Glycogen Synthase Kinase (GSK) 3β Directly Phosphorylates Serine 212 in the Regulatory Loop and Inhibits Microtubule Affinity-regulating Kinase (MARK) 2
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MARK/Par-1, a kinase family with diverse functions particularly in inducing cell polarity, can phosphorylate microtubule-associated proteins in their repeat domain and cause their detachment from microtubules, and thereby microtubule destabilization. Because of its role in abnormal phosphorylation of the Tau protein in Alzheimer disease, we searched for regulatory kinases. MARK family kinases can be activated by phosphorylation of a conserved threonine (Thr-208 in MARK2), and inactivated by phosphorylation of a serine (Ser-212), both in the activation loop of the catalytic domain. Activation is achieved by the kinases MARKK/TAO1 or LKB1, although the inactivating kinase was unknown. We show here that GSK3beta serves the role of the inhibitory kinase. Because GSK3beta can also phosphorylate Tau at sites outside the repeat domain, the activation of GSK3beta, and concomitant inactivation of MARK can shift the pattern of pathological phosphorylation of Tau protein in Alzheimer disease.
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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 [121]
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LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR‐1
Lizcano, J. M., Göransson, O., Toth, R., Deak, M., Morrice, N. A., Boudeau, J., Hawley, S. A., Udd, L., Mäkelä, T. P., Hardie, D. G., et al. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600110 · Cited by 1,381 · see citing works
Augustinack, J. C., Schneider, A., Mandelkow, E.-M., & Hyman, B. T. (2002) · Acta Neuropathologica · doi:10.1007/s004010100423 · Cited by 998 · see citing works
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- Chen, Y. H., Wang, Q. J., Hu, H. S., Yu, P. S., Zhu, J., Drewes, G., Piwnica- Worms, H., and Luo, Z. G. (2006) Proc. Natl. Acad. Sci. 103, 8534 -8539
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A tissue-specific atlas of mouse protein phosphorylation and expression
Huttlin, E. L., Jedrychowski, M. P., Elias, J. E., Goswami, T., Rad, R., Beausoleil, S. A., Villén, J., Haas, W., Sowa, M. E., & Gygi, S. P. (2010) · Cell · doi:10.1016/j.cell.2010.12.001 · Cited by 1,778 · see citing works
Zempel, H., Thies, E., Mandelkow, E., & Mandelkow, E.-M. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.2357-10.2010 · Cited by 686 · see citing works
“…polyclonal amyloid- (Cell Signaling Technology; 1:200); mAb 12E8 (1:500); mAb AT8 (1:100); polyclonal MARK phospho-T208 [prepared as described by Timm et al. (2008); 1:100]; phosphop70S6Kinase (pT389, clone 108D2, Cell Signaling Technology; 1:50); polyclonal BRSK1 (Acris, 1:100); phospho-MAPK…”
Self-citationAmbegaokar, S. S., & Jackson, G. R. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr432 · Cited by 113 · see citing works
- Authors
- Timm, T., Balusamy, K., Li, X., Biernat, J., Mandelkow, E., & Mandelkow, E.-M.
- Affiliations
- Max Planck Unit for Structural Molecular Biology (DE)
- Corresponding author
- Mandelkow, Eva-Maria
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-07
- Volume
- 283
- Issue
- 27
- Pages
- 18873-18882
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2158278714
- Cited by
- 95
- References
- 2
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 2 · 2023: 2 · 2022: 9 · 2020: 2 · 2019: 4 · 2018: 10 · 2017: 7 · 2016: 5 · 2015: 4 · 2014: 3 · 2013: 8 · 2012: 4
- FWCI
- 6.28
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- glycogen synthase kinase-3β, MARK2, regulatory loop, kinase inactivation, tau phosphorylation, Alzheimer's disease, microtubule destabilization, cell polarity, LKB1
- MeSH terms
- Glycogen Synthase Kinase 3 beta, AMP-Activated Protein Kinase Kinases, Alzheimer Disease, Animals, Cricetulus, Enzyme Activation, Cricetinae, Microtubules, Phosphorylation, CHO Cells, PC12 Cells, tau Proteins, Protein Serine-Threonine Kinases, Protein Structure, Secondary, Protein Structure, Tertiary, MAP Kinase Kinase Kinases, Glycogen Synthase Kinase 3, Rats
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