau–microtubule interactions. However, when Thr231 alone or Thr231 and Ser235 in tau were mutated to Ala, phosphorylation by GSK3β did not decrease the association of tau with the cytoskeleton. Further, T231A tau was still able to efficiently bind microtubules after phosphorylation by GSK3β. Expression of each tau construct alone increased tubulin acetylation, a marker of microtubule stability. However, when cells were cotransfected with wild‐type tau and GSK3β, the level of tubulin acetylation was decreased to vector‐transfected levels. In contrast, coexpression of GSK3β with mutated tau (T231A/S235A) did not significantly decrease the levels of acetylated tubulin. These results strongly indicate that phosphorylation of Thr231 in tau by GSK3β plays a critical role in regulating tau's ability to bind and stabilize microtubules.
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In Alzheimer's disease and other tauopathies, tau becomes abnormally hyperphosphorylated, reducing its microtubule affinity and promoting aggregation.
“In Alzheimer’s disease and other tauopathies, tau becomes abnormally hyperphosphorylated, reducing its microtubule affinity and promoting aggregation (Schneider et al., 1999; Cho and Johnson, 2004).”
From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as Cho and Johnson, 2004
Tau phosphorylated at Thr231 is often found detached from microtubules in vitro and in cultured cells.
“and is often found detached from microtubules in vitro and in cultured cells [51, 90].”
Cites
Microtubules containing acetylated alpha-tubulin in mammalian cells in culture.
Piperno, G., LeDizet, M., & Chang, X. J. (1987) · The Journal of cell biology · doi:10.1083/jcb.104.2.289 · Cited by 873 · see citing works
The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein
Lu, P.-J., Wulf, G., Zhou, X. Z., Davies, P., & Lu, K. P. (1999) · Nature · doi:10.1038/21650 · Cited by 721 · see citing works
Monoclonal antibody PHF‐1 recognizes tau protein phosphorylated at serine residues 396 and 404
Otvos, L., Feiner, L., Lang, E., Szendrei, G. I., Goedert, M., & Lee, V. M. (1994) · Journal of Neuroscience Research · doi:10.1002/jnr.490390607 · Cited by 488 · see citing works
Goedert, M., Jakes, R., Crowther, R. A., Cohen, P., Vanmechelen, E., Vandermeeren, M., & Cras, P. (1994) · Biochemical Journal · doi:10.1042/bj3010871 · Cited by 375 · 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
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Cited by
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Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells
Israel, M. A., Yuan, S. H., Bardy, C., Reyna, S. M., Mu, Y., Herrera, C., Hefferan, M. P., Van Gorp, S., Nazor, K. L., Boscolo, F. S., et al. (2012) · Nature · doi:10.1038/nature10821 · Cited by 1,253 · see citing works
Glycogen synthase kinase-3 (GSK3): Inflammation, diseases, and therapeutics
Jope, R. S., Yuskaitis, C. J., & Beurel, E. (2007) · Neurochemical Research · doi:10.1007/s11064-006-9128-5 · Cited by 774 · see citing works
A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo
Yuzwa, S. A., Macauley, M. S., Heinonen, J. E., Shan, X., Dennis, R. J., He, Y., Whitworth, G. E., Stubbs, K. A., McEachern, E. J., Davies, G. J., et al. (2008) · Nature Chemical Biology · doi:10.1038/nchembio.96 · Cited by 717 · 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
Self-citationSARS‐CoV‐2 targets neurons of 3D human brain organoids
Ramani, A., Müller, L., Ostermann, P. N., Gabriel, E., Abida‐Islam, P., Müller‐Schiffmann, A., Mariappan, A., Goureau, O., Gruell, H., Walker, A., et al. (2020) · The EMBO Journal · doi:10.15252/embj.2020106230 · Cited by 518 · see citing works
Green, K. N., Steffan, J. S., Martinez-Coria, H., Sun, X., Schreiber, S. S., Thompson, L. M., & LaFerla, F. M. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.3203-08.2008 · Cited by 404 · see citing works
Histone deacetylase 6 interacts with the microtubule‐associated protein tau
Ding, H., Dolan, P. J., & Johnson, G. V. W. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05564.x · Cited by 387 · see citing works
Self-citationAlquezar, C., Arya, S., & Kao, A. W. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2020.595532 · Cited by 367 · see citing works
Tunneling nanotube (TNT)-mediated neuron-to neuron transfer of pathological Tau protein assemblies
