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Event: 1647

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

GSK3beta inactivation

Short name

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Biological Context

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Level of Biological Organization
Molecular

Cell term

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Cell term
cell

Organ term

Organ term
organ

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

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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)	Open for citation & comment

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
Homo sapiens	Homo sapiens	High	NCBI
zebra fish	Danio rerio	High	NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
All life stages	High

Sex Applicability

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Term	Evidence
Unspecific	High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

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).

・Glycogen synthase kinase 3beta (GSK3 beta) is inhibited by CHIR99021 (C. H. Li et al., 2017; C. C. Liu et al., 2016; Sineva & Pospelov, 2010).

・Glycogen synthase kinase 3beta (GSK3 beta) is inhibited by BIO (6-bromoindirubin-3’-oxime) (Mohammed et al., 2016; Sineva & Pospelov, 2010).

・Kenpaullone is a dual inhibitor for GSK3 alpha/beta and HPK1/GCK-like kinase (Y. M. Yang et al., 2013; Yao et al., 1999).

・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).

・CHIR98014 inhibits GSK3beta (Guerrero et al., 2014; Lian et al., 2014).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

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

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

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)

References

List of the literature that was cited for this KE description. More help

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.