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WNT5A
Identifiers
Aliases	WNT5A, hWnt family member 5A
External IDs	OMIM: 164975; MGI: 98958; HomoloGene: 20720; GeneCards: WNT5A; OMA:WNT5A - orthologs
Gene location (Human) Chr. Chromosome 3 (human) Band 3p14.3 Start 55,465,715 bp End 55,490,539 bp
Gene location (Mouse) Chr. Chromosome 14 (mouse) Band 14 A3|14 16.8 cM Start 28,226,707 bp End 28,249,405 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in stromal cell of endometrium parotid gland decidua oral cavity germinal epithelium gums palpebral conjunctiva gingival epithelium urethra periodontal fiber Top expressed in tail of embryo Gonadal ridge molar stria vascularis vas deferens hand utricle transitional epithelium of urinary bladder genital tubercle tooth germ More reference expression data BioGPS n/a
Gene ontology Molecular function protein domain specific binding DNA-binding transcription factor activity chemoattractant activity involved in axon guidance receptor tyrosine kinase-like orphan receptor binding signaling receptor binding cytokine activity frizzled binding receptor ligand activity protein binding phospholipid binding Cellular component endocytic vesicle membrane endoplasmic reticulum lumen extracellular region cell surface extracellular exosome plasma membrane Golgi lumen clathrin-coated endocytic vesicle membrane extracellular space clathrin-coated vesicle membrane extracellular matrix collagen-containing extracellular matrix postsynapse glutamatergic synapse Biological process somitogenesis cellular response to retinoic acid planar cell polarity pathway involved in outflow tract morphogenesis excitatory synapse assembly non-canonical Wnt signaling pathway positive regulation of protein phosphorylation negative chemotaxis positive regulation of protein catabolic process paraxial mesoderm formation convergent extension involved in axis elongation positive regulation of protein kinase C activity cellular response to molecule of bacterial origin positive regulation of protein localization to synapse hindgut morphogenesis positive regulation of JNK cascade mesodermal to mesenchymal transition involved in gastrulation regulation of protein localization heart looping protein phosphorylation epithelial cell proliferation involved in mammary gland duct elongation face development establishment of epithelial cell apical/basal polarity notochord morphogenesis positive regulation of mesenchymal cell proliferation mesenchymal-epithelial cell signaling negative regulation of epithelial cell proliferation planar cell polarity pathway involved in cardiac muscle tissue morphogenesis cellular response to interferon-gamma positive regulation of thymocyte apoptotic process tube closure positive regulation of non-canonical Wnt signaling pathway type B pancreatic cell development negative regulation of mesenchymal cell proliferation primitive streak formation cellular response to transforming growth factor beta stimulus cellular response to calcium ion dopaminergic neuron differentiation positive regulation of type I interferon-mediated signaling pathway cell fate commitment negative regulation of fat cell differentiation limb morphogenesis convergent extension lung development positive regulation of fibroblast proliferation optic cup formation involved in camera-type eye development hematopoietic stem cell proliferation embryonic digit morphogenesis regulation of branching involved in mammary gland duct morphogenesis negative regulation of axon extension involved in axon guidance positive regulation of peptidyl-serine phosphorylation chemorepulsion of dopaminergic neuron axon positive regulation of transcription, DNA-templated negative regulation of prostatic bud formation planar cell polarity pathway involved in cardiac right atrium morphogenesis positive regulation of endocytosis morphogenesis of an epithelium JNK cascade cartilage development positive regulation of GTPase activity axis elongation embryonic limb morphogenesis positive regulation of cartilage development neural tube development pericardium morphogenesis positive regulation of interleukin-6 production post-anal tail morphogenesis convergent extension involved in organogenesis digestive tract morphogenesis roof of mouth development cell differentiation neuron projection morphogenesis male gonad development positive regulation of inflammatory response lateral sprouting involved in mammary gland duct morphogenesis positive regulation of macrophage cytokine production positive regulation of epithelial cell proliferation urinary bladder development planar cell polarity pathway involved in ventricular septum morphogenesis positive regulation of JUN kinase activity establishment of planar polarity hypophysis morphogenesis negative regulation of synapse assembly wound healing positive regulation of macrophage activation negative regulation of apoptotic process positive regulation of ossification planar cell polarity pathway involved in axis elongation negative regulation of melanin biosynthetic process positive regulation of angiogenesis embryonic skeletal system development cervix development uterus development Wnt signaling pathway, planar cell polarity pathway Wnt signaling pathway, calcium modulating pathway positive regulation of NF-kappaB transcription factor activity epithelial to mesenchymal transition canonical Wnt signaling pathway planar cell polarity pathway involved in pericardium morphogenesis positive regulation of protein binding negative regulation of transcription, DNA-templated ameboidal-type cell migration midbrain development planar cell polarity pathway involved in gastrula mediolateral intercalation positive regulation of protein kinase activity positive regulation of cell-cell adhesion mediated by cadherin neurogenesis activation of protein kinase B activity positive regulation of endothelial cell proliferation axonogenesis non-canonical Wnt signaling pathway via JNK cascade activation of GTPase activity positive regulation of cytokine production vagina development positive regulation of protein kinase C signaling development of primary male sexual characteristics mammary gland branching involved in thelarche positive regulation of interferon-gamma production somite development keratinocyte differentiation planar cell polarity pathway involved in neural tube closure axon guidance negative regulation of BMP signaling pathway positive regulation of endothelial cell migration genitalia development negative regulation of fibroblast growth factor receptor signaling pathway positive regulation of response to cytokine stimulus multicellular organism development inhibitory synapse assembly neural tube closure determination of left/right symmetry lens development in camera-type eye positive regulation of peptidyl-threonine phosphorylation cochlea morphogenesis inner ear morphogenesis positive regulation of T cell chemotaxis olfactory bulb interneuron development positive regulation of cell population proliferation positive regulation of neuron projection development positive regulation of meiotic nuclear division melanocyte proliferation cellular response to lipopolysaccharide cell migration anterior/posterior axis specification, embryo chemoattraction of serotonergic neuron axon positive regulation of transcription by RNA polymerase II anterior/posterior pattern specification midgut development planar cell polarity pathway involved in midbrain dopaminergic neuron differentiation midbrain dopaminergic neuron differentiation neuron differentiation Wnt signaling pathway involved in midbrain dopaminergic neuron differentiation negative regulation of cell proliferation in midbrain negative regulation of canonical Wnt signaling pathway planar cell polarity pathway involved in axon guidance Wnt signaling pathway response to organic substance positive regulation of timing of anagen membrane organization positive regulation of canonical Wnt signaling pathway presynapse assembly postsynapse assembly regulation of signaling receptor activity positive regulation of gene expression regulation of I-kappaB kinase/NF-kappaB signaling positive regulation of G protein-coupled receptor signaling pathway regulation of inflammatory response regulation of synapse organization secondary palate development regulation of postsynapse organization regulation of postsynaptic cytosolic calcium ion concentration positive regulation of neuron projection arborization positive regulation of neuron death Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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 Mb Chr 14: 28.23 – 28.25 Mb PubMed search
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Protein Wnt-5a is a protein that in humans is encoded by the WNT5A gene.

