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Event: 1645
Key Event Title
Wnt ligand stimulation
Short name
Biological Context
Level of Biological Organization |
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Molecular |
Cell term
Cell term |
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cell |
Organ term
Organ term |
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organ |
Key Event Components
Key Event Overview
AOPs Including This Key Event
Taxonomic Applicability
Term | Scientific Term | Evidence | Link |
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Homo sapiens | Homo sapiens | High | NCBI |
Life Stages
Life stage | Evidence |
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All life stages | Moderate |
Sex Applicability
Term | Evidence |
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Unspecific | High |
Key Event Description
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
- 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
- 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
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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
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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
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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