GSK-3: tricks of the trade for a multi-tasking kinase
- PMID: 12615961
- PMCID: PMC3006448
- DOI: 10.1242/jcs.00384
GSK-3: tricks of the trade for a multi-tasking kinase
Abstract
Glycogen synthase kinase 3 (GSK-3) is a multifunctional serine/threonine kinase found in all eukaryotes. The enzyme is a key regulator of numerous signalling pathways, including cellular responses to Wnt, receptor tyrosine kinases and G-protein-coupled receptors and is involved in a wide range of cellular processes, ranging from glycogen metabolism to cell cycle regulation and proliferation. GSK-3 is unusual in that it is normally active in cells and is primarily regulated through inhibition of its activity. Another peculiarity compared with other protein kinases is its preference for primed substrates, that is, substrates previously phosphorylated by another kinase. Several recent advances have improved our understanding of GSK-3 regulation in multiple pathways. These include the solution of the crystal structure of GSK-3, which has provided insight into GSK-3's penchant for primed substrates and the regulation of GSK-3 by serine phosphorylation, and findings related to the involvement of GSK-3 in the Wnt/beta-catenin and Hedgehog pathways. Finally, since increased GSK-3 activity may be linked to pathology in diseases such as Alzheimer's disease and non-insulin-dependent diabetes mellitus, several new GSK-3 inhibitors, such as the aloisines, the paullones and the maleimides, have been developed. Although they are just starting to be characterized in cell culture experiments, these new inhibitors hold promise as therapeutic agents.
Figures
![Fig. 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3006448/bin/nihms1576f1.gif)
![Fig. 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3006448/bin/nihms1576f2a.gif)
![Fig. 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3006448/bin/nihms1576f2a.gif)
![Fig. 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3006448/bin/nihms1576f3.gif)
Similar articles
-
The interaction of glycogen synthase kinase-3 (GSK-3) with the cell cycle.Prog Cell Cycle Res. 2003;5:489-95. Prog Cell Cycle Res. 2003. PMID: 14593744 Review.
-
Dysregulation of glycogen synthase kinase-3beta signaling in hepatocellular carcinoma cells.Hepatology. 2002 Dec;36(6):1528-36. doi: 10.1053/jhep.2002.37192. Hepatology. 2002. PMID: 12447879
-
Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin.EMBO J. 1998 Mar 2;17(5):1371-84. doi: 10.1093/emboj/17.5.1371. EMBO J. 1998. PMID: 9482734 Free PMC article.
-
Evidence for involvement of Wnt signaling pathway in IB-MECA mediated suppression of melanoma cells.Oncogene. 2002 Jun 6;21(25):4060-4. doi: 10.1038/sj.onc.1205531. Oncogene. 2002. PMID: 12037688
-
Effects of mutations in Wnt/β-catenin, hedgehog, Notch and PI3K pathways on GSK-3 activity-Diverse effects on cell growth, metabolism and cancer.Biochim Biophys Acta. 2016 Dec;1863(12):2942-2976. doi: 10.1016/j.bbamcr.2016.09.004. Epub 2016 Sep 6. Biochim Biophys Acta. 2016. PMID: 27612668 Review.
Cited by
-
Evaluation of the effect of GSK-3β on liver cancer based on the PI3K/AKT pathway.Front Cell Dev Biol. 2024 Aug 2;12:1431423. doi: 10.3389/fcell.2024.1431423. eCollection 2024. Front Cell Dev Biol. 2024. PMID: 39156976 Free PMC article. Review.
-
GSK3-Driven Modulation of Inflammation and Tissue Integrity in the Animal Model.Int J Mol Sci. 2024 Jul 29;25(15):8263. doi: 10.3390/ijms25158263. Int J Mol Sci. 2024. PMID: 39125833 Free PMC article. Review.
-
Unraveling Cancer's Wnt Signaling: Dynamic Control through Protein Kinase Regulation.Cancers (Basel). 2024 Jul 28;16(15):2686. doi: 10.3390/cancers16152686. Cancers (Basel). 2024. PMID: 39123414 Free PMC article. Review.
-
Hydrostatic pressure drives sprouting angiogenesis via adherens junction remodelling and YAP signalling.Commun Biol. 2024 Aug 3;7(1):940. doi: 10.1038/s42003-024-06604-9. Commun Biol. 2024. PMID: 39097636 Free PMC article.
-
Ghrelin/GHSR System in Depressive Disorder: Pathologic Roles and Therapeutic Implications.Curr Issues Mol Biol. 2024 Jul 10;46(7):7324-7338. doi: 10.3390/cimb46070434. Curr Issues Mol Biol. 2024. PMID: 39057075 Free PMC article. Review.
References
-
- Ali A, Hoeflich KP, Woodgett JR. Glycogen synthase kinase-3: properties, functions, and regulation. Chem Rev. 2001;101:2527–2540. - PubMed
-
- Armstrong JL, Bonavaud SM, Toole BJ, Yeaman SJ. Regulation of glycogen synthesis by amino acids in cultured human muscle cells. J Biol Chem. 2001;276:952–956. - PubMed
-
- Aza-Blanc P, Ramirez-Weber FA, Laget MP, Schwartz C, Kornberg TB. Proteolysis that is inhibited by hedgehog targets Cubitus interruptus protein to the nucleus and converts it to a repressor. Cell. 1997;89:1043–1053. - PubMed
-
- Ballou LM, Tian PY, Lin HY, Jiang YP, Lin RZ. Dual regulation of glycogen synthase kinase-3beta by the alpha1A-adrenergic receptor. J Biol Chem. 2001;276:40910–40916. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources