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Relationship: 2070


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Porcupine-induced Wnt secretion and Wnt signaling activation leads to beta-catenin activation

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

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 Do not cite Under Review

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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

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

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

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).

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

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

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help

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).

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

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).

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

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
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

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

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Wnt/beta-catenin signaling, which regulates key cellular functions including proliferation, is a highly conserved pathway through evolution (Pai et al., 2017).


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

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

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