WNT5A
Identifiers
AliasesWNT5A, hWnt family member 5A
External IDsOMIM: 164975 MGI: 98958 HomoloGene: 20720 GeneCards: WNT5A
Orthologs
SpeciesHumanMouse
Entrez

7474

22418

Ensembl

ENSG00000114251

ENSMUSG00000021994

UniProt

P41221

P22725

RefSeq (mRNA)

NM_001256105
NM_003392
NM_001377271
NM_001377272

NM_001256224
NM_009524

RefSeq (protein)

NP_001243034
NP_003383
NP_001364200
NP_001364201

NP_001243153
NP_033550

Location (UCSC)Chr 3: 55.47 – 55.49 MbChr 14: 28.23 – 28.25 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Protein Wnt-5a is a protein that in humans is encoded by the WNT5A gene.[5][6]

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.[7] 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.[8][9] 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.[6] 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.[10][11]

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.[12][13][14][15][16] Wnt5a-knockout mice (Wnt5a-/-) died shortly after birth and displayed a plethora of abnormalities, making loss of Wnt5a lethal.[15] 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.[15] As seen in the vertebral column, the nose, mandible, tongue and limbs were also shortened with loss of Wnt5a in both mice and chicks.[15][17] Wnt5a is normally expressed at the distal end of limb buds and is involved with outgrowth and patterning of the limbs.[18][15][17] 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 [15][17]

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.[19] 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).[20] 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.[19] Other members of the WNT family that are required for the development of the reproductive tract are Wnt4 and Wnt7a.[20] 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.[19] In addition to these two developments Wnt5a it needed for the complete process of estrogen mediated cellular and molecular responses.[19]

Wnt ligands

Wnt ligands are classically described as acting in an autocrine/paracrine manner.[21][22][23] Wnts are also hydrophobic with significant post-translational palmitoylation and glycosylation.[24][25] These post-translational modifications are important for docking to extracellular lipoprotein particles allowing them to travel systemically.[26][27] 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.[28] 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.[29] 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.[29] These 18 amino acids appear to have contrasting roles in cancer. Specifically, Wnt5a-L inhibits proliferation and Wnt5a-S increases proliferation.[29] 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.[30] 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.[31]

Cardiovascular Disease

Increasing evidence has implicated Wnt5a in chronic inflammatory disorders.[32] In particular Wnt5a has been implicated in atherosclerosis.[33][34] 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.[35][36] 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:[37]

