Biology:Protein Wnt-5a

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Generic protein structure example

Protein Wnt-5a is a protein that in humans is encoded by the WNT5A gene.[1][2]

Function

The WNT gene family consists of structurally related genes that encode secreted signaling lipid modified glycoproteins. These proteins have been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and patterning during embryogenesis.[3] This gene is a member of the WNT gene family. The WNT5A is highly expressed in the dermal papilla of depilated skin. It encodes a protein showing 98%, 98%, and 87% amino acid identity to the mouse, rat and the xenopus Wnt5a protein, respectively. Wnts, specifically Wnt5a, have also been positively correlated and implicated in inflammatory diseases such as rheumatoid arthritis, tuberculosis, and atherosclerosis. A central player and active secretor of Wnt5a in both cancer and these inflammatory diseases are macrophages.[4][5] Experiments performed in Xenopus laevis embryos have identified that human frizzled-5 (hFz5) is the receptor for the Wnt5a ligand and the Wnt5a/hFz5 signaling mediates axis induction.[2] However, non-canonical Wnt5a has also been shown to bind to Ror1/2, RYK, and RTK depending on cell and receptor context to mediate a variety of functions ranging from cell proliferation, polarity, differentiation and apoptosis.[6][7]

Development

The Wnt5a gene is also a key component in posterior development of the female reproductive tract, development of the uterine glands postnatally, and the process of estrogen mediated cellular and molecular responses.[8] Wnt5a is expressed throughout the endometrial stroma of the mammalian female reproductive tracts and is required in the development of the posterior formation of the Müllerian ducts (cervix, vagina).[9] A Wnt5a absence study was performed by Mericskay et al. on mice and showed the anterior Müllerian-derived structures (oviducts and uterine horns) could easily be identified, and the posterior derived structures (cervix and vagina) were absent showing that this gene is a requirement for its development.[8] Other members of the WNT family that are required for the development of the reproductive tract are Wnt4 and Wnt7a.[9] Failure to develop reproductive tract will result in infertility. Not only is the WNT5A gene responsible for this formation but also is significate in the postnatal production of the uterine glands otherwise known as adenogenesis which is essential for adult function.[8] In addition to these two developments Wnt5a it needed for the complete process of estrogen mediated cellular and molecular responses.[8]

Wnt ligands

Wnt ligands are classically described as acting in an autocrine/paracrine manner.[10][11][12] Wnts are also hydrophobic with significant post-translational palmitoylation and glycosylation.[13][14] These post-translational modifications are important for docking to extracellular lipoprotein particles allowing them to travel systemically.[15][16] Additionally, due to the high degree of sequence homology between Wnts many are characterized by their downstream actions.

Clinical significance

Cancer

Wnt5a is implicated in many different types of cancers.[17] However, no consistent correlation occurs between cancer aggressiveness and Wnt5a signaling up-regulation or down-regulation. The WNT5A gene has been shown to encode two distinct isoforms, each with unique functions in the context of cancer.[18] The two isoforms are termed Wnt5a-long (Wnt5a-L) and Wnt5a-short (Wnt5a-S) because Wnt5a-L is 18 amino acids longer than Wnt5a-S.[18] These 18 amino acids appear to have contrasting roles in cancer. Specifically, Wnt5a-L inhibits proliferation and Wnt5a-S increases proliferation.[18] This may account for the discrepancies as to the role of Wnt5a in various cancers; however, the significance of these two isoforms is not completely clear.[19] Elevated levels of beta-catenin in both primary and metastases of malignant melanoma have been correlated to improved survival and a decrease in cell markers of proliferation.[20]

Cardiovascular Disease

Increasing evidence has implicated Wnt5a in chronic inflammatory disorders.[21] In particular Wnt5a has been implicated in atherosclerosis.[22][23] It has been previously reported that there is an association between Wnt5a mRNA and protein expression and histopathological severity of human atherosclerotic lesions as well as co-expression of Wnt5a and TLR4 in foam cells/macrophages of murine and human atherosclerotic lesions.[24][25] However, the role of Wnt proteins in the process and development of inflammation in atherosclerosis and other inflammatory conditions is not yet clear.

Therapeutics

Some of the benefits of targeting this signaling pathway include:[26]

• Many of the current DNA-targeting anticancer drugs carry the risk of giving rise to secondary tumors or additional primary cancers.

• Preferentially killing rapidly replicating malignant cells via cytotoxic agents cause serious side effects by injuring normal cells, particularly hematopoietic cells, intestinal cells, hair follicle and germ cells.

