API

Relationship: 1924

Title

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Wnt ligand stimulation leads to Frizzled activation

Upstream event

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Wnt ligand stimulation

Downstream event

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Frizzled activation

Key Event Relationship Overview

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AOPs Referencing Relationship

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

Taxonomic Applicability

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Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI

Sex Applicability

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Sex Evidence
Unspecific High

Life Stage Applicability

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Term Evidence
All life stages Moderate

Key Event Relationship Description

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Wnt ligand binds to Frizzled receptor (FZD), which leads to the Wnt signaling activation (Nile, Mukund, Stanger, Wang, & Hannoush, 2017).

Evidence Supporting this KER

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Biological Plausibility

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Upon the stimulation with Wnt ligand, Wnt ligand binds to FZD and form the complex with LRP5/6 (MacDonald et al., 2009).

Empirical Evidence

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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; X. Jiang et al., 2015).

Wnt binds to FZD and activate the Wnt signaling (Clevers & Nusse, 2012; Janda et al., 2012; Nile et al., 2017). Wnt binding towards FZD induce the formation of the protein complex with LRP5/6 and DVL, leading to the down-stream signaling activation (Clevers & Nusse, 2012).

Uncertainties and Inconsistencies

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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 (X. Jiang et al., 2015). DVL-dependent regulation of FZD level is involved in mTORC1 signaling suppression via Wnt/beta-catenin signaling (H. Zeng et al., 2018).

Quantitative Understanding of the Linkage

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Response-response Relationship

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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).

Time-scale

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FZD7 enhances the activity of canonical Wnt/beta-catenin signaling with the treatment of WNT3A for 1 to 6 hrs (Cao et al., 2017).

Known modulating factors

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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).

Known Feedforward/Feedback loops influencing this KER

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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

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Wnt ligand stimulation leads to FZD activation in Homo sapiens (Clevers & Nusse, 2012).

References

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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. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/18322270. 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. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/29029485. doi:10.18632/oncotarget.19586

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

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. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/18505822. doi:10.1128/MCB.00222-08

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. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30361437. 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. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/22653731. 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. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/25891077. 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. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/19619488. 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. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28377511. doi:10.1073/pnas.1618293114

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. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/18505732. doi:10.1074/jbc.M800014200

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. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30297426. doi:10.1073/pnas.1808575115