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Event: 1645

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Wnt ligand stimulation

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Wnt ligand stimulation
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Cell term
cell

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Organ term
organ

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
All life stages Moderate

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Unspecific High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Site of action: The site of action for the molecular initiating event is the cell membrane.

WNTs are secreted proteins that contain 22-24 conserved cysteine residues (Foulquier et al., 2018). The WNT molecules consist of molecular families including WNT1, WNT2, WNT2B/WNT13, WNT3, WNT4, WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT10B, WNT11 and WNT16. (Clevers & Nusse, 2012; Katoh, 2001; Kusserow et al., 2005)

Wnt proteins consists of 350-400 amino acids (Saito-Diaz et al., 2013).

WNT ligands are known to trigger at least three different downstream signaling cascades including canonical WNT/beta-catenin signaling pathway, non-canonical WNT/Ca2+ pathway and planer cell polarity (PCP) pathway(De, 2011; Lai, Chien, & Moon, 2009; Willert & Nusse, 2012). WNTs bind to Frizzled proteins, which are seven-pass transmembrane receptors with an extracellular N-terminal cysteine-rich domain (Bhanot et al., 1996; Clevers, 2006). Wnt signaling begins with the binding of Wnt ligand towards the Frizzled receptors (Mohammed et al., 2016).

Canonical Wnt pathway consists of Wnt, GSK3beta and beta-catenin cascade (Clevers & Nusse, 2012; Hatsell, Rowlands, Hiremath, & Cowin, 2003).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help
  • Secretion of WNT requires a number of other dedicated factors including the sortin receptor Wntless (WLS), which binds to Wnt and escorts it to the cell surface (Banziger et al., 2006; Ching & Nusse, 2006)
  • Wnt signaling is activated by the gene mutations of the signaling components (Ziv et al., 2017).
  • Wnt1, Wnt3a and Wnt5a protein expression are measured by immunoblotting using antibodies for Wnt1, Wnt3a and Wnt5a, respectively (J. Du et al., 2016; B. Wang et al., 2017).
  • WNT2, of which expression is detected by quantitative PCR, immunoblotting and immunohistochemistry, induces EMT (Zhou et al., 2016).
  • Wnt2B (Wnt13) mediates mesenchymal-epithelial-transition (MET) in vitro (Homo sapiens)(Schwab et al., 2018).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help
  • The up-regulation of WNT ligand expression occurs in Homo sapiens (B. Wang et al., 2017).
  • The Wnt genes play an important roles in the secretion from cells, glycosylation and tight association with the cell surface and extracellular matrix in Drosophila melanogaster (Willert & Nusse, 2012).
  • Wnt5a expression leads to epithelial-mesenchymal transition (EMT) and metastasis in non-small-cell lung cancer in Homo sapiens (B. Wang et al., 2017).
  • WNT2 expression lead to EMT induction in Homo sapiens (Zhou et al., 2016).

References

List of the literature that was cited for this KE description. More help

Asem, M. S., Buechler, S., Wates, R. B., Miller, D. L., & Stack, M. S. (2016). Wnt5a Signaling in Cancer. Cancers (Basel), 8(9). Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/27571105. doi:10.3390/cancers8090079

Banziger, C., Soldini, D., Schutt, C., Zipperlen, P., Hausmann, G., & Basler, K. (2006). Wntless, a conserved membrane protein dedicated to the secretion of Wnt proteins from signaling cells. Cell, 125(3), 509-522. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/16678095. doi:10.1016/j.cell.2006.02.049

Bartscherer, K., Pelte, N., Ingelfinger, D., & Boutros, M. (2006). Secretion of Wnt ligands requires Evi, a conserved transmembrane protein. Cell, 125(3), 523-533. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/16678096. doi:10.1016/j.cell.2006.04.009

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

Ching, W., & Nusse, R. (2006). A dedicated Wnt secretion factor. Cell, 125(3), 432-433. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/16678089. doi:10.1016/j.cell.2006.04.018

Clevers, H. (2006). Wnt/beta-catenin signaling in development and disease. Cell, 127(3), 469-480. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/17081971. doi:10.1016/j.cell.2006.10.018

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

De, A. (2011). Wnt/Ca2+ signaling pathway: a brief overview. Acta Biochim Biophys Sin (Shanghai), 43(10), 745-756. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/21903638. doi:10.1093/abbs/gmr079

