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Relationship: 1925

Title

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

Frizzled activation leads to GSK3beta inactivation

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Frizzled activation

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

GSK3beta inactivation

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

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

Frizzled receptor (FZD) activation leads to Glycogen synthase kinase 3 (GSK3) beta inactivation, which leads to dephosphorylation of beta-catenin (Clevers & Nusse, 2012).

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

Upon Wnt ligand stimulation, FZD is activated and Axin is recruited to the phosphorylated tail of LRP dimerized with the activated FZD, the seven-transmembrane receptor, followed by GSK3beta inactivation to prevent beta-catenin degradation (Aberle, Bauer, Stappert, Kispert, & Kemler, 1997) (Clevers & Nusse, 2012).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

The ligand-stimulated FZD induces the regulation of the phosphorylation by GSK3beta to inactivate GSK3beta which phosphorylates beta-catenin (Clevers & Nusse, 2012).
The binding of Axin to the cytoplasmic tail of LRP5 bound to Wnt is crucial for the Wnt signaling pathway regulation and GSK3 beta inactivation in Wnt/beta-catenin signaling (Mao et al., 2001).
Axin-LRP6 binding is the important step for the phosphorylation of the LRP5/6 tail by GSK3 beta which phosphorylates the serine in the PPPSP motif found in beta-catenin, Axin, APC (He, Semenov, Tamai, & Zeng, 2004; Tamai et al., 2004; Zeng et al., 2005).

Wnt3a induces phosphorylation of LRP6 leading to beta-catenin activation, while beta-catenin is not activated in FZD-inhibited cells (Zeng et al., 2008).

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

WNT5A inhibits WNT/beta-catenin signaling and exhibits tumor-suppressive activity (Ying et al., 2008).
WNT5A promotes resistance of melanoma cell (Anastas et al., 2014).

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

FZD and LRP5/6 form dimers and Axin binds to the cytoplasmic tail of LRP5/6, which is phosphorylated by GSK3beta, followed by the inactivation of GSK3beta in Wnt/beta-catenin signaling (Mao et al., 2001) (He et al., 2004; Tamai et al., 2004; Zeng et al., 2005).

Axin is required for WNT3-induced FZD and LRP6 activation leading to the recruitment of GSK3beta to the plasma membrane (Zeng et al., 2008).

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

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

GSK3beta activity is inhibited by 1, 10, and 100 uM of LRP6 PPPSPxS peptides dose-dependently in vitro (Piao et al., 2008).

Time-scale

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

GSK3beta activity inhibition by LRP6 PPPSPxS peptides is measured in the reaction for 30 min at 37 °C in vitro (Piao et al., 2008).

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

The recruitment of GSK3beta together with Axin to LRP5/6 upon FZD activation decreases the phosphorylation of beta-catenin by GSK3beta (He et al., 2004; Tamai et al., 2004; Zeng et al., 2005).

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

FZD activation leads to GSK3beta inactivation by the sequestration inside multivesicular endosomes in Homo sapiens (Taelman et al., 2010).

References

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

Aberle, H., Bauer, A., Stappert, J., Kispert, A., & Kemler, R. (1997). beta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J, 16(13), 3797-3804. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/9233789. doi:10.1093/emboj/16.13.3797

Anastas, J. N., Kulikauskas, R. M., Tamir, T., Rizos, H., Long, G. V., von Euw, E. M., . . . Moon, R. T. (2014). WNT5A enhances resistance of melanoma cells to targeted BRAF inhibitors. J Clin Invest, 124(7), 2877-2890. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/24865425. doi:10.1172/JCI70156

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

He, X., Semenov, M., Tamai, K., & Zeng, X. (2004). LDL receptor-related proteins 5 and 6 in Wnt/β-catenin signaling: Arrows point the way. Development, 131(8), 1663. Retrieved from http://dev.biologists.org/content/131/8/1663.abstract. doi:10.1242/dev.01117

Mao, J., Wang, J., Liu, B., Pan, W., Farr, G. H., Flynn, C., . . . Wu, D. (2001). Low-Density Lipoprotein Receptor-Related Protein-5 Binds to Axin and Regulates the Canonical Wnt Signaling Pathway. Molecular Cell, 7(4), 801-809. Retrieved from http://www.sciencedirect.com/science/article/pii/S1097276501002246. doi:https://doi.org/10.1016/S1097-2765(01)00224-6

Piao, S., Lee, S. H., Kim, H., Yum, S., Stamos, J. L., Xu, Y., . . . Ha, N. C. (2008). Direct inhibition of GSK3beta by the phosphorylated cytoplasmic domain of LRP6 in Wnt/beta-catenin signaling. PLoS One, 3(12), e4046. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/19107203. doi:10.1371/journal.pone.0004046

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

Tamai, K., Zeng, X., Liu, C., Zhang, X., Harada, Y., Chang, Z., & He, X. (2004). A Mechanism for Wnt Coreceptor Activation. Molecular Cell, 13(1), 149-156. Retrieved from http://www.sciencedirect.com/science/article/pii/S1097276503004842. doi:https://doi.org/10.1016/S1097-2765(03)00484-2

Ying, J., Li, H., Yu, J., Ng, K. M., Poon, F. F., Wong, S. C., . . . Tao, Q. (2008). WNT5A exhibits tumor-suppressive activity through antagonizing the Wnt/beta-catenin signaling, and is frequently methylated in colorectal cancer. Clin Cancer Res, 14(1), 55-61. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/18172252. doi:10.1158/1078-0432.CCR-07-1644

Zeng, X., Huang, H., Tamai, K., Zhang, X., Harada, Y., Yokota, C., . . . He, X. (2008). Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions. Development, 135(2), 367. Retrieved from http://dev.biologists.org/content/135/2/367.abstract. doi:10.1242/dev.013540

Zeng, X., Tamai, K., Doble, B., Li, S., Huang, H., Habas, R., . . . He, X. (2005). A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation. Nature, 438(7069), 873-877. Retrieved from https://doi.org/10.1038/nature04185. doi:10.1038/nature04185