Protein Kinase MARK/PAR-1 Is Required for Neurite Outgrowth and Establishment of Neuronal Polarity
Open accessAbstract
Protein kinases of the microtubule affinity-regulating kinase (MARK) family were originally discovered because of their ability to phosphorylate certain sites in tau protein (KXGS motifs in the repeat domain). This type of phosphorylation is enhanced in abnormal tau from Alzheimer brain tissue and causes the detachment of tau from microtubules. MARK-related kinases (PAR-1 and KIN1) occur in various organisms and are involved in establishing and maintaining cell polarity. Herein, we report the ability of MARK2 to affect the differentiation and outgrowth of cell processes from neuroblastoma and other cell models. MARK2 phosphorylates tau protein at the KXGS motifs; this results in the detachment of tau from microtubules and their destabilization. The formation of neurites in N2a cells is blocked if MARK2 is inactivated, either by transfecting a dominant negative mutant, or by MARK2 inhibitors such as hymenialdisine. Alternatively, neurites are blocked if the target KXGS motifs on tau are rendered nonphosphorylatable by point mutations. The results suggest that MARK2 contributes to the plasticity of microtubules needed for neuronal polarity and the growth of neurites.
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MAPs bundle actin filaments and cross-link the cellular cytoskeleton formed by microtubules and actin filaments.
“In addition, MAPs bundle actin filaments and cross-link the cellular cytoskeleton formed by microtubules and actin filaments (Fig. 1a)3–10.”
From Multivalent cross-linking of actin filaments and microtubules through the microtubule-associated protein Tau (2017) · cites this paper as [9]
The Discussion (page unavailable) says MAPs can interact with the actin cytoskeleton and may regulate microtubule bundling. It does not say MAPs bundle actin filaments or cross-link actin filaments with microtubules; the cited bundling concerns microtubules, not actin. (LLM, conf=0.85)
Experimental — accuracy not yet measuredCellular studies showed that phosphorylation of the KXGS motifs causes MAP2 and Tau to localize to the actin cytoskeleton.
“cellular studies showed that phosphorylation of the KXGS motifs cause MAP2 and Tau to localize to the actin cytoskeleton9.”
From Multivalent cross-linking of actin filaments and microtubules through the microtubule-associated protein Tau (2017) · cites this paper as [9]
The Discussion reports a cellular study in which phosphorylation of MAP2’s KXGS motifs led to its translocation to the actin network. For Tau, however, the paper says it “hypothesize[s]” such translocation; the cellular observations described there show MARK2, not phosphorylated Tau, colocalizing with actin. The claim overstates the Tau finding as demonstrated. (LLM, conf=0.90)
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Cites
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Research works printed but not linked: 2
- Levin, D.E., and Bishop, J.M. (1990). A putative protein-kinase gene (kin1 + ) is important for growth polarity in Schizosaccharomyces pombe . Proc. Natl. Acad. Sci. USA 87, 8272-8276.
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“This could explain the increase in activity of MARK, cdk5 and others; for example, CaMK-I activates MARK2 and this pathway contributes to neuronal differentiation (Biernat et al., 2002; Uboha et al., 2007; He et al., 2008; Wu et al., 2010).”
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Self-citationLKB1 and AMPK regulate synaptic remodeling in old age
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“Microtubule affinity regulating kinase (MARK), the mammalian homolog of PAR-1, could phosphorylate tau in vitro and was found to associate with NFT in AD brains (Drewes et al., 1997; Chin et al., 2000; Biernat et al., 2002).”
BackgroundTwo PTP receptors mediate CSPG inhibition by convergent and divergent signaling pathways in neurons
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- Authors
- Biernat, J., Wu, Y.-Z., Timm, T., Zheng-Fischhöfer, Q., Mandelkow, E., Meijer, L., & Mandelkow, E.-M.
- Affiliations
- Max Planck Unit for Structural Molecular Biology (DE)
- Max-Planck-Unit for Structural Molecular Biology, Hamburg, Germany; and
- Centre National de la Recherche Scientifique (FR)
- Venue
- Molecular Biology of the Cell
- Published
- 2002-11
- Volume
- 13
- Issue
- 11
- Pages
- 4013-4028
- ISSN
- 1059-1524 (ISSN-L)
- 1939-4586
- PMC
- PMC133611
- OpenAlex
- W2136221184
- Cited by
- 279
- References
- 2
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 9 · 2023: 3 · 2022: 8 · 2021: 4 · 2020: 15 · 2019: 4 · 2018: 8 · 2017: 14 · 2016: 16 · 2015: 8 · 2014: 13 · 2013: 13 · 2012: 11
- FWCI
- 3.65
- 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)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- MARK2, protease-activated receptor 1, tau phosphorylation, neurite outgrowth, neuronal polarity, microtubule destabilization, neuroblastoma cells, N2a cells, hymenialdisine, dominant-negative mutant, cell differentiation
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Animals, Azepines, Cell Line, Enzyme Inhibitors, Flavonoids, Humans, Neurons, Piperidines, Pyrroles, Recombinant Fusion Proteins, Signal Transduction, Neurites, Cell Polarity, tau Proteins, Protein Serine-Threonine Kinases, Amino Acid Motifs, Glycogen Synthase Kinase 3, Mice
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