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GSK3 takes centre stage more than 20 years after its discovery
Open accessAbstract
Identified originally as a regulator of glycogen metabolism, glycogen synthase kinase-3 (GSK3) is now a well-established component of the Wnt signalling pathway, which is essential for setting up the entire body pattern during embryonic development. It may also play important roles in protein synthesis, cell proliferation, cell differentiation, microtubule dynamics and cell motility by phosphorylating initiation factors, components of the cell-division cycle, transcription factors and proteins involved in microtubule function and cell adhesion. Generation of the mouse knockout of GSK3β, as well as studies in neurons, also suggest an important role in apoptosis. The substrate specificity of GSK3 is unusual in that efficient phosphorylation of many of its substrates requires the presence of another phosphorylated residue optimally located four amino acids C-terminal to the site of GSK3 phosphorylation. Recent experiments, including the elucidation of its three-dimensional structure, have enhanced our understanding of the molecular basis for the unique substrate specificity of GSK3. Insulin and growth factors inhibit GSK3 by triggering its phosphorylation, turning the N-terminus into a pseudosubstrate inhibitor that competes for binding with the ‘priming phosphate’ of substrates. In contrast, Wnt proteins inhibit GSK3 in a completely different way, by disrupting a multiprotein complex comprising GSK3 and its substrates in the Wnt signalling pathway, which do not appear to require a ‘priming phosphate’. These latest findings have generated an enormous amount of interest in the development of drugs that inhibit GSK3 and which may have therapeutic potential for the treatment of diabetes, stroke and Alzheimer's disease.
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“Glycogen synthase is the key insulin-regulated enzyme that controls the rate of muscle glycogen synthesis [148, 150, 200, 212–214].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [213]
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Metadata
- Authors
- FRAME, S., & COHEN, P.
- Affiliations
- University of Dundee (GB)
- Corresponding author
- FRAME, Sheelagh
- COHEN, Philip
- ORCID
- COHEN, Philip
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2001-09-24
- Volume
- 359
- Issue
- 1
- Pages
- 1-16
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC1222116
- OpenAlex
- W1964631519
- Cited by
- 1,433
- References
- 148
- Citations by year
- 2026: 13 · 2025: 29 · 2024: 22 · 2023: 32 · 2022: 37 · 2021: 24 · 2020: 38 · 2019: 45 · 2018: 46 · 2017: 42 · 2016: 43 · 2015: 47 · 2014: 75 · 2013: 83 · 2012: 86
- FWCI
- 3.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- 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
- glycogen synthase kinase-3, GSK3β, Wnt signalling pathway, glycogen metabolism, substrate specificity, protein phosphorylation, apoptosis, growth factor inhibition, GSK-3 inhibitors, Alzheimer's disease, diabetes mellitus, stroke, embryonic development, microtubule dynamics, cell motility
- MeSH terms
- Animals, Humans, Glycogen Synthase Kinase 3
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