Dissanayake, S. K., Wade, M., Johnson, C. E., O'Connell, M. P., Leotlela, P. D., French, A. D., . . . Weeraratna, A. T. (2007). The Wnt5A/protein kinase C pathway mediates motility in melanoma cells via the inhibition of metastasis suppressors and initiation of an epithelial to mesenchymal transition. J Biol Chem, 282(23), 17259-17271. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/17426020. doi:10.1074/jbc.M700075200

Du, J., Zu, Y., Li, J., Du, S., Xu, Y., Zhang, L., . . . Yang, C. (2016). Extracellular matrix stiffness dictates Wnt expression through integrin pathway. Sci Rep, 6, 20395. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/26854061. doi:10.1038/srep20395

Foulquier, S., Daskalopoulos, E. P., Lluri, G., Hermans, K. C. M., Deb, A., & Blankesteijn, W. M. (2018). WNT Signaling in Cardiac and Vascular Disease. Pharmacol Rev, 70(1), 68-141. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/29247129. doi:10.1124/pr.117.013896

Goodman, R. M., Thombre, S., Firtina, Z., Gray, D., Betts, D., Roebuck, J., . . . Selva, E. M. (2006). Sprinter: a novel transmembrane protein required for Wg secretion and signaling. Development, 133(24), 4901-4911. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/17108000. doi:10.1242/dev.02674

Hasegawa, K., Yasuda, S. Y., Teo, J. L., Nguyen, C., McMillan, M., Hsieh, C. L., . . . Kahn, M. (2012). Wnt signaling orchestration with a small molecule DYRK inhibitor provides long-term xeno-free human pluripotent cell expansion. Stem Cells Transl Med, 1(1), 18-28. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/23197636. doi:10.5966/sctm.2011-0033

Hatsell, S., Rowlands, T., Hiremath, M., & Cowin, P. (2003). Beta-catenin and Tcfs in mammary development and cancer. J Mammary Gland Biol Neoplasia, 8(2), 145-158. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/14635791.

Jiang, J. (2017). CK1 in Developmental Signaling: Hedgehog and Wnt. Curr Top Dev Biol, 123, 303-329. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28236970. doi:10.1016/bs.ctdb.2016.09.002

Johnsen, J. I., Dyberg, C., Fransson, S., & Wickström, M. (2018). Molecular mechanisms and therapeutic targets in neuroblastoma. Pharmacological Research, 131, 164-176. Retrieved from http://www.sciencedirect.com/science/article/pii/S1043661817316699. doi:https://doi.org/10.1016/j.phrs.2018.02.023

Jordan, N. V., Prat, A., Abell, A. N., Zawistowski, J. S., Sciaky, N., Karginova, O. A., . . . Johnson, G. L. (2013). SWI/SNF chromatin-remodeling factor Smarcd3/Baf60c controls epithelial-mesenchymal transition by inducing Wnt5a signaling. Mol Cell Biol, 33(15), 3011-3025. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/23716599. doi:10.1128/MCB.01443-12

Kahn, M. (2014). Can we safely target the WNT pathway? Nat Rev Drug Discov, 13(7), 513-532. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/24981364. doi:10.1038/nrd4233

Katoh, M. (2001). Molecular cloning and characterization of human WNT3. Int J Oncol, 19(5), 977-982. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/11604997.

Kremenevskaja, N., von Wasielewski, R., Rao, A. S., Schofl, C., Andersson, T., & Brabant, G. (2005). Wnt-5a has tumor suppressor activity in thyroid carcinoma. Oncogene, 24(13), 2144-2154. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/15735754. doi:10.1038/sj.onc.1208370

Kusserow, A., Pang, K., Sturm, C., Hrouda, M., Lentfer, J., Schmidt, H. A., . . . Holstein, T. W. (2005). Unexpected complexity of the Wnt gene family in a sea anemone. Nature, 433(7022), 156-160. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/15650739. doi:10.1038/nature03158

Lai, S. L., Chien, A. J., & Moon, R. T. (2009). Wnt/Fz signaling and the cytoskeleton: potential roles in tumorigenesis. Cell Res, 19(5), 532-545. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/19365405. doi:10.1038/cr.2009.41

Liu, J. X., Hu, B., Wang, Y., Gui, J. F., & Xiao, W. (2009). Zebrafish eaf1 and eaf2/u19 mediate effective convergence and extension movements through the maintenance of wnt11 and wnt5 expression. J Biol Chem, 284(24), 16679-16692. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/19380582. doi:10.1074/jbc.M109.009654

