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Relationship: 2070
Title
Porcupine-induced Wnt secretion and Wnt signaling activation leads to beta-catenin activation
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|---|---|
Increases in cellular reactive oxygen species and chronic reactive oxygen species leading to human treatment-resistant gastric cancer | adjacent | Moderate | Moderate | Shihori Tanabe (send email) | Open for comment. Do not cite | EAGMST Under Review |
Taxonomic Applicability
Term | Scientific Term | Evidence | Link |
---|---|---|---|
Homo sapiens | Homo sapiens | High | NCBI |
Sex Applicability
Sex | Evidence |
---|---|
Unspecific | High |
Life Stage Applicability
Term | Evidence |
---|---|
All life stages | High |
Key Event Relationship Description
Secreted Wnt ligand stimulates Wnt/beta-catenin signaling, in which beta-catenin is activated. Wnt ligand binds to Frizzled receptor, which leads to GSK3beta inactivation. GSK3beta inactivation leads to beta-catenin dephosphorylation, which avoids the ubiquitination of the beta-catenin and stabilizes the beta-catenin (Clevers & Nusse, 2012). The translocation of stabilized beta-catenin induces the transcription of genes involved in proliferation (Pai et al., 2017).
Evidence Collection Strategy
Evidence Supporting this KER
Biological Plausibility
Canonical Wnt pathway consists of Wnt, GSK3beta, and beta-catenin cascade (Clevers & Nusse, 2012; Hatsell, Rowlands, Hiremath, & Cowin, 2003).
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
[Incidence concordance]
Dishevelled (DVL), a positive regulator of Wnt signaling, form the complex with FZD and lead to trigger the Wnt signaling together with Wnt coreceptor low-density lipoprotein (LDL) receptor-related protein 6 (LRP6) (Clevers & Nusse, 2012; Jiang, Charlat, Zamponi, Yang, & Cong, 2015). Wnt binds to FZD and activates the Wnt signaling (Clevers & Nusse, 2012; Janda, Waghray, Levin, Thomas, & Garcia, 2012; Nile, Mukund, Stanger, Wang, & Hannoush, 2017). Wnt binding towards FZD induces the formation of the protein complex with LRP5/6 and DVL, leading to the downstream signaling activation including beta-catenin (Clevers & Nusse, 2012).
Uncertainties and Inconsistencies
Some Wnt ligands bind to FZD, leading to Wnt/beta-catenin signaling inactivation. DVL, a positive regulator of Wnt signaling, has a controversial role to promote Wnt receptor degradation (Jiang et al., 2015). DVL-dependent regulation of FZD level is involved in mTORC1 signaling suppression via Wnt/beta-catenin signaling (Zeng et al., 2018)
GSK3beta phosphorylates LRP6 as well as remaining GSK3 beta phosphorylates beta-catenin which would be ubiquitinated and degradated (MacDonald et al., 2009).
Known modulating factors
FZD5 can activate WNT3A/beta-catenin signaling in a dose-dependent manner (Hua et al., 2018). The increase in FZD5 protein enhances cell response to WNT3A. (Hua et al., 2018). LRP5 can augment WNT3A/beta-catenin signaling in a dose-dependent manner (Hua et al., 2018). The binding of Wnt and FZD induce the formation of the protein complex with the Dvl, Axin, CK1 GSK3, beta-catenin and APC to induce the beta-catenin translocation into the nucleus (Clevers & Nusse, 2012).
Quantitative Understanding of the Linkage
Response-response Relationship
Wnt3 promotes proliferation and survival in HUVECs (Shen et al., 2018).
GSK3beta inhibition by 1 uM of SB216763 or 5 uM 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
FZD7 enhances the activity of canonical Wnt/beta-catenin signaling with the treatment of WNT3A for 1 to 6 hrs (Cao et al., 2017). 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 Feedforward/Feedback loops influencing this KER
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). The Wnt ligand is antagonized with secreted Frizzled-related proteins (sFRPs) and Wnt inhibitory protein (WIF), both of which can bind Wnts and inhibit interactions between WNT and FZD (Bovolenta, Esteve, Ruiz, Cisneros, & Lopez-Rios, 2008; Clevers & Nusse, 2012). The Dickkopf 1 (DKK1) can disrupts Wnt-induced FZD-LRP6 complex formation (Clevers & Nusse, 2012; Ellwanger et al., 2008; Semenov, Zhang, & He, 2008).
