Protein Wnt-5a explained

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

WNT5A is a signaling molecule expressed embryonically during gastrulation in various developing body regions including the caudal mesoderm of the primitive streak, lateral mesoderm, cranial neural crest cells, midbrain, frontal face region, limb buds, mammary gland mesenchyme, caudal region, genital primordia and tailbud.^{[8] [9] [10] [11] [12]} Wnt5a-knockout mice (Wnt5a-/-) died shortly after birth and displayed a plethora of abnormalities, making loss of Wnt5a lethal.^[11] When compared to wild-type (WT) controls, Wnt5a-/- embryos developed shorter primitive streaks. Following primitive streak formation, during body axis patterning, Wnt5a-/- embryos also developed a shortened anterior-posterior (A-P) body axis in which the vertebral column was reduced in size due to smaller vertebrae and the lack of a proportion of caudal vertebrae. The resulting abnormalities found were fusion of vertebrae and ribs, and fusion and absence of thoracic, sacral, and tail vertebrae. Since Wnt5a is strongly expressed in the posterior portion of developing embryos, it is not surprising that the lower body were more greatly affected. The tail especially lacked vertebrae and was significantly shortened.^[11] As seen in the vertebral column, the nose, mandible, tongue and limbs were also shortened with loss of Wnt5a in both mice and chicks.^{[11] [13]} Wnt5a is normally expressed at the distal end of limb buds and is involved with outgrowth and patterning of the limbs.^{[14] [11] [13]} With loss of Wnt5a, limb shortening is exaggerated as it continues towards the digits. Similar to the vertebral column, more distal structures were found fused and some absent ^{[11] [13]}

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.^[15] 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).^[16] 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.^[15] Other members of the WNT family that are required for the development of the reproductive tract are Wnt4 and Wnt7a.^[16] 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.^[15] In addition to these two developments Wnt5a it needed for the complete process of estrogen mediated cellular and molecular responses.^[15]

Wnt ligands

Wnt ligands are classically described as acting in an autocrine/paracrine manner.^{[17] [18] [19]} Wnts are also hydrophobic with significant post-translational palmitoylation and glycosylation.^{[20] [21]} These post-translational modifications are important for docking to extracellular lipoprotein particles allowing them to travel systemically.^{[22] [23]} 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.^[24] 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.^[25] 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. These 18 amino acids appear to have contrasting roles in cancer. Specifically, Wnt5a-L inhibits proliferation and Wnt5a-S increases proliferation. 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.^[26] 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.^[27]

Cardiovascular Disease

Increasing evidence has implicated Wnt5a in chronic inflammatory disorders.^[28] In particular Wnt5a has been implicated in atherosclerosis.^{[29] [30]} 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.^{[31] [32]} 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:^[33]

• 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.

