WNT5A

WNT5A
Identifiers
Aliases WNT5A, hWnt family member 5A
External IDs MGI: 98958 HomoloGene: 20720 GeneCards: WNT5A
Orthologs
Species Human Mouse
Entrez

7474

22418

Ensembl

ENSG00000114251

ENSMUSG00000021994

UniProt

P41221

P22725

RefSeq (mRNA)

NM_001256105
NM_003392

NM_001256224
NM_009524

RefSeq (protein)

NP_001243034.1
NP_003383.2

NP_001243153.1
NP_033550.2

Location (UCSC) Chr 3: 55.47 – 55.49 Mb Chr 14: 28.5 – 28.53 Mb
PubMed search [1] [2]
Wikidata
View/Edit HumanView/Edit Mouse

Protein Wnt-5a is a protein that in humans is encoded by the WNT5A gene.[3][4]

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.[5] 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 caner and these inflammatory diseases are macrophages.[6][7] 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.[4] 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.[8][9]

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.[10] 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).[11] 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.[10] Other members of the WNT family that are required for the development of the reproductive tract are Wnt4 and Wnt7a.[11] 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.[10] In addition to these two developments Wnt5a it needed for the complete process of estrogen mediated cellular and molecular responses.[10]

Wnt ligands

Wnt ligands are classically described as acting in an autocrine/paracrine manner.[12][13][14] Wnts are also hydrophobic with significant post-translational palmitoylation and glycosylation.[15][16] These post-translational modifications are important for docking to extracellular lipoprotein particles allowing them to travel systemically.[17][18] 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.[19] However, no consistent correlation occurs between cancer aggressiveness and Wnt5a signaling up-regulation or down-regulation. Interestingly, the WNT5A gene has been shown to encode two distinct isoforms, each with unique functions in the context of cancer.[20] 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.[20] These 18 amino acids appear to have contrasting roles in cancer. Specifically, Wnt5a-L inhibits proliferation and Wnt5a-S increases proliferation.[20] 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.[21] 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.[22]

Cardiovascular Disease

Increasing evidence has implicated Wnt5a in chronic inflammatory disorders.[23] In particular Wnt5a has been implicated in atherosclerosis.[24] 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.[25][26] 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:[27]

