API

Relationship: 1926

Title

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GSK3beta inactivation leads to β-catenin activation

Upstream event

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GSK3beta inactivation

Downstream event

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β-catenin activation

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
Wnt ligand stimulation and Wnt signalling activation lead to cancer malignancy adjacent High Moderate

Taxonomic Applicability

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Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI

Sex Applicability

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Sex Evidence
Unspecific High

Life Stage Applicability

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Term Evidence
All life stages High

Key Event Relationship Description

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GSK3beta inactivation leads to beta-catenin dephosphorylation, which avoids the ubiquitination of the beta-catenin and stabilize the beta-catenin (Clevers & Nusse, 2012).

Evidence Supporting this KER

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Biological Plausibility

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GSK3beta recruitment to LRP6 leads to form un-phosphorylated beta-catenin inducing the stabilization and translocation of the beta-catenin (MacDonald, Tamai, & He, 2009).

Stabilized beta-catenin accumulates in cytosol and translocates into the nucleus leading to beta-catenin activation (MacDonald et al., 2009).

Empirical Evidence

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GSK3beta inactivation induces the beta-catenin stabilization (Pez et al., 2013).

GSK3beta inactivation induces beta-catenin translocation into the nucleus (MacDonald et al., 2009; Pez et al., 2013).

WNT2 knockdown induces the accumulation of GSK3beta in the cytoplasm and reduced the expression of beta-catenin, which WNT2 overexpression reduces the expression of GSK3beta in the cytoplasm and induces beta-catenin translocation into the nucleus (Wang, Li, & Kidder, 2010).

WNT2 siRNA knockdown increases the GSK3beta expression and decreases beta-catenin expression, and WNT2 overexpression reduces the GSK3beta and increases beta-catenin in granulosa cells in Mus musculus (Wang et al., 2010).

Uncertainties and Inconsistencies

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GSK3beta phosphorylates LRP6 as well as remaining GSK3 beta phosphorylates beta-catenin which would be ubiquitinated and degradated (MacDonald et al., 2009).

Quantitative Understanding of the Linkage

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Response-response Relationship

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GSK3beta inhibition by 1 mM of SB216763 or 5 mM of BRD3731 results in the decreased phosphorylation and stabilization of beta-catenin (Stump et al., 2019). The level of beta-catenin is increased by the inhibition of GSK3beta kinase activity (Stump et al., 2019). GSK3beta inhibition by small interference RNA (siRNA) of GSK3beta results in the decreased phosphorylation and increased expression of beta-catenin (Stump et al., 2019).

Time-scale

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The treatment with SB216763 or BRD3731, GSK3beta inhibitors, decreases phosphorylated beta-catenin and increased beta-catenin expression in 48 hours (Stump et al., 2019). The cells are treated with GSK3beta small interference RNA (siRNA) for 48 hours to silence the expression of GSK3beta, which results in the activation of beta-catenin pathway (Stump et al., 2019).

Known modulating factors

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Sortilin, a member of the sorting receptor family that transport intracellular proteins, regulates GSK3-beta, beta-catenin and Twist pathway activation to induce epithelial-mesenchymal transition and glioblastoma invasion (Yang et al., 2019).

Known Feedforward/Feedback loops influencing this KER

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Beta-catenin is required and sufficient for the sequestration of GSK3 in acidic cytoplasmic endosomes (Taelman et al., 2010). Beta-catenin, of which level increases in Wnt signaling, facilitates GSK3 sequestration leading to feed-forward loop formation (Taelman et al., 2010).

Domain of Applicability

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GSK3-beta inhibition induced beta-catenin activation in human lung lymphatic endothelial cells (Homo sapiens) (Stump et al., 2019).

References

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Clevers, H., & Nusse, R. (2012). Wnt/beta-catenin signaling and disease. Cell, 149(6), 1192-1205. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/22682243. doi:10.1016/j.cell.2012.05.012

MacDonald, B. T., Tamai, K., & He, X. (2009). Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell, 17(1), 9-26. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/19619488. doi:10.1016/j.devcel.2009.06.016

Pez, F., Lopez, A., Kim, M., Wands, J. R., Caron de Fromentel, C., & Merle, P. (2013). Wnt signaling and hepatocarcinogenesis: molecular targets for the development of innovative anticancer drugs. J Hepatol, 59(5), 1107-1117. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/23835194. doi:10.1016/j.jhep.2013.07.001

Stump, B., Shrestha, S., Lamattina, A. M., Louis, P. H., Cho, W., Perrella, M. A., . . . El-Chemaly, S. (2019). Glycogen synthase kinase 3-beta inhibition induces lymphangiogenesis through beta-catenin-dependent and mTOR-independent pathways. PLoS One, 14(4), e0213831. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30964887. doi:10.1371/journal.pone.0213831

Taelman, V. F., Dobrowolski, R., Plouhinec, J. L., Fuentealba, L. C., Vorwald, P. P., Gumper, I., . . . De Robertis, E. M. (2010). Wnt signaling requires sequestration of glycogen synthase kinase 3 inside multivesicular endosomes. Cell, 143(7), 1136-1148. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/21183076. doi:10.1016/j.cell.2010.11.034

Wang, H. X., Li, T. Y., & Kidder, G. M. (2010). WNT2 regulates DNA synthesis in mouse granulosa cells through beta-catenin. Biol Reprod, 82(5), 865-875. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/20107203. doi:10.1095/biolreprod.109.080903

Yang, W., Wu, P. F., Ma, J. X., Liao, M. J., Wang, X. H., Xu, L. S., . . . Yi, L. (2019). Sortilin promotes glioblastoma invasion and mesenchymal transition through GSK-3beta/beta-catenin/twist pathway. Cell Death Dis, 10(3), 208. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30814514. doi:10.1038/s41419-019-1449-9