• Differentiated tumor cells in a state of quiescence are typically not affected by drugs can may account for tumor recurrence.

References

  1. ↑ "Molecular cloning of the human proto-oncogene Wnt-5A and mapping of the gene (WNT5A) to chromosome 3p14-p21". Genomics 18 (2): 249–60. November 1993. doi:10.1006/geno.1993.1463. PMID 8288227. 
  2. ↑ 2.0 2.1 "Entrez Gene: WNT5A wingless-type MMTV integration site family, member 5A". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7474. 
  3. ↑ "Wnt5a: a player in the pathogenesis of atherosclerosis and other inflammatory disorders". Atherosclerosis 237 (1): 155–62. November 2014. doi:10.1016/j.atherosclerosis.2014.08.027. PMID 25240110. 
  4. ↑ Blumenthal, Antje; Ehlers, Stefan; Lauber, Jörg; Buer, Jan; Lange, Christoph; Goldmann, Torsten; Heine, Holger; Brandt, Ernst et al. (2006-08-01). "The Wingless homolog WNT5A and its receptor Frizzled-5 regulate inflammatory responses of human mononuclear cells induced by microbial stimulation" (in en). Blood 108 (3): 965–973. doi:10.1182/blood-2005-12-5046. ISSN 0006-4971. PMID 16601243. 
  5. ↑ Sen, Malini; Chamorro, Mario; Reifert, Jack; Corr, Maripat; Carson, Dennis A. (2001-04-01). "Blockade of Wnt-5A/Frizzled 5 signaling inhibits rheumatoid synoviocyte activation" (in en). Arthritis & Rheumatism 44 (4): 772–781. doi:10.1002/1529-0131(200104)44:4<772::aid-anr133>3.0.co;2-l. ISSN 1529-0131. PMID 11315916. 
  6. ↑ Gordon, Michael D.; Nusse, Roel (2006-08-11). "Wnt Signaling: Multiple Pathways, Multiple Receptors, and Multiple Transcription Factors" (in en). Journal of Biological Chemistry 281 (32): 22429–22433. doi:10.1074/jbc.R600015200. ISSN 0021-9258. PMID 16793760. 
  7. ↑ Mikels, Amanda; Minami, Yasuhiro; Nusse, Roel (2009-10-30). "Ror2 Receptor Requires Tyrosine Kinase Activity to Mediate Wnt5A Signaling" (in en). Journal of Biological Chemistry 284 (44): 30167–30176. doi:10.1074/jbc.M109.041715. ISSN 0021-9258. PMID 19720827. 
  8. ↑ 8.0 8.1 8.2 8.3 "Wnt5a is required for proper epithelial-mesenchymal interactions in the uterus". Development 131 (9): 2061–72. May 2004. doi:10.1242/dev.01090. PMID 15073149. 
  9. ↑ 9.0 9.1 "WNTs in the neonatal mouse uterus: potential regulation of endometrial gland development". Biology of Reproduction 84 (2): 308–19. February 2011. doi:10.1095/biolreprod.110.088161. PMID 20962251. 
  10. ↑ "Non-Canonical Wnt Predominates in Activated Rat Hepatic Stellate Cells, Influencing HSC Survival and Paracrine Stimulation of Kupffer Cells". PLOS ONE 10 (11): e0142794. 2015-01-01. doi:10.1371/journal.pone.0142794. PMID 26566235. Bibcode: 2015PLoSO..1042794C. 
  11. ↑ "Wnt/β-catenin signaling and disease". Cell 149 (6): 1192–205. June 2012. doi:10.1016/j.cell.2012.05.012. PMID 22682243. 
  12. ↑ "Glucose induces an autocrine activation of the Wnt/beta-catenin pathway in macrophage cell lines" (in en). The Biochemical Journal 416 (2): 211–8. December 2008. doi:10.1042/BJ20081426. PMID 18823284. https://semanticscholar.org/paper/1f2919f4bca515abe16ca1c2c63969f34e1a725f. 
  13. ↑ "The Wnt signaling pathway in development and disease". Annual Review of Cell and Developmental Biology 20 (1): 781–810. 2004-10-08. doi:10.1146/annurev.cellbio.20.010403.113126. PMID 15473860. 
  14. ↑ "Post-translational palmitoylation and glycosylation of Wnt-5a are necessary for its signalling" (in en). The Biochemical Journal 402 (3): 515–23. March 2007. doi:10.1042/BJ20061476. PMID 17117926. 
