API

Event: 1646

Key Event Title

?

Frizzled activation

Short name

?

Frizzled activation

Biological 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

?



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