• 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. 1 2 3 GRCh38: Ensembl release 89: ENSG00000114251 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000021994 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ 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.
  6. 1 2 "Entrez Gene: WNT5A wingless-type MMTV integration site family, member 5A".
  7. ↑ 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. PMC 4252768. PMID 25240110.
  8. ↑ Blumenthal A, Ehlers S, Lauber J, Buer J, Lange C, Goldmann T, Heine H, Brandt E, Reiling N (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. S2CID 13491469.
  9. ↑ Sen M, Chamorro M, Reifert J, Corr M, Carson DA (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)44:4<772::aid-anr133>3.0.co;2-l. ISSN 1529-0131. PMID 11315916.
  10. ↑ Gordon MD, Nusse R (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.
  11. ↑ Mikels A, Minami Y, Nusse R (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 2781572. PMID 19720827.
  12. ↑ Gavin BJ, McMahon JA, McMahon AP (December 1990). "Expression of multiple novel Wnt-1/int-1-related genes during fetal and adult mouse development". Genes & Development. 4 (12B): 2319–32. doi:10.1101/gad.4.12b.2319. PMID 2279700.
  13. ↑ Parr BA, Shea MJ, Vassileva G, McMahon AP (September 1993). "Mouse Wnt genes exhibit discrete domains of expression in the early embryonic CNS and limb buds". Development. 119 (1): 247–61. doi:10.1242/dev.119.1.247. PMID 8275860.
  14. ↑ Takada S, Stark KL, Shea MJ, Vassileva G, McMahon JA, McMahon AP (January 1994). "Wnt-3a regulates somite and tailbud formation in the mouse embryo". Genes & Development. 8 (2): 174–89. doi:10.1101/gad.8.2.174. PMID 8299937.
  15. 1 2 3 4 5 6 Yamaguchi TP, Bradley A, McMahon AP, Jones S (March 1999). "A Wnt5a pathway underlies outgrowth of multiple structures in the vertebrate embryo". Development. 126 (6): 1211–23. doi:10.1242/dev.126.6.1211. PMID 10021340.
  16. ↑ Chu EY, Hens J, Andl T, Kairo A, Yamaguchi TP, Brisken C, Glick A, Wysolmerski JJ, Millar SE (October 2004). "Canonical WNT signaling promotes mammary placode development and is essential for initiation of mammary gland morphogenesis". Development. 131 (19): 4819–29. doi:10.1242/dev.01347. PMID 15342465. S2CID 25175909.
  17. 1 2 3 Kawakami Y, Wada N, Nishimatsu SI, Ishikawa T, Noji S, Nohno T (February 1999). "Involvement of Wnt-5a in chondrogenic pattern formation in the chick limb bud". Development, Growth & Differentiation. 41 (1): 29–40. doi:10.1046/j.1440-169x.1999.00402.x. PMID 10445500. S2CID 23245166.
  18. ↑ Dealy CN, Roth A, Ferrari D, Brown AM, Kosher RA (October 1993). "Wnt-5a and Wnt-7a are expressed in the developing chick limb bud in a manner suggesting roles in pattern formation along the proximodistal and dorsoventral axes". Mechanisms of Development. 43 (2–3): 175–86. doi:10.1016/0925-4773(93)90034-u. PMID 8297789. S2CID 21392840.
  19. 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. S2CID 21259864.
  20. 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. PMC 3071266. PMID 20962251.
  21. ↑ 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. Bibcode:2015PLoSO..1042794C. doi:10.1371/journal.pone.0142794. PMC 4643911. PMID 26566235.
  22. ↑ 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.
  23. ↑ 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. S2CID 1178267.
  24. ↑ 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. CiteSeerX 10.1.1.322.311. doi:10.1146/annurev.cellbio.20.010403.113126. PMID 15473860.
  25. ↑ 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 1863570. PMID 17117926.
  26. ↑ 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. Bibcode:2005Natur.435...58P. doi:10.1038/nature03504. PMID 15875013. S2CID 4347286.
  27. ↑ 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. hdl:1874/33221. PMID 19207483. S2CID 29594183.
  28. ↑ 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 5040981. PMID 27571105.
  29. 1 2 3 Bauer M, Bénard J, Gaasterland T, Willert K, Cappellen D (2013). "WNT5A encodes two isoforms with distinct functions in cancers". PLOS ONE. 8 (11): e80526. Bibcode:2013PLoSO...880526B. doi:10.1371/journal.pone.0080526. PMC 3832467. PMID 24260410.
  30. ↑ 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 4713724. PMID 26514730.
  31. ↑ Chien AJ, Moore EC, Lonsdorf AS, Kulikauskas RM, Rothberg BG, Berger AJ, Major MB, Hwang ST, Rimm DL (2009-01-27). "Activated Wnt/β-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. Bibcode:2009PNAS..106.1193C. doi:10.1073/pnas.0811902106. ISSN 0027-8424. PMC 2626610. PMID 19144919.
  32. ↑ 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. PMID 17203201.
  33. ↑ Bhatt PM, Malgor R (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. PMC 4252768. PMID 25240110.
  34. ↑ Akoumianakis I, Sanna F, Margaritis M, Badi I, Akawi N, Herdman L, Coutinho P, Fagan H, Antonopoulos AS (2019-09-18). "Adipose tissue–derived WNT5A regulates vascular redox signaling in obesity via USP17/RAC1-mediated activation of NADPH oxidases". Science Translational Medicine. 11 (510): eaav5055. doi:10.1126/scitranslmed.aav5055. hdl:1983/a397d5fa-6ef7-474a-a60f-4f8bb2bd4986. ISSN 1946-6234. PMC 7212031. PMID 31534019.
  35. ↑ Bhatt PM, Lewis CJ, House DL, Keller CM, Kohn LD, Silver MJ, McCall KD, Goetz DJ, Malgor R (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. PMC 4270053. PMID 25530821.
  36. ↑ Christman MA, Goetz DJ, Dickerson E, McCall KD, Lewis CJ, Benencia F, Silver MJ, Kohn LD, Malgor R (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. S2CID 25952721.
  37. ↑ Dihlmann S, von Knebel Doeberitz M (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. PMID 15472907. S2CID 72668377.

Further reading

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