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] 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.[23][24] 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:[25]
• 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 hematopoeitic 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
↑Clark CC, Cohen I, Eichstetter I, Cannizzaro LA, McPherson JD, Wasmuth JJ, Iozzo RV (November 1993). "Molecular cloning of the human proto-oncogene Wnt-5A and mapping of the gene (WNT5A) to chromosome 3p14-p21". Genomics. 18 (2): 249–60. doi:10.1006/geno.1993.1463. PMID8288227.
↑ 8.08.18.28.3Mericskay M, Kitajewski J, Sassoon D (May 2004). "Wnt5a is required for proper epithelial-mesenchymal interactions in the uterus". Development. 131 (9): 2061–72. doi:10.1242/dev.01090. PMID15073149.
↑Neumann S, Coudreuse DY, van der Westhuyzen DR, Eckhardt ER, Korswagen HC, Schmitz G, Sprong H (March 2009). "Mammalian Wnt3a is released on lipoprotein particles". Traffic. 10 (3): 334–43. doi:10.1111/j.1600-0854.2008.00872.x. PMID19207483.
↑Katoh M, Katoh M (2007). "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. PMID17203201.
↑Dihlmann, Susanne; von Knebel Doeberitz, Magnus (2005-02-10). "Wnt/β-catenin-pathway as a molecular target for future anti-cancer therapeutics". International Journal of Cancer. 113 (4): 515–524. doi:10.1002/ijc.20609. ISSN1097-0215. PMID15472907.
Further reading
Mericskay M, Kitajewski J, Sassoon D (May 2004). "Wnt5a is required for proper epithelial-mesenchymal interactions in the uterus". Development. 131 (9): 2061–72. doi:10.1242/dev.01090. PMID15073149.
Danielson KG, Pillarisetti J, Cohen IR, Sholehvar B, Huebner K, Ng LJ, Nicholls JM, Cheah KS, Iozzo RV (December 1995). "Characterization of the complete genomic structure of the human WNT-5A gene, functional analysis of its promoter, chromosomal mapping, and expression in early human embryogenesis". The Journal of Biological Chemistry. 270 (52): 31225–34. doi:10.1074/jbc.270.52.31225. PMID8537388.
Bonaldo MF, Lennon G, Soares MB (September 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID8889548.
Wright M, Aikawa M, Szeto W, Papkoff J (September 1999). "Identification of a Wnt-responsive signal transduction pathway in primary endothelial cells". Biochemical and Biophysical Research Communications. 263 (2): 384–8. doi:10.1006/bbrc.1999.1344. PMID10491302.
Gazit A, Yaniv A, Bafico A, Pramila T, Igarashi M, Kitajewski J, Aaronson SA (October 1999). "Human frizzled 1 interacts with transforming Wnts to transduce a TCF dependent transcriptional response". Oncogene. 18 (44): 5959–66. doi:10.1038/sj.onc.1202985. PMID10557084.
Saitoh T, Mine T, Katoh M (May 2002). "Frequent up-regulation of WNT5A mRNA in primary gastric cancer". International Journal of Molecular Medicine. 9 (5): 515–9. doi:10.3892/ijmm.9.5.515. PMID11956659.
Weeraratna AT, Jiang Y, Hostetter G, Rosenblatt K, Duray P, Bittner M, Trent JM (April 2002). "Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma". Cancer Cell. 1 (3): 279–88. doi:10.1016/S1535-6108(02)00045-4. PMID12086864.
Saitoh T, Katoh M (September 2002). "Expression and regulation of WNT5A and WNT5B in human cancer: up-regulation of WNT5A by TNFalpha in MKN45 cells and up-regulation of WNT5B by beta-estradiol in MCF-7 cells". International Journal of Molecular Medicine. 10 (3): 345–9. doi:10.3892/ijmm.10.3.345. PMID12165812.
Murphy LL, Hughes CC (October 2002). "Endothelial cells stimulate T cell NFAT nuclear translocation in the presence of cyclosporin A: involvement of the wnt/glycogen synthase kinase-3 beta pathway". Journal of Immunology. 169 (7): 3717–25. doi:10.4049/jimmunol.169.7.3717. PMID12244165.
Taki M, Kamata N, Yokoyama K, Fujimoto R, Tsutsumi S, Nagayama M (July 2003). "Down-regulation of Wnt-4 and up-regulation of Wnt-5a expression by epithelial-mesenchymal transition in human squamous carcinoma cells". Cancer Science. 94 (7): 593–7. doi:10.1111/j.1349-7006.2003.tb01488.x. PMID12841867.
Nishioka K, Dennis JE, Gao J, Goldberg VM, Caplan AI (April 2005). "Sustained Wnt protein expression in chondral constructs from mesenchymal stem cells". Journal of Cellular Physiology. 203 (1): 6–14. doi:10.1002/jcp.20196. PMID15389636.
Blanc E, Roux GL, Bénard J, Raguénez G (February 2005). "Low expression of Wnt-5a gene is associated with high-risk neuroblastoma". Oncogene. 24 (7): 1277–83. doi:10.1038/sj.onc.1208255. PMID15592517.
Kremenevskaja N, von Wasielewski R, Rao AS, Schöfl C, Andersson T, Brabant G (March 2005). "Wnt-5a has tumor suppressor activity in thyroid carcinoma". Oncogene. 24 (13): 2144–54. doi:10.1038/sj.onc.1208370. PMID15735754.