API
Event: 1646
Key Event Title
Short name
Frizzled activationBiological Context
| Level of Biological Organization |
|---|
| Molecular |
Cell term
| Cell term |
|---|
| cell |
Organ term
| Organ term |
|---|
| organ |
Key Event Components
| Process | Object | Action |
|---|
Key Event Overview
AOPs Including This Key Event
| AOP Name | Role of event in AOP |
|---|---|
| Wnt activation leading to cancer malignancy | KeyEvent |
Stressors
| Name |
|---|
| Wnt ligand |
Taxonomic Applicability
| Term | Scientific Term | Evidence | Link | |
|---|---|---|---|---|
| Homo sapiens | Homo sapiens | High | NCBI |
Life Stages
| Life stage | Evidence |
|---|---|
| All life stages | High |
Sex Applicability
| Term | Evidence |
|---|---|
| Unspecific | High |
Key Event Description
Wnt ligands bind to Frizzled (FZD) receptors which are seven transmembrane-domain protein receptors (Nile, Mukund, Stanger, Wang, & Hannoush, 2017). At least 10 FZD receptors are identified in human cells. FZD receptor is activated by Wnt ligand binding (MacDonald, Tamai, & He, 2009).
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, Charlat, Zamponi, Yang, & Cong, 2015). DVL, however, has a controversial role to promote Wnt receptor degradation (X. Jiang et al., 2015). Meanwhile, DVL-dependent regulation of FZD level is involved in mTORC1 signaling suppression via Wnt/beta-catenin signaling (H. Zeng et al., 2018).
How It Is Measured or Detected
- Frizzled receptor protein level on the cell surface is measured by flow cytometry with pan-FZD antibody (X. Jiang et al., 2015; H. Zeng et al., 2018).
- DVL protein level is measured by immunoblotting with anti-DVL2 antibody (H. Zeng et al., 2018).
- Fzd mRNA level is measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR) (H. Zeng et al., 2018).
Domain of Applicability
Oligomerization of FZD and low-density lipoprotein receptor-related protein 5/6 (LRP5/6) activates Wnt/beta-catenin signaling in Homo sapiens. (Hua et al., 2018).
Evidence for Perturbation by Stressor
Wnt ligand
Wnt ligands bind to Frizzled receptor leading to the activation (Bhanot et al., 1996; Janda, Waghray, Levin, Thomas, & Garcia, 2012).
References
Bhanot, P., Brink, M., Samos, C. H., Hsieh, J.-C., Wang, Y., Macke, J. P., . . . Nusse, R. (1996). A new member of the frizzled family from Drosophila functions as a Wingless receptor. Nature, 382, 225. Retrieved from https://doi.org/10.1038/382225a0. doi:10.1038/382225a0
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
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
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