Domain of Applicability
Wnt/beta-catenin signaling, which regulates key cellular functions including proliferation, is a highly conserved pathway through evolution (Pai et al., 2017).
References
Bovolenta, P., Esteve, P., Ruiz, J. M., Cisneros, E., & Lopez-Rios, J. (2008). Beyond Wnt inhibition: new functions of secreted Frizzled-related proteins in development and disease. J Cell Sci, 121(Pt 6), 737-746. doi:10.1242/jcs.026096
Cao, T. T., Xiang, D., Liu, B. L., Huang, T. X., Tan, B. B., Zeng, C. M., . . . Fu, L. (2017). FZD7 is a novel prognostic marker and promotes tumor metastasis via WNT and EMT signaling pathways in esophageal squamous cell carcinoma. Oncotarget, 8(39), 65957-65968. doi:10.18632/oncotarget.19586
Clevers, H., & Nusse, R. (2012). Wnt/beta-catenin signaling and disease. Cell, 149(6), 1192-1205. doi:10.1016/j.cell.2012.05.012
Ellwanger, K., Saito, H., Clement-Lacroix, P., Maltry, N., Niedermeyer, J., Lee, W. K., . . . Niehrs, C. (2008). Targeted disruption of the Wnt regulator Kremen induces limb defects and high bone density. Mol Cell Biol, 28(15), 4875-4882. doi:10.1128/MCB.00222-08
Hatsell, S., Rowlands, T., Hiremath, M., & Cowin, P. (2003). Beta-catenin and Tcfs in mammary development and cancer. J Mammary Gland Biol Neoplasia, 8(2), 145-158. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/14635791
Hua, Y., Yang, Y., Li, Q., He, X., Zhu, W., Wang, J., & Gan, X. (2018). Oligomerization of Frizzled and LRP5/6 protein initiates intracellular signaling for the canonical WNT/beta-catenin pathway. J Biol Chem, 293(51), 19710-19724. doi:10.1074/jbc.RA118.004434
Janda, C. Y., Waghray, D., Levin, A. M., Thomas, C., & Garcia, K. C. (2012). Structural basis of Wnt recognition by Frizzled. Science, 337(6090), 59-64. doi:10.1126/science.1222879
Jiang, X., Charlat, O., Zamponi, R., Yang, Y., & Cong, F. (2015). Dishevelled promotes Wnt receptor degradation through recruitment of ZNRF3/RNF43 E3 ubiquitin ligases. Mol Cell, 58(3), 522-533. doi:10.1016/j.molcel.2015.03.015
MacDonald, B. T., Tamai, K., & He, X. (2009). Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell, 17(1), 9-26. doi:10.1016/j.devcel.2009.06.016
Nile, A. H., Mukund, S., Stanger, K., Wang, W., & Hannoush, R. N. (2017). Unsaturated fatty acyl recognition by Frizzled receptors mediates dimerization upon Wnt ligand binding. Proc Natl Acad Sci U S A, 114(16), 4147-4152. doi:10.1073/pnas.1618293114
Pai SG, Carneiro BA, Mota JM, Costa R, Leite CA, Barroso-Sousa R, Kaplan JB, Chae YK, Giles FJ. Wnt/beta-catenin pathway: modulating anticancer immune response. J Hematol Oncol. 2017 May 5;10(1):101. doi: 10.1186/s13045-017-0471-6. PMID: 28476164; PMCID: PMC5420131.
Semenov, M. V., Zhang, X., & He, X. (2008). DKK1 antagonizes Wnt signaling without promotion of LRP6 internalization and degradation. J Biol Chem, 283(31), 21427-21432. doi:10.1074/jbc.M800014200
Shen, M., Bai, D., Liu, B., Lu, X., Hou, R., Zeng, C., . . . Yin, T. (2018). Dysregulated Txnip-ROS-Wnt axis contributes to the impaired ischemic heart repair in diabetic mice. Biochimica et biophysica acta. Molecular basis of disease, 1864(12), 3735-3745. doi:10.1016/j.bbadis.2018.09.029
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. 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. doi:10.1016/j.cell.2010.11.034
Zeng, H., Lu, B., Zamponi, R., Yang, Z., Wetzel, K., Loureiro, J., . . . Cong, F. (2018). mTORC1 signaling suppresses Wnt/beta-catenin signaling through DVL-dependent regulation of Wnt receptor FZD level. Proc Natl Acad Sci U S A, 115(44), E10362-E10369. doi:10.1073/pnas.1808575115