Tardivel, M., Bégard, S., Bousset, L., Dujardin, S., Coens, A., Melki, R., Buée, L., & Colin, M. (2016) · Acta Neuropathologica Communications · doi:10.1186/s40478-016-0386-4 · Cited by 305 · see citing works
Cripps, D., Thomas, S. N., Jeng, Y., Yang, F., Davies, P., & Yang, A. J. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m512786200 · Cited by 312 · see citing works
Diabetes mellitus and Alzheimer's disease: GSK-3β as a potential link
Zhang, Y., Huang, N.-Q., Yan, F., Jin, H., Zhou, S.-Y., Shi, J.-S., & Jin, F. (2018) · Behavioural Brain Research · doi:10.1016/j.bbr.2017.11.015 · Cited by 301 · see citing works
The Emerging Link between O-GlcNAc and Alzheimer Disease
Zhu, Y., Shan, X., Yuzwa, S. A., & Vocadlo, D. J. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.r114.601351 · Cited by 267 · see citing works
Yuskaitis, C. J., & Jope, R. S. (2009) · Cellular Signalling · doi:10.1016/j.cellsig.2008.10.014 · Cited by 240 · see citing works
Ochalek, A., Mihalik, B., Avci, H. X., Chandrasekaran, A., Téglási, A., Bock, I., Giudice, M. L., Táncos, Z., Molnár, K., László, L., et al. (2017) · Alzheimer's Research & Therapy · doi:10.1186/s13195-017-0317-z · Cited by 225 · see citing works
Kirouac, L., Rajic, A. J., Cribbs, D. H., & Padmanabhan, J. (2017) · eneuro · doi:10.1523/eneuro.0149-16.2017 · Cited by 207 · 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
Gold from the sea: Marine compounds as inhibitors of the hallmarks of cancer
Schumacher, M., Kelkel, M., Dicato, M., & Diederich, M. (2011) · Biotechnology Advances · doi:10.1016/j.biotechadv.2011.02.002 · Cited by 138 · see citing works
Nakajima, A., Aoyama, Y., Nguyen, T.-T. L., Shin, E.-J., Kim, H.-C., Yamada, S., Nakai, T., Nagai, T., Yokosuka, A., Mimaki, Y., et al. (2013) · Behavioural Brain Research · doi:10.1016/j.bbr.2013.05.025 · Cited by 115 · 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
Galas, M.-C., Dourlen, P., Bégard, S., Ando, K., Blum, D., Hamdane, M., & Buée, L. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m601849200 · Cited by 97 · see citing works
The toxicity of tau in Alzheimer disease: turnover, targets and potential therapeutics
Pritchard, S. M., Dolan, P. J., Vitkus, A., & Johnson, G. V. W. (2011) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2011.01273.x · Cited by 89 · see citing works
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Habtemariam, S. (2018) · Molecules · doi:10.3390/molecules23010117 · Cited by 55 · see citing works
Killick, R., Hughes, T. R., Morgan, B. P., & Lovestone, S. (2013) · Neuroscience Letters · doi:10.1016/j.neulet.2012.11.008 · Cited by 17 · see citing works
Zhang, Z., Zhao, R., Tang, Y., Wen, S., Wang, D., & Qi, J. (2011) · Neurochemical Research · doi:10.1007/s11064-011-0405-6 · Cited by 11 · see citing works
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Tridente, G., Jana, A., Nath, A., & Ashraf, G. M. (2023) · Receptor Tyrosine Kinases in Neurodegenerative and Psychiatric Disorders · doi:10.1016/b978-0-443-18677-6.00015-4 · Cited by 8 · see citing works
Beaudet, D., Berger, C. L., & Hendricks, A. G. (2026) · eLife · doi:10.7554/elife.110011
- Authors
- Cho, J., & Johnson, G. V. W.
- Affiliations
- University of Alabama at Birmingham (US)
- Corresponding author
- Johnson, Gail V. W.
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2003-12-22
- Volume
- 88
- Issue
- 2
- Pages
- 349-358
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W1528790659
- Cited by
- 282
- References
- 5
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 12 · 2023: 15 · 2022: 9 · 2021: 13 · 2020: 24 · 2019: 8 · 2018: 23 · 2017: 12 · 2016: 10 · 2015: 7 · 2014: 18 · 2013: 12 · 2012: 17
- FWCI
- 5.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Aetna Foundation
- John Douglas French Alzheimer's Foundation
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (NS35060, R01NS035060)
- 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, glycogen synthase kinase-3β, microtubule stabilization, tubulin acetylation, site-specific phosphorylation, tauopathy
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Animals, Cricetinae, Microtubules, Mutation, Phosphorylation, Protein Binding, Threonine, CHO Cells, tau Proteins, Glycogen Synthase Kinase 3
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