Further reading

• Mericskay M, Kitajewski J, Sassoon D . Wnt5a is required for proper epithelial-mesenchymal interactions in the uterus . Development . 131 . 9 . 2061–72 . May 2004 . 15073149 . 10.1242/dev.01090 . 21259864 .
• Hayashi K, Yoshioka S, Reardon SN, Rucker EB, Spencer TE, DeMayo FJ, Lydon JP, MacLean JA . WNTs in the neonatal mouse uterus: potential regulation of endometrial gland development . Biology of Reproduction . 84 . 2 . 308–19 . February 2011 . 20962251 . 10.1095/biolreprod.110.088161 . 3071266.
• Wnt5a . Signaling Gateway Molecule Pages . 2011-12-20 . 2016-11-17 . https://web.archive.org/web/20161117063221/http://www.signaling-gateway.org/molecule/query?afcsid=A002385 . dead .
• Smolich BD, McMahon JA, McMahon AP, Papkoff J . Wnt family proteins are secreted and associated with the cell surface . Molecular Biology of the Cell . 4 . 12 . 1267–75 . December 1993 . 8167409 . 275763 . 10.1091/mbc.4.12.1267 .
• Danielson KG, Pillarisetti J, Cohen IR, Sholehvar B, Huebner K, Ng LJ, Nicholls JM, Cheah KS, Iozzo RV . 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 . December 1995 . 8537388 . 10.1074/jbc.270.52.31225 . free .
• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery . Genome Research . 6 . 9 . 791–806 . September 1996 . 8889548 . 10.1101/gr.6.9.791 . free .
• He X, Saint-Jeannet JP, Wang Y, Nathans J, Dawid I, Varmus H . A member of the Frizzled protein family mediating axis induction by Wnt-5A . Science . 275 . 5306 . 1652–4 . March 1997 . 9054360 . 10.1126/science.275.5306.1652 . 36777692 . Submitted manuscript .
• Wright M, Aikawa M, Szeto W, Papkoff J . Identification of a Wnt-responsive signal transduction pathway in primary endothelial cells . Biochemical and Biophysical Research Communications . 263 . 2 . 384–8 . September 1999 . 10491302 . 10.1006/bbrc.1999.1344 .
• Gazit A, Yaniv A, Bafico A, Pramila T, Igarashi M, Kitajewski J, Aaronson SA . Human frizzled 1 interacts with transforming Wnts to transduce a TCF dependent transcriptional response . Oncogene . 18 . 44 . 5959–66 . October 1999 . 10557084 . 10.1038/sj.onc.1202985 . 2009505 .
• Saitoh T, Mine T, Katoh M . Frequent up-regulation of WNT5A mRNA in primary gastric cancer . International Journal of Molecular Medicine . 9 . 5 . 515–9 . May 2002 . 11956659 . 10.3892/ijmm.9.5.515 .
• Weeraratna AT, Jiang Y, Hostetter G, Rosenblatt K, Duray P, Bittner M, Trent JM . Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma . Cancer Cell . 1 . 3 . 279–88 . April 2002 . 12086864 . 10.1016/S1535-6108(02)00045-4 . free .
• Saitoh T, Katoh M . 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 . September 2002 . 12165812 . 10.3892/ijmm.10.3.345 .
• Murphy LL, Hughes CC . 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 . October 2002 . 12244165 . 10.4049/jimmunol.169.7.3717 . free .
• Thrasivoulou C, Millar M, Ahmed A . Activation of intracellular calcium by multiple Wnt ligands and translocation of β-catenin into the nucleus: a convergent model of Wnt/Ca2+ and Wnt/β-catenin pathways . The Journal of Biological Chemistry . 288 . 50 . 35651–9 . December 2013 . 24158438 . 10.1074/jbc.M112.437913 . 3861617. free .
• Ishitani T, Kishida S, Hyodo-Miura J, Ueno N, Yasuda J, Waterman M, Shibuya H, Moon RT, Ninomiya-Tsuji J, Matsumoto K . The TAK1-NLK mitogen-activated protein kinase cascade functions in the Wnt-5a/Ca(2+) pathway to antagonize Wnt/beta-catenin signaling . Molecular and Cellular Biology . 23 . 1 . 131–9 . January 2003 . 12482967 . 140665 . 10.1128/MCB.23.1.131-139.2003 .
• Hocevar BA, Mou F, Rennolds JL, Morris SM, Cooper JA, Howe PH . Regulation of the Wnt signaling pathway by disabled-2 (Dab2) . The EMBO Journal . 22 . 12 . 3084–94 . June 2003 . 12805222 . 162138 . 10.1093/emboj/cdg286 .
• Taki M, Kamata N, Yokoyama K, Fujimoto R, Tsutsumi S, Nagayama M . 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 . July 2003 . 12841867 . 10.1111/j.1349-7006.2003.tb01488.x . 46098300 . free . 11160266 .
• Glinsky GV, Glinskii AB, Stephenson AJ, Hoffman RM, Gerald WL . Gene expression profiling predicts clinical outcome of prostate cancer . The Journal of Clinical Investigation . 113 . 6 . 913–23 . March 2004 . 15067324 . 362118 . 10.1172/JCI20032 .
• Nishioka K, Dennis JE, Gao J, Goldberg VM, Caplan AI . Sustained Wnt protein expression in chondral constructs from mesenchymal stem cells . Journal of Cellular Physiology . 203 . 1 . 6–14 . April 2005 . 15389636 . 10.1002/jcp.20196 . 35609184 .
• Blanc E, Roux GL, Bénard J, Raguénez G . Low expression of Wnt-5a gene is associated with high-risk neuroblastoma . Oncogene . 24 . 7 . 1277–83 . February 2005 . 15592517 . 10.1038/sj.onc.1208255 . free .
• Kremenevskaja N, von Wasielewski R, Rao AS, Schöfl C, Andersson T, Brabant G . Wnt-5a has tumor suppressor activity in thyroid carcinoma . Oncogene . 24 . 13 . 2144–54 . March 2005 . 15735754 . 10.1038/sj.onc.1208370 . 10356112 .
• Wang Q, Symes AJ, Kane CA, Freeman A, Nariculam J, Munson P, Thrasivoulou C, Masters JR, Ahmed A . A novel role for Wnt/Ca2+ signaling in actin cytoskeleton remodeling and cell motility in prostate cancer . PLOS ONE . 5 . 5 . e10456 . May 2010 . 20454608 . 2864254 . 10.1371/journal.pone.0010456 . Hotchin . 2010PLoSO...510456W . Neil A. . free .

Notes and References

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2. Web site: Entrez Gene: WNT5A wingless-type MMTV integration site family, member 5A.
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15. Mericskay M, Kitajewski J, Sassoon D . Wnt5a is required for proper epithelial-mesenchymal interactions in the uterus . Development . 131 . 9 . 2061–72 . May 2004 . 15073149 . 10.1242/dev.01090 . 21259864 .
16. Hayashi K, Yoshioka S, Reardon SN, Rucker EB, Spencer TE, DeMayo FJ, Lydon JP, MacLean JA . WNTs in the neonatal mouse uterus: potential regulation of endometrial gland development . Biology of Reproduction . 84 . 2 . 308–19 . February 2011 . 20962251 . 10.1095/biolreprod.110.088161 . 3071266.
17. Corbett L, Mann J, Mann DA . 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 . 26566235 . 4643911 . 10.1371/journal.pone.0142794 . 2015PLoSO..1042794C . free .
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21. Kurayoshi M, Yamamoto H, Izumi S, Kikuchi A . Post-translational palmitoylation and glycosylation of Wnt-5a are necessary for its signalling . en . The Biochemical Journal . 402 . 3 . 515–23 . March 2007 . 17117926 . 1863570 . 10.1042/BJ20061476 .
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