Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells
Open accessAbstract
Background Exposing eukaryotic cells to lithium ions (Li+) during development has marked effects on cell fate and organization. The phenotypic consequences of Li+ treatment on Xenopus embryos and sporulating Dictyostelium are similar to the effects of inhibition or disruption, respectively, of a highly conserved protein serine/threonine kinase, glycogen synthase kinase-3 (GSK-3). In Drosophila, the GSK-3 homologue is encoded by zw3sgg, a segment-polarity gene involved in embryogenesis that acts downstream of wg. In higher eukaryotes, GSK-3 has been implicated in signal transduction pathways downstream of phosphoinositide 3-kinase and mitogen-activated protein kinases. Results We investigated the effect of Li+ on the activity of the GSK-3 family. At physiological doses, Li+ inhibits the activity of human GSK-3 beta and Drosophila Zw3Sgg, but has no effect on other protein kinases. The effect of Li+ on GSK-3 is reversible in vitro. Treatment of cells with Li+ inhibits GSK-3-dependent phosphorylation of the microtubule-associated protein Tau. Li+ treatment of Drosophila S2 cells and rat PC12 cells induces accumulation of cytoplasmic Armadillo/beta-catenin, demonstrating that Li+ can mimic Wingless signalling in intact cells, consistent with its inhibition of GSK-3. Conclusions Li+ acts as a specific inhibitor of the GSK-3 family of protein kinases in vitro and in intact cells, and mimics Wingless signalling. This reveals a possible molecular mechanism of Li+ action on development and differentiation.
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Sorafenib was effective in modulating transcriptional activity through TCF site and in decreasing β-catenin protein levels in cells with truncated/mutated β-catenin (HepG2, SNU398), in cells with wild type β-catenin (SNU387), and in cells with wild type β-catenin and induction of Wnt-signaling by GSK3β-inhibitor LiCl (Huh7).
“Sorafenib was effective in modulating transcriptional activity through TCF site, and in decreasing β-catenin protein levels in cells with truncated/mutated β-catenin (HepG2, SNU398), in cells with wild type β-catenin (SNU387) and in cells with wild type β-catenin and induction of Wnt-signaling by GSK3β-inhibitor LiCl (Huh7) (Fig. 4A, Suppl. Fig. 7) (16).”
From Wnt-Pathway Activation in Two Molecular Classes of Hepatocellular Carcinoma and Experimental Modulation by Sorafenib (2012) · cites this paper as [16]
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- Authors
- Stambolic, V., Ruel, L., & Woodgett, J. R.
- Affiliations
- University of Toronto (CA)
- Corresponding author
- Woodgett, James R.
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 1996-12
- Volume
- 6
- Issue
- 12
- Pages
- 1664-1669
- ISSN
- 0960-9822 (ISSN-L)
- OpenAlex
- W1979993283
- Cited by
- 1,321
- References
- 0
- Citations by year
- 2026: 13 · 2025: 27 · 2024: 23 · 2023: 25 · 2022: 22 · 2021: 27 · 2020: 32 · 2019: 41 · 2018: 34 · 2017: 36 · 2016: 40 · 2015: 46 · 2014: 67 · 2013: 60 · 2012: 60
- FWCI
- 10.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Current Biology (publishedVersion)
- PubMed (publishedVersion)
- 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
- lithium, glycogen synthase kinase-3, GSK3β, Wingless signalling, tau phosphorylation, protein kinase inhibition, cell fate, development (biology), Dictyostelium, Xenopus embryo, PC12 cells
- MeSH terms
- Animals, Cell Line, Humans, Microtubule-Associated Proteins, Proto-Oncogene Proteins, Signal Transduction, PC12 Cells, Protein Serine-Threonine Kinases, Calcium-Calmodulin-Dependent Protein Kinases, Lithium Chloride, COS Cells, Drosophila Proteins, Glycogen Synthase Kinases, Glycogen Synthase Kinase 3, Wnt1 Protein, Rats
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