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Key Event Title
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|GSK3beta inactivation leads to increased mortality||MolecularInitiatingEvent||Vid Modic (send email)||Under development: Not open for comment. Do not cite|
|All life stages||High|
Key Event Description
The protein encoded by gsk3b gene is a serine-threonine kinase belonging to the glycogen synthase kinase subfamily. It is a negative regulator of glucose homeostasis and is involved in energy metabolism, inflammation, ER-stress, mitochondrial dysfunction, and apoptotic pathways. Defects in this gene have been associated with Parkinson disease and Alzheimer disease (GSK3B Gene - GeneCards). GSK3b has been identified within mitochondria (Hoshi et al., 1996), as well as in the cytoplasm (Anichtchik et al., 2008).
GSK3b kinase is constitutively active in resting cells and undergoes a rapid and transient inhibition in response to a number of external signals. GSK3b activity is regulated by site-specific phosphorylation. Full activity of GSK3b generally requires phosphorylation at tyrosine 216 (Tyr216), and conversely, phosphorylation at serine 9 (Ser9) inhibits GSK3b activity. Phosphorylation of Ser9 is the most common and important regulatory mechanism. Many kinases are capable of phosphorylating Ser9, including p70 S6 kinase, extracellular signal-regulated kinases (ERKs), p90Rsk (also called MAP-KAP kinase-1), protein kinase B (also called Akt), certain isoforms of protein kinase C (PKC) and cyclic AMP-dependent protein kinase (protein kinase A, PKA). In opposition to the inhibitory modulation of GSK3b that occurs by serine phosphorylation, tyrosine phosphorylation of GSK3b increases the enzyme’s activity (Grimes and Jope, 2001; Luo, 2012).
・CHIR and BIO treatments lead to a slight upregulation of the primary transcripts of the miR-302-367 cluster and miR-181 family of miRNAs, which activate Wnt/beta-catenin signaling (Y. Wu et al., 2015).
・SB216763 inhibits GSK3beta (Naujok et al., 2014).
・TWS119 inhibits GSK3beta (Tang et al., 2018).
How It Is Measured or Detected
Inactivation of GSK3 beta is measured by Wnt/beta-catenin activity assay, in which the vector containing the firefly luciferase gene controlled by TCF/LEF binding sites is transfected in the cells (Naujok et al., 2014). Phosphorylation of GSK3beta at residue Ser9 leads to the inactivation of GSK3beta. Phosphorylation of GSK3 beta is measured by immunoblotting with anti-phospho-GSK3beta (Huang et al., 2019).
Domain of Applicability
Phosphorylation of GSK3beta is induced, which means the inactivation of GSK3beta, in Homo sapiens (Huang et al., 2019). Evidence for this KE is also provided for zebrafish (Anichtchik et al., 2008; Wang et al. 2018)
Evidence for Perturbation by Stressor
Overview for Molecular Initiating Event
CHIR99021 inhibits GSK3beta (Wu et al., 2015) .
BIO (6-bromoindirubin-3’-oxime) inhibits GSK3beta (Wu et al., 2015).
Kenpaullone inhibits GSK3beta (Yang et al., 2013).
SB216763 inhibits GSK3betat (Naujok, Lentes, Diekmann, Davenport, & Lenzen, 2014).
TWS119 inhibits GSK3beta (Tang et al., 2018).
CHIR98014 inhibits GSK3beta (Guerrero et al., 2014; Lian et al., 2014).
