API

Event: 1645

Key Event Title

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Wnt ligand stimulation

Short name

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Wnt ligand stimulation

Biological Context

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Level of Biological Organization
Molecular

Cell term

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Cell term
cell


Organ term

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Organ term
organ


Key Event Components

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Process Object Action

Key Event Overview


AOPs Including This Key Event

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AOP Name Role of event in AOP
Wnt activation leading to cancer malignancy MolecularInitiatingEvent

Stressors

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Taxonomic Applicability

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Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI

Life Stages

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Life stage Evidence
All life stages Moderate

Sex Applicability

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Term Evidence
Unspecific High

Key Event Description

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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

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  • 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

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  • 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).

Evidence for Perturbation by Stressor


Overview for Molecular Initiating Event

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•WNT secretion from the cells requires a number of factors including the sorting receptor Wntless (Banziger et al., 2006; Bartscherer, Pelte, Ingelfinger, & Boutros, 2006; Goodman et al., 2006).

・Wnt signaling activation is occurred by WNTs. WNT5A can activate Wnt signaling leading to EMT (Dissanayake et al., 2007) and inhibit Wnt signaling as well (Kremenevskaja et al., 2005). 

・Dickkopf WNT signaling pathway inhibitor 2 (DKK2) inhibits Wnt signaling (Mu et al., 2017).

・Zebrafish eaf1 and eaf2/u19 mediate effective convergence and extension movements through the maintenance of wnt11 and wnt5 expression (J. X. Liu, Hu, Wang, Gui, & Xiao, 2009).

・The inhibitors for WNT signaling include WNT inhibitory factor 1 (WIF-1) (Yan et al., 2018; Jiao Zhang et al., 2014).

・The casein kinase 1 (CK1), serine (Ser)/threonine (Thr) protein kinases are involved in Wnt and Hedgehog pathways (J. Jiang, 2017). 

・IQ-1 and ID-8 are modulators for Wnt signaling (Hasegawa et al., 2012; Miyabayashi et al., 2007) (Kahn, 2014).

・WNT activates Wnt signaling which is involved in neuroblastoma (Johnsen, Dyberg, Fransson, & Wickström, 2018).

・Wnt5a is involved in non-canonical WNT signaling pathways, through binding to different members of the Frizzled- and Ror-family receptors (Asem, Buechler, Wates, Miller, & Stack, 2016).

・WNT5A induces EMT via non-canonical WNT signaling related to molecules such as PKC and JNK (Dissanayake et al., 2007; Jordan et al., 2013) Abell et al., 2011).

・WNT2B/WNT13 has been identified as human genes, and induces mesenchymal to epithelial transition (MET) in cooperation with FZD in colorectal cancer (Schwab et al., 2018).

Wnt8 activates WNT/beta-catenin signaling leading to induction of EMT in Sea urchin (Thiery, Acloque, Huang, & Nieto, 2009).



WNT2

WNT2 induces EMT in cervical cancer (Zhou et al., 2016).


Wnt

Wnt stimulation induces EMT.


WNT5A

WNT5A induces EMT in non-small-cell lung cancer (Wang, Tang, Gong, Zhu, & Liu, 2017).


References

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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