Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis
Open accessAbstract
The inactivation of glycogen synthase kinase (GSK)3 has been proposed to play important roles in insulin and Wnt signalling. To define the role that inactivation of GSK3 plays, we generated homozygous knockin mice in which the protein kinase B phosphorylation sites on GSK3alpha (Ser21) and GSK3beta (Ser9) were changed to Ala. The knockin mice were viable and were not diabetic. Using these mice we show that inactivation of GSK3beta rather than GSK3alpha is the major route by which insulin activates muscle glycogen synthase. In contrast, we demonstrate that the activation of muscle glycogen synthase by contraction, the stimulation of muscle glucose uptake by insulin, or the activation of hepatic glycogen synthase by glucose do not require GSK3 phosphorylation on Ser21/Ser9. GSK3 also becomes inhibited in the Wnt-signalling pathway, by a poorly defined mechanism. In GSK3alpha/GSK3beta homozygous knockin cells, Wnt3a induces normal inactivation of GSK3, as judged by the stabilisation of beta-catenin and stimulation of Wnt-dependent transcription. These results establish the function of Ser21/Ser9 phosphorylation in several processes in which GSK3 inactivation has previously been implicated.
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GSK3 knockin mice express normal levels of both GSK3 isoforms, GSK3α and GSK3β, but with serine-to-alanine mutations, S9A-GSK3β and S21A-GSK3α, to maintain GSK3 maximally active.
“GSK3 knockin mice express normal levels of both GSK3 isoforms, GSK3α and GSK3β, but with serine-to-alanine mutations, S9A-GSK3β and S21A-GSK3α, to maintain GSK3 maximally active, since it cannot be inhibited by serinephosphorylation (43, 44).”
From Inflammatory T helper 17 cells promote depression-like behavior in mice (2013) · cites this paper as [43]
Mutation of two Akt phosphorylation sites on GSK3 (S9 and S21) to alanine prevents inhibition of GSK3 and results in impaired insulin-stimulated glycogen synthesis.
“Similarly, mutation of two Akt phosphorylation sites on GSK3 (S9 and S21) to alanine prevents inhibition of GSK3 and results in impaired insulin-stimulated glycogen synthesis [128].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [128]
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- Authors
- McManus, E. J., Sakamoto, K., Armit, L. J., Ronaldson, L., Shpiro, N., Marquez, R., & Alessi, D. R.
- Affiliations
- University of Dundee (GB)
- Corresponding author
- Alessi, Dario R
- Venue
- The EMBO Journal
- Published
- 2005-03-24
- Volume
- 24
- Issue
- 8
- Pages
- 1571-1583
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1142569
- OpenAlex
- W2019041110
- Cited by
- 594
- References
- 39
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 14 · 2023: 28 · 2022: 23 · 2021: 25 · 2020: 31 · 2019: 21 · 2018: 23 · 2017: 22 · 2016: 31 · 2015: 18 · 2014: 33 · 2013: 38 · 2012: 46
- FWCI
- 14.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion)
- Funders
- Pfizer
- AstraZeneca
- GlaxoSmithKline
- University of Dundee
- Merck KGaA
- Diabetes UK
- Medical Research Council
- 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 › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- glycogen synthase kinase-3, GSK3 phosphorylation, insulin signaling, Wnt signaling, glycogen synthase, muscle glucose uptake, muscle contraction, Wnt3a, GSK3α, GSK3β, knock-in mice
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Animals, Enzyme Activation, Glycogen, Humans, Insulin, Liver, Mice, Transgenic, Phosphorylation, Proteins, Proto-Oncogene Proteins, Signal Transduction, Gene Expression Regulation, Enzymologic, Protein Serine-Threonine Kinases, Muscle, Skeletal, Glycogen Synthase Kinase 3, Proto-Oncogene Proteins c-akt, Wnt Proteins, Mice, Wnt3 Protein, Wnt3A Protein
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