API

Event: 1647

Key Event Title

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GSK3beta inactivation

Short name

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GSK3beta inactivation

Biological Context

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Level of Biological Organization
Molecular

Cell term

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Cell term
cell


Organ term

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Organ term
organ


Key Event Components

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Process Object Action

Key Event Overview


AOPs Including This Key Event

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AOP Name Role of event in AOP
Wnt activation leading to cancer malignancy KeyEvent

Stressors

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Taxonomic Applicability

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Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI

Life Stages

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Life stage Evidence
All life stages High

Sex Applicability

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Term Evidence
Unspecific High

Key Event Description

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・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

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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

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Phosphorylation of GSK3beta is induced, which means the inactivation of GSK3beta, in Homo sapiens (Huang et al., 2019).


Evidence for Perturbation by Stressor



CHIR99021

CHIR99021 inhibits GSK3beta (Wu et al., 2015) .


BIO (6-bromoindirubin-3’-oxime)

BIO (6-bromoindirubin-3’-oxime) inhibits GSK3beta (Wu et al., 2015).


Kenpaullone

Kenpaullone inhibits GSK3beta (Yang et al., 2013).


SB216763

SB216763 inhibits GSK3betat (Naujok, Lentes, Diekmann, Davenport, & Lenzen, 2014).


TWS119

TWS119 inhibits GSK3beta (Tang et al., 2018).


CHIR98014

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


References

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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

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

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

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.