Relationship: 1925



Frizzled activation leads to GSK3beta inactivation

Upstream event


Frizzled activation

Downstream event


GSK3beta inactivation

Key Event Relationship Overview


AOPs Referencing Relationship


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

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


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

Evidence Supporting this KER


Biological Plausibility


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


  • 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


  • 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).

Quantitative Understanding of the Linkage


Response-response Relationship


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



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 modulating factors


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).

Known Feedforward/Feedback loops influencing this KER


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


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



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