Anichtchik, O. et al. (2008) ‘Loss of PINK1 function affects development and results in neurodegeneration in zebrafish’, Journal of Neuroscience, 28(33), pp. 8199–8207. doi: 10.1523/JNEUROSCI.0979-08.2008
Grimes, C. A. and Jope, R. S. (2001) ‘The multifaceted roles of glycogen synthase kinase 3β in cellular signaling’, Progress in Neurobiology, 65(4), pp. 391–426. doi: 10.1016/S0301-0082(01)00011-9
GSK3B Gene - GeneCards | GSK3B Protein | GSK3B Antibody (no date). Available at: https://www.genecards.org/cgi-bin/carddisp.pl?gene=GSK3B (Accessed: 3 October 2021)
Guerrero, F., Herencia, C., Almaden, Y., Martinez-Moreno, J. M., Montes de Oca, A., Rodriguez-Ortiz, M. E., . . . Munoz-Castaneda, J. R. (2014). TGF-beta prevents phosphate-induced osteogenesis through inhibition of BMP and Wnt/beta-catenin pathways. PLoS One, 9(2), e89179. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/24586576. doi:10.1371/journal.pone.0089179
Hoshi, M. et al. (1996) Regulation of mitochondrial pyruvate dehydrogenase activity by tau protein kinase I/glycogen synthase kinase 3p3 in brain, Neurobiology
Huang, J. Q., Wei, F. K., Xu, X. L., Ye, S. X., Song, J. W., Ding, P. K., . . . Gong, L. Y. (2019). SOX9 drives the epithelial-mesenchymal transition in non-small-cell lung cancer through the Wnt/beta-catenin pathway. J Transl Med, 17(1), 143. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/31060551. doi:10.1186/s12967-019-1895-2
Li, C. H., Liu, C. W., Tsai, C. H., Peng, Y. J., Yang, Y. H., Liao, P. L., . . . Kang, J. J. (2017). Cytoplasmic aryl hydrocarbon receptor regulates glycogen synthase kinase 3 beta, accelerates vimentin degradation, and suppresses epithelial-mesenchymal transition in non-small cell lung cancer cells. Arch Toxicol, 91(5), 2165-2178. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/27752740. doi:10.1007/s00204-016-1870-0
Lian, X., Bao, X., Al-Ahmad, A., Liu, J., Wu, Y., Dong, W., . . . Palecek, S. P. (2014). Efficient differentiation of human pluripotent stem cells to endothelial progenitors via small-molecule activation of WNT signaling. Stem Cell Reports, 3(5), 804-816. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/25418725. doi:10.1016/j.stemcr.2014.09.005
Liu, C. C., Cai, D. L., Sun, F., Wu, Z. H., Yue, B., Zhao, S. L., . . . Yan, D. W. (2016). FERMT1 mediates epithelial–mesenchymal transition to promote colon cancer metastasis via modulation of β-catenin transcriptional activity. Oncogene, 36, 1779. Retrieved from https://doi.org/10.1038/onc.2016.339. doi:10.1038/onc.2016.339 https://www.nature.com/articles/onc2016339 - supplementary-information
Luo, J. (2012) ‘The role of GSK3beta in the development of the central nervous system’, Front. Biol, 7(3), pp. 212–220. doi: 10.1007/s11515-012-1222-2
Mohammed, M. K., Shao, C., Wang, J., Wei, Q., Wang, X., Collier, Z., . . . Lee, M. J. (2016). Wnt/beta-catenin signaling plays an ever-expanding role in stem cell self-renewal, tumorigenesis and cancer chemoresistance. Genes Dis, 3(1), 11-40. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/27077077. doi:10.1016/j.gendis.2015.12.004
Naujok, O., Lentes, J., Diekmann, U., Davenport, C., & Lenzen, S. (2014). Cytotoxicity and activation of the Wnt/beta-catenin pathway in mouse embryonic stem cells treated with four GSK3 inhibitors. BMC Res Notes, 7, 273. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/24779365. doi:10.1186/1756-0500-7-273
Sineva, G. S., & Pospelov, V. A. (2010). Inhibition of GSK3beta enhances both adhesive and signalling activities of beta-catenin in mouse embryonic stem cells. Biol Cell, 102(10), 549-560. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/20626347. doi:10.1042/BC20100016
Tang, Y. Y., Sheng, S. Y., Lu, C. G., Zhang, Y. Q., Zou, J. Y., Lei, Y. Y., . . . Hong, H. (2018). Effects of Glycogen Synthase Kinase-3beta Inhibitor TWS119 on Proliferation and Cytokine Production of TILs From Human Lung Cancer. J Immunother, 41(7), 319-328. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/29877972. doi:10.1097/CJI.0000000000000234
Wang, Z. et al. (2018) ‘The role of gastrulation brain homeobox 2 (gbx2) in the development of the ventral telencephalon in zebrafish embryos’, Differentiation, 99(December 2017), pp. 28–40. doi: 10.1016/j.diff.2017.12.005
Wu, Y., Liu, F., Liu, Y., Liu, X., Ai, Z., Guo, Z., & Zhang, Y. (2015). GSK3 inhibitors CHIR99021 and 6-bromoindirubin-3'-oxime inhibit microRNA maturation in mouse embryonic stem cells. Sci Rep, 5, 8666. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/25727520. doi:10.1038/srep08666
Yang, Y. M., Gupta, S. K., Kim, K. J., Powers, B. E., Cerqueira, A., Wainger, B. J., . . . Rubin, L. L. (2013). A small molecule screen in stem-cell-derived motor neurons identifies a kinase inhibitor as a candidate therapeutic for ALS. Cell Stem Cell, 12(6), 713-726. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/23602540. doi:10.1016/j.stem.2013.04.003
Yao, Z., Zhou, G., Wang, X. S., Brown, A., Diener, K., Gan, H., & Tan, T. H. (1999). A novel human STE20-related protein kinase, HGK, that specifically activates the c-Jun N-terminal kinase signaling pathway. J Biol Chem, 274(4), 2118-2125. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/9890973.