Phosphorylation by p38 MAPK as an Alternative Pathway for GSK3β Inactivation
Open accessAbstract
Glycogen synthase kinase 3β (GSK3β) is involved in metabolism, neurodegeneration, and cancer. Inhibition of GSK3β activity is the primary mechanism that regulates this widely expressed active kinase. Although the protein kinase Akt inhibits GSK3β by phosphorylation at the N terminus, preventing Akt-mediated phosphorylation does not affect the cell-survival pathway activated through the GSK3β substrate β-catenin. Here, we show that p38 mitogen-activated protein kinase (MAPK) also inactivates GSK3β by direct phosphorylation at its C terminus, and this inactivation can lead to an accumulation of β-catenin. p38 MAPK–mediated phosphorylation of GSK3β occurs primarily in the brain and thymocytes. Activation of β-catenin–mediated signaling through GSK3β inhibition provides a potential mechanism for p38 MAPK–mediated survival in specific tissues.
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Multiple studies provide evidence that MAPK modulates the activities of the Wnt/β-catenin pathway.
“Furthermore, multiple studies have provided evidence of the involvement of MAPK in modulating the activities of the Wnt/β-catenin pathway.”
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- Authors
- Thornton, T. M., Pedraza-Alva, G., Deng, B., Wood, C. D., Aronshtam, A., Clements, J. L., Sabio, G., Davis, R. J., Matthews, D. E., Doble, B., & Rincon, M.
- Affiliations
- University of Vermont (US)
- Department of Medicine/Immunobiology Program, University of Vermont, Burlington, VT 05405–0068, USA.
- Venue
- Science
- Published
- 2008-05-02
- Volume
- 320
- Issue
- 5876
- Pages
- 667-670
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC2597039
- OpenAlex
- W2056907950
- Cited by
- 484
- References
- 0
- Citations by year
- 2026: 11 · 2025: 19 · 2024: 19 · 2023: 22 · 2022: 20 · 2021: 29 · 2020: 32 · 2019: 18 · 2018: 31 · 2017: 21 · 2016: 24 · 2015: 28 · 2014: 33 · 2013: 34 · 2012: 40
- FWCI
- 14.01
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- Figshare (submittedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI051454)
- National Center for Research Resources (P20RR021905, P20RR016462, P20RR015557)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- GSK3β, p38 MAPK, protein phosphorylation, β-catenin, Akt, Wnt signaling, cell survival signaling, thymocytes, brain
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Animals, Brain, Humans, Phosphorylation, Serine, Thymus Gland, Glycogen Synthase Kinase 3, Protein Kinase Inhibitors, p38 Mitogen-Activated Protein Kinases, Proto-Oncogene Proteins c-akt, beta Catenin, Mice
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