MARKK, a Ste20‐like kinase, activates the polarity‐inducing kinase MARK/PAR‐1
Open accessAbstract
MARK, a kinase family related to PAR-1 involved in establishing cell polarity, phosphorylates microtubule-associated proteins (tau/MAP2/MAP4) at KXGS motifs, causes detachment from microtubules, and their disassembly. The sites are prominent in tau from Alzheimer's disease brains. We studied the activation of MARK and identified the upstream kinase, MARKK, a member of the Ste20 kinase family. It phosphorylates MARK within the activation loop (T208 in MARK2). A fraction of MARK in brain tissue is doubly phosphorylated (at T208/S212), reminiscent of the activation of MAP kinase; however, the phosphorylation of the second site in MARK (S212) is inhibitory. In cells the activity of MARKK enhances microtubule dynamics through the activation of MARK and leads to phosphorylation and detachment of tau or equivalent MAPs from microtubules. Overexpression of MARK eventually leads to microtubule breakdown and cell death, but in neuronal cells the primary effect is to allow the development of neurites during differentiation.
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GSK-3β has recently been shown to phosphorylate a key regulatory Ser in PAR-1; however, it remains unclear whether this activates or inactivates PAR-1.
“GSK-3β has recently been shown to phosphorylate a key regulatory Ser in PAR-1; however, it remains unclear whether this activates (119) or inactivates PAR-1 (120,121).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [120]
LKB-1 phosphorylates and activates PAR-1, but also phosphorylates the inactivating Ser-9 on GSK-3β and may be the elusive GSK-3β kinase activated by Wnt signaling.
“LKB-1 phosphorylates and activates PAR-1 (120,122,123), but also phosphorylates the inactivating Ser-9 on GSK-3β and may be the elusive GSK-3β kinase activated by Wnt signaling (124).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [120]
This source is cited for the PAR-1 activation clause, not the separately cited GSK-3β clause. The Introduction identifies MARKK as a kinase that phosphorylates and activates MARK/PAR-1, but neither it nor the passages retrieved for LKB-1 say that LKB-1 does so. The copy does not rule out LKB-1 as another activating kinase. (LLM, conf=0.76)
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Research works printed but not linked: 1
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LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR‐1
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Molecular pathways that influence human tau-induced pathology in Caenorhabditis elegans
Kraemer, B. C., Burgess, J. K., Chen, J. H., Thomas, J. H., & Schellenberg, G. D. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl067 · Cited by 150 · see citing works
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“Conversely, it has been suggested that par-1 may regulate GSK-3b activity by ‘priming’ the tau protein, whereby tau phosphorylation by PAR-1 is required before GSK-3b or Cdk5 can phosphorylate tau (92).”
BackgroundInfluentialWang, J.-W., Imai, Y., & Lu, B. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.5094-06.2007 · Cited by 80 · see citing works
“This latter result is consistent with previous in vitro studies of similar mutations in mammalian MARK family kinases, which caused either no or subtle activation of kinase activity in some family members (Timm et al., 2003; Lizcano et al., 2004).”
BackgroundResultLilley, B. N., Pan, Y. A., & Sanes, J. R. (2013) · Neuron · doi:10.1016/j.neuron.2013.05.017 · Cited by 63 · see citing works
- Authors
- Timm, T., Li, X., Biernat, J., Jiao, J., Mandelkow, E., Vandekerckhove, J., & Mandelkow, E.
- Affiliations
- Max Planck Unit for Structural Molecular Biology (DE)
- Ghent University (BE)
- Corresponding author
- Mandelkow, Eva‐Maria
- ORCID
- Timm, Thomas
- Venue
- The EMBO Journal
- Published
- 2003-10-01
- Volume
- 22
- Issue
- 19
- Pages
- 5090-5101
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC204455
- OpenAlex
- W2063368579
- Cited by
- 198
- References
- 0
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 9 · 2023: 7 · 2022: 9 · 2021: 3 · 2020: 8 · 2019: 7 · 2018: 7 · 2017: 10 · 2016: 7 · 2015: 7 · 2014: 9 · 2013: 8 · 2012: 12
- FWCI
- 3.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- Mark, protease-activated receptor 1, cell polarity, tau phosphorylation, microtubule dynamics, MAP2, MAP4, microtubule disassembly, neuronal differentiation, neurite development, Alzheimer's disease, cell death
- MeSH terms
- Amino Acid Sequence, Animals, Molecular Sequence Data, Swine, Protein Serine-Threonine Kinases, Mitogen-Activated Protein Kinases, Caenorhabditis elegans Proteins
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