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Event: 1754
Key Event Title
Porcupine-induced Wnt secretion and Wnt signaling activation
Short name
Biological Context
Level of Biological Organization |
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Cellular |
Cell term
Cell term |
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cell |
Organ term
Organ term |
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organ |
Key Event Components
Process | Object | Action |
---|---|---|
Wnt protein secretion | protein-serine O-palmitoleoyltransferase porcupine | increased |
Key Event Overview
AOPs Including This Key Event
AOP Name | Role of event in AOP | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|
Increases in ROS and chronic ROS leading to human treatment-resistant gastric cancer | KeyEvent | Shihori Tanabe (send email) | Open for comment. Do not cite | Under Review |
Taxonomic Applicability
Life Stages
Life stage | Evidence |
---|---|
All life stages | Moderate |
Sex Applicability
Term | Evidence |
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Unspecific | High |
Key Event Description
Porcupine, which is a trans-membrane endoplasmic reticulum O-acyl transferase, is important for the secretion of Wnt ligands(Saha et al., 2016a). 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; M. Katoh, 2001; Kusserow et al., 2005)
Wnt proteins consist 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).
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).
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).
- Frizzled receptor protein level on the cell surface is measured by flow cytometry with pan-FZD antibody (Jiang et al., 2015; Zeng et al., 2018). DVL protein level is measured by immunoblotting with anti-DVL2 antibodies (Zeng et al., 2018).
- Fzd mRNA level is measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR) (Zeng et al., 2018).
- The up-regulation of WNT ligand expression occurs in Homo sapiens (B. Wang et al., 2017).
- The Wnt genes play an important role in the secretion from cells, glycosylation, and tight association with the cell surface and extracellular matrix in Drosophila melanogaster (Willert & Nusse, 2012).
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).
References
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. doi:10.1016/j.cell.2006.02.049
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. doi:10.1038/382225a0
Ching, W., & Nusse, R. (2006). A dedicated Wnt secretion factor. Cell, 125(3), 432-433. doi:10.1016/j.cell.2006.04.018
Clevers, H. (2006). Wnt/beta-catenin signaling in development and disease. Cell, 127(3), 469-480. doi:10.1016/j.cell.2006.10.018
Clevers, H., & Nusse, R. (2012). Wnt/beta-catenin signaling and disease. Cell, 149(6), 1192-1205. 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. doi:10.1093/abbs/gmr079
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. 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. doi:10.1124/pr.117.013896
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. doi:10.1074/jbc.RA118.004434
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. doi:10.1016/j.molcel.2015.03.015
Katoh, M. (2001). Molecular cloning and characterization of human WNT3. International journal of oncology, 19(5), 977-982. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/11604997
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. 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. doi:10.1038/cr.2009.41
MacDonald, B. T., Tamai, K., & He, X. (2009). Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell, 17(1), 9-26. doi:10.1016/j.devcel.2009.06.016
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. doi:10.1016/j.gendis.2015.12.004
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. doi:10.1073/pnas.1618293114
Saha, S., Aranda, E., Hayakawa, Y., Bhanja, P., Atay, S., Brodin, N. P., . . . Pollard, J. W. (2016). Macrophage-derived extracellular vesicle-packaged WNTs rescue intestinal stem cells and enhance survival after radiation injury. Nature Communications, 7(1), 13096. doi:10.1038/ncomms13096
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. doi:10.3109/08977194.2012.752737
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). doi:10.1042/BSR20171092
Willert, K., & Nusse, R. (2012). Wnt proteins. Cold Spring Harb Perspect Biol, 4(9), a007864. doi:10.1101/cshperspect.a007864
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. doi:10.1073/pnas.1808575115
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. 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. doi:10.1016/j.jvir.2016.11.004