The Development of Cell Processes Induced by tau Protein Requires Phosphorylation of Serine 262 and 356 in the Repeat Domain and Is Inhibited by Phosphorylation in the Proline-rich Domains
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The differentiation of neurons and the outgrowth of neurites depends on microtubule-associated proteins such as tau protein. To study this process, we have used the model of Sf9 cells, which allows efficient transfection with microtubule-associated proteins (via baculovirus vectors) and observation of the resulting neurite-like extensions. We compared the phosphorylation of tau23 (the embryonic form of human tau) with mutants in which critical phosphorylation sites were deleted by mutating Ser or Thr residues into Ala. One can broadly distinguish two types of sites, the KXGS motifs in the repeats (which regulate the affinity of tau to microtubules) and the SP or TP motifs in the domains flanking the repeats (which contain epitopes for antibodies diagnostic of Alzheimer’s disease). Here we report that both types of sites can be phosphorylated by endogenous kinases of Sf9 cells, and that the phosphorylation pattern of the transfected tau is very similar to that of neurons, showing that Sf9 cells can be regarded as an approximate model for the neuronal balance between kinases and phosphatases. We show that mutations in the repeat domain and in the flanking domains have opposite effects. Mutations of KXGS motifs in the repeats (Ser262, 324, and 356) strongly inhibit the outgrowth of cell extensions induced by tau, even though this type of phosphorylation accounts for only a minor fraction of the total phosphate. This argues that the temporary detachment of tau from microtubules (by phosphorylation at KXGS motifs) is a necessary condition for establishing cell polarity at a critical point in space or time. Conversely, the phosphorylation at SP or TP motifs represents the majority of phosphate (>80%); mutations in these motifs cause an increase in cell extensions, indicating that this type of phosphorylation retards the differentiation of the cells.
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The interaction of MAPs with actin is important for neurite outgrowth.
“The interaction of MAPs with actin is important for neurite outgrowth11, 12.”
From Multivalent cross-linking of actin filaments and microtubules through the microtubule-associated protein Tau (2017) · cites this paper as [12]
The Introduction says MAPs regulate microtubules involved in neurite growth. In “A Model Relating tau Phosphorylation to Process Formation” (page unavailable), the paper says MAP interactions with cytoskeletal elements are important in process formation and separately mentions softening of the actin cortex. It does not specifically say that MAP–actin interactions are important for neurite outgrowth. (LLM, conf=0.81)
Experimental — accuracy not yet measuredThe interaction of Tau with actin is important for neurite outgrowth and synaptic dysfunction.
“The interaction of Tau with actin is important for neurite outgrowth and synaptic dysfunction11, 12, 22.”
From Multivalent cross-linking of actin filaments and microtubules through the microtubule-associated protein Tau (2017) · cites this paper as [12]
The introduction and 'A Model Relating tau Phosphorylation to Process Formation' (page unavailable) link tau to neurite or cell-process outgrowth and mention softening of the actin cortex before a process forms. They do not establish that a tau–actin interaction drives outgrowth, and they do not address synaptic dysfunction. (LLM, conf=0.83)
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Cites
A68: a Major Subunit of Paired Helical Filaments and Derivatized Forms of Normal Tau
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“This shift is also characteristic of Alzheimer tau (A68 protein, Lee et al., 1991).”
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Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease
Wesseling, H., Mair, W., Kumar, M., Schlaffner, C. N., Tang, S., Beerepoot, P., Fatou, B., Guise, A. J., Cheng, L., Takeda, S., et al. (2020) · Cell · doi:10.1016/j.cell.2020.10.029 · Cited by 688 · see citing works
“These sites include three KXGS motifs, which are known to regulate neurite extension and binding of Tau to microtubules (Biernat et al., 1993; Biernat and Mandelkow, 1999).”
BackgroundTau 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
Morris, M., Knudsen, G. M., Maeda, S., Trinidad, J. C., Ioanoviciu, A., Burlingame, A. L., & Mucke, L. (2015) · Nature Neuroscience · doi:10.1038/nn.4067 · Cited by 472 · see citing works
Alquezar, C., Arya, S., & Kao, A. W. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2020.595532 · Cited by 367 · see citing works
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Interplay of pathogenic forms of human tau with different autophagic pathways
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Self-citationTau co-organizes dynamic microtubule and actin networks
Elie, A., Prezel, E., Guérin, C., Denarier, E., Ramirez-Rios, S., Serre, L., Andrieux, A., Fourest-Lieuvin, A., Blanchoin, L., & Arnal, I. (2015) · Scientific Reports · doi:10.1038/srep09964 · Cited by 200 · see citing works
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Self-citationAn acetylation–phosphorylation switch that regulates tau aggregation propensity and function
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- Authors
- Biernat, J., & Mandelkow, E.-M.
- Affiliations
- Max Planck Unit for Structural Molecular Biology (DE)
- Venue
- Molecular Biology of the Cell
- Published
- 1999-03
- Volume
- 10
- Issue
- 3
- Pages
- 727-740
- ISSN
- 1059-1524 (ISSN-L)
- 1939-4586
- PMC
- PMC25198
- OpenAlex
- W2151003489
- Cited by
- 149
- References
- 2
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 4 · 2023: 3 · 2022: 2 · 2021: 10 · 2020: 10 · 2019: 2 · 2018: 7 · 2017: 6 · 2016: 3 · 2015: 7 · 2014: 9 · 2013: 7 · 2012: 3
- FWCI
- 5.10
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular Biology of the Cell (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- 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, phosphorylation sites, microtubule-associated proteins, neurite outgrowth, cell polarity, neuronal differentiation, Sf9 cells, baculovirus expression system, microtubule binding, kinase-phosphatase balance
- MeSH terms
- Animals, Cells, Cultured, Humans, Insecta, Phosphoproteins, Phosphorylation, Proline, Recombinant Proteins, Serine, Transfection, Neurites, Cell Polarity, tau Proteins, Repetitive Sequences, Amino Acid
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