• 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

  1. ↑ "Human PubMed Reference:".
  2. ↑ "Mouse PubMed Reference:".
  3. ↑ 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. PMID 8288227.
  4. 1 2 "Entrez Gene: WNT5A wingless-type MMTV integration site family, member 5A".
  5. ↑ Bhatt PM, Malgor R (November 2014). "Wnt5a: a player in the pathogenesis of atherosclerosis and other inflammatory disorders". Atherosclerosis. 237 (1): 155–62. doi:10.1016/j.atherosclerosis.2014.08.027. PMID 25240110.
  6. ↑ Blumenthal, Antje; Ehlers, Stefan; Lauber, Jörg; Buer, Jan; Lange, Christoph; Goldmann, Torsten; Heine, Holger; Brandt, Ernst; Reiling, Norbert (2006-08-01). "The Wingless homolog WNT5A and its receptor Frizzled-5 regulate inflammatory responses of human mononuclear cells induced by microbial stimulation". Blood. 108 (3): 965–973. doi:10.1182/blood-2005-12-5046. ISSN 0006-4971. PMID 16601243.
  7. ↑ 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". Arthritis & Rheumatism. 44 (4): 772–781. doi:10.1002/1529-0131(200104)44:43.0.CO;2-L. ISSN 1529-0131.
  8. ↑ Gordon, Michael D.; Nusse, Roel (2006-08-11). "Wnt Signaling: Multiple Pathways, Multiple Receptors, and Multiple Transcription Factors". Journal of Biological Chemistry. 281 (32): 22429–22433. doi:10.1074/jbc.R600015200. ISSN 0021-9258. PMID 16793760.
  9. ↑ Mikels, Amanda; Minami, Yasuhiro; Nusse, Roel (2009-10-30). "Ror2 Receptor Requires Tyrosine Kinase Activity to Mediate Wnt5A Signaling". Journal of Biological Chemistry. 284 (44): 30167–30176. doi:10.1074/jbc.M109.041715. ISSN 0021-9258. PMC 2781572Freely accessible. PMID 19720827.
  10. 1 2 3 4 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. PMID 15073149.
  11. 1 2 Hayashi K, Yoshioka S, Reardon SN, Rucker EB, Spencer TE, DeMayo FJ, Lydon JP, MacLean JA (February 2011). "WNTs in the neonatal mouse uterus: potential regulation of endometrial gland development". Biology of Reproduction. 84 (2): 308–19. doi:10.1095/biolreprod.110.088161. PMID 20962251.
  12. ↑ Corbett L, Mann J, Mann DA (2015-01-01). "Non-Canonical Wnt Predominates in Activated Rat Hepatic Stellate Cells, Influencing HSC Survival and Paracrine Stimulation of Kupffer Cells". PloS One. 10 (11): e0142794. doi:10.1371/journal.pone.0142794. PMC 4643911Freely accessible. PMID 26566235.
  13. ↑ Clevers H, Nusse R (June 2012). "Wnt/β-catenin signaling and disease". Cell. 149 (6): 1192–205. doi:10.1016/j.cell.2012.05.012. PMID 22682243.
  14. ↑ Anagnostou SH, Shepherd PR (December 2008). "Glucose induces an autocrine activation of the Wnt/beta-catenin pathway in macrophage cell lines". The Biochemical Journal. 416 (2): 211–8. doi:10.1042/BJ20081426. PMID 18823284.
  15. ↑ Logan CY, Nusse R (2004-10-08). "The Wnt signaling pathway in development and disease". Annual Review of Cell and Developmental Biology. 20 (1): 781–810. doi:10.1146/annurev.cellbio.20.010403.113126. PMID 15473860.
  16. ↑ Kurayoshi M, Yamamoto H, Izumi S, Kikuchi A (March 2007). "Post-translational palmitoylation and glycosylation of Wnt-5a are necessary for its signalling". The Biochemical Journal. 402 (3): 515–23. doi:10.1042/BJ20061476. PMC 1863570Freely accessible. PMID 17117926.
  17. ↑ Panáková D, Sprong H, Marois E, Thiele C, Eaton S (May 2005). "Lipoprotein particles are required for Hedgehog and Wingless signalling". Nature. 435 (7038): 58–65. doi:10.1038/nature03504. PMID 15875013.
  18. ↑ 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. PMID 19207483.
  19. ↑ Asem MS, Buechler S, Wates RB, Miller DL, Stack MS (August 2016). "Wnt5a Signaling in Cancer". Cancers. 8 (9): 79. doi:10.3390/cancers8090079. PMC 5040981Freely accessible. PMID 27571105.
  20. 1 2 3 Bauer M, Bénard J, Gaasterland T, Willert K, Cappellen D. "WNT5A encodes two isoforms with distinct functions in cancers". PloS One. 8 (11): e80526. doi:10.1371/journal.pone.0080526. PMC 3832467Freely accessible. PMID 24260410.
  21. ↑ Kumawat K, Gosens R (February 2016). "WNT-5A: signaling and functions in health and disease". Cellular and Molecular Life Sciences. 73 (3): 567–87. doi:10.1007/s00018-015-2076-y. PMC 4713724Freely accessible. PMID 26514730.
  22. ↑ Chien, Andy J.; Moore, Erin C.; Lonsdorf, Anke S.; Kulikauskas, Rima M.; Rothberg, Bonnie Gould; Berger, Aaron J.; Major, Michael B.; Hwang, Sam T.; Rimm, David L. (2009-01-27). "Activated Wnt/ß-catenin signaling in melanoma is associated with decreased proliferation in patient tumors and a murine melanoma model". Proceedings of the National Academy of Sciences. 106 (4): 1193–1198. doi:10.1073/pnas.0811902106. ISSN 0027-8424. PMC 2626610Freely accessible. PMID 19144919.
  23. ↑ https://www.spandidos-publications.com/ijmm/19/2/273/download. Missing or empty |title= (help)
  24. ↑ Bhatt, Pooja M.; Malgor, Ramiro. "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. PMC 4252768Freely accessible. PMID 25240110.
  25. ↑ Bhatt, Pooja M.; Lewis, Christopher J.; House, Denise L.; Keller, Chad M.; Kohn, Leonard D.; Silver, Mitchell J.; McCall, Kelly D.; Goetz, Douglas J.; Malgor, Ramiro (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. ISSN 1877-3826. PMC 4270053Freely accessible. PMID 25530821.
  26. ↑ Christman, Mark A.; Goetz, Douglas J.; Dickerson, Eric; McCall, Kelly D.; Lewis, Christopher J.; Benencia, Fabian; Silver, Mitchell J.; Kohn, Leonard D.; Malgor, Ramiro (2008-06-01). "Wnt5a is expressed in murine and human atherosclerotic lesions". American Journal of Physiology - Heart and Circulatory Physiology. 294 (6): H2864–H2870. doi:10.1152/ajpheart.00982.2007. ISSN 0363-6135. PMID 18456733.
  27. ↑ 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. ISSN 1097-0215.

Further reading

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