Miyabayashi, T., Teo, J. L., Yamamoto, M., McMillan, M., Nguyen, C., & Kahn, M. (2007). Wnt/beta-catenin/CBP signaling maintains long-term murine embryonic stem cell pluripotency. Proc Natl Acad Sci U S A, 104(13), 5668-5673. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/17372190. doi:10.1073/pnas.0701331104

Mohammed, M. K., Shao, C., Wang, J., Wei, Q., Wang, X., Collier, Z., . . . Lee, M. J. (2016). Wnt/beta-catenin signaling plays an ever-expanding role in stem cell self-renewal, tumorigenesis and cancer chemoresistance. Genes Dis, 3(1), 11-40. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/27077077. doi:10.1016/j.gendis.2015.12.004

Mu, J., Hui, T., Shao, B., Li, L., Du, Z., Lu, L., . . . Xiang, T. (2017). Dickkopf-related protein 2 induces G0/G1 arrest and apoptosis through suppressing Wnt/beta-catenin signaling and is frequently methylated in breast cancer. Oncotarget, 8(24), 39443-39459. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28467796. doi:10.18632/oncotarget.17055

Nusse, R., & Clevers, H. (2017). Wnt/beta-Catenin Signaling, Disease, and Emerging Therapeutic Modalities. Cell, 169(6), 985-999. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28575679. doi:10.1016/j.cell.2017.05.016

Saito-Diaz, K., Chen, T. W., Wang, X., Thorne, C. A., Wallace, H. A., Page-McCaw, A., & Lee, E. (2013). The way Wnt works: components and mechanism. Growth Factors, 31(1), 1-31. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/23256519. doi:10.3109/08977194.2012.752737

Schwab, R. H. M., Amin, N., Flanagan, D. J., Johanson, T. M., Phesse, T. J., & Vincan, E. (2018). Wnt is necessary for mesenchymal to epithelial transition in colorectal cancer cells. Dev Dyn, 247(3), 521-530. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28560804. doi:10.1002/dvdy.24527

Thiery, J. P., Acloque, H., Huang, R. Y., & Nieto, M. A. (2009). Epithelial-mesenchymal transitions in development and disease. Cell, 139(5), 871-890. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/19945376. doi:10.1016/j.cell.2009.11.007

Wang, B., Tang, Z., Gong, H., Zhu, L., & Liu, X. (2017). Wnt5a promotes epithelial-to-mesenchymal transition and metastasis in non-small-cell lung cancer. Biosci Rep, 37(6). Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/29054966. doi:10.1042/BSR20171092

Willert, K., & Nusse, R. (2012). Wnt proteins. Cold Spring Harb Perspect Biol, 4(9), a007864. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/22952392. doi:10.1101/cshperspect.a007864

Yan, T.-f., Wu, M.-j., Xiao, B., Hu, Q., Fan, Y.-H., & Zhu, X.-G. (2018). Knockdown of HOXC6 inhibits glioma cell proliferation and induces cell cycle arrest by targeting WIF-1 in vitro and vivo. Pathology - Research and Practice, 214(11), 1818-1824. Retrieved from http://www.sciencedirect.com/science/article/pii/S0344033818308380. doi:https://doi.org/10.1016/j.prp.2018.09.001

Zhang, J., Zhou, B., Liu, Y., Chen, K., Bao, P., Wang, Y., . . . Li, Y. (2014). Wnt inhibitory factor-1 functions as a tumor suppressor through modulating Wnt/β-catenin signaling in neuroblastoma. Cancer Letters, 348(1), 12-19. Retrieved from http://www.sciencedirect.com/science/article/pii/S0304383514001025. doi:https://doi.org/10.1016/j.canlet.2014.02.011

Zhou, Y., Huang, Y., Cao, X., Xu, J., Zhang, L., Wang, J., . . . Zheng, M. (2016). WNT2 Promotes Cervical Carcinoma Metastasis and Induction of Epithelial-Mesenchymal Transition. PLoS One, 11(8), e0160414. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/27513465. doi:10.1371/journal.pone.0160414

Ziv, E., Yarmohammadi, H., Boas, F. E., Petre, E. N., Brown, K. T., Solomon, S. B., . . . Erinjeri, J. P. (2017). Gene Signature Associated with Upregulation of the Wnt/beta-Catenin Signaling Pathway Predicts Tumor Response to Transarterial Embolization. J Vasc Interv Radiol, 28(3), 349-355 e341. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28126478. doi:10.1016/j.jvir.2016.11.004