  15. ↑ "Lipoprotein particles are required for Hedgehog and Wingless signalling". Nature 435 (7038): 58–65. May 2005. doi:10.1038/nature03504. PMID 15875013. Bibcode: 2005Natur.435...58P. 
  16. ↑ "Mammalian Wnt3a is released on lipoprotein particles" (in en). Traffic 10 (3): 334–43. March 2009. doi:10.1111/j.1600-0854.2008.00872.x. PMID 19207483. 
  17. ↑ "Wnt5a Signaling in Cancer" (in en). Cancers 8 (9): 79. August 2016. doi:10.3390/cancers8090079. PMID 27571105. 
  18. ↑ 18.0 18.1 18.2 "WNT5A encodes two isoforms with distinct functions in cancers". PLOS ONE 8 (11): e80526. 2013. doi:10.1371/journal.pone.0080526. PMID 24260410. Bibcode: 2013PLoSO...880526B. 
  19. ↑ "WNT-5A: signaling and functions in health and disease" (in en). Cellular and Molecular Life Sciences 73 (3): 567–87. February 2016. doi:10.1007/s00018-015-2076-y. PMID 26514730. 
  20. ↑ Chien, Andy J.; Moore, Erin C.; Lonsdorf, Anke S.; Kulikauskas, Rima M.; Rothberg, Bonnie Gould; Berger, Aaron J.; Major, Michael B.; Hwang, Sam T. et al. (2009-01-27). "Activated Wnt/β-catenin signaling in melanoma is associated with decreased proliferation in patient tumors and a murine melanoma model" (in en). Proceedings of the National Academy of Sciences 106 (4): 1193–1198. doi:10.1073/pnas.0811902106. ISSN 0027-8424. PMID 19144919. Bibcode: 2009PNAS..106.1193C. 
  21. ↑ "STAT3-induced WNT5A signaling loop in embryonic stem cells, adult normal tissues, chronic persistent inflammation, rheumatoid arthritis and cancer (Review)". Int. J. Mol. Med. 19 (2): 273–8. 2007. PMID 17203201. 
  22. ↑ Bhatt, Pooja M.; Malgor, Ramiro (2014). "Wnt5a: A player in the pathogenesis of atherosclerosis and other inflammatory disorders". Atherosclerosis 237 (1): 155–162. doi:10.1016/j.atherosclerosis.2014.08.027. PMID 25240110. 
  23. ↑ Akoumianakis, Ioannis; Sanna, Fabio; Margaritis, Marios; Badi, Ileana; Akawi, Nadia; Herdman, Laura; Coutinho, Patricia; Fagan, Harry et al. (2019-09-18). "Adipose tissue–derived WNT5A regulates vascular redox signaling in obesity via USP17/RAC1-mediated activation of NADPH oxidases" (in en). Science Translational Medicine 11 (510): eaav5055. doi:10.1126/scitranslmed.aav5055. ISSN 1946-6234. PMID 31534019. PMC 7212031. https://research-information.bris.ac.uk/en/publications/adipose-tissuederived-wnt5a-regulates-vascular-redox-signaling-in-obesity-via-usp17rac1mediated-activation-of-nadph-oxidases(a397d5fa-6ef7-474a-a60f-4f8bb2bd4986).html. 
  24. ↑ Bhatt, Pooja M.; Lewis, Christopher J.; House, Denise L.; Keller, Chad M.; Kohn, Leonard D.; Silver, Mitchell J.; McCall, Kelly D.; Goetz, Douglas J. et al. (2012-01-01). "Increased Wnt5a mRNA Expression in Advanced Atherosclerotic Lesions, and Oxidized LDL Treated Human Monocyte-Derived Macrophages". The Open Circulation & Vascular Journal 5: 1–7. doi:10.2174/1877382601205010001. ISSN 1877-3826. PMID 25530821. 
  25. ↑ Christman, Mark A.; Goetz, Douglas J.; Dickerson, Eric; McCall, Kelly D.; Lewis, Christopher J.; Benencia, Fabian; Silver, Mitchell J.; Kohn, Leonard D. et al. (2008-06-01). "Wnt5a is expressed in murine and human atherosclerotic lesions" (in en). American Journal of Physiology. Heart and Circulatory Physiology 294 (6): H2864–H2870. doi:10.1152/ajpheart.00982.2007. ISSN 0363-6135. PMID 18456733. 
  26. ↑ Dihlmann, Susanne; von Knebel Doeberitz, Magnus (2005-02-10). "Wnt/β-catenin-pathway as a molecular target for future anti-cancer therapeutics" (in en). International Journal of Cancer 113 (4): 515–524. doi:10.1002/ijc.20609. ISSN 1097-0215. PMID 15472907. 

Further reading




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