API

Relationship: 1925

Title

?

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).

Time-scale

?

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).

References

?


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