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. 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. 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. 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.

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

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

Wnt ligands

Wnt ligands are classically described as acting in an autocrine/paracrine manner. Wnts are also hydrophobic with significant post-translational palmitoylation and glycosylation. These post-translational modifications are important for docking to extracellular lipoprotein particles allowing them to travel systemically. 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. 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. 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. 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.

Cardiovascular Disease

Increasing evidence has implicated Wnt5a in chronic inflammatory disorders. In particular Wnt5a has been implicated in atherosclerosis. 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. 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:

• 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

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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. PMID 15073149. S2CID 21259864.
• 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.
• "Wnt5a". Signaling Gateway Molecule Pages. Archived from the original on 2016-11-17. Retrieved 2011-12-20.
• Smolich BD, McMahon JA, McMahon AP, Papkoff J (December 1993). "Wnt family proteins are secreted and associated with the cell surface". Molecular Biology of the Cell. 4 (12): 1267–75. doi:10.1091/mbc.4.12.1267. PMC 275763. PMID 8167409.
• 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. PMID 8537388.
• 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. PMID 8889548.
• He X, Saint-Jeannet JP, Wang Y, Nathans J, Dawid I, Varmus H (March 1997). "A member of the Frizzled protein family mediating axis induction by Wnt-5A". Science (Submitted manuscript). 275 (5306): 1652–4. doi:10.1126/science.275.5306.1652. PMID 9054360. S2CID 36777692.
• 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. PMID 10491302.
• 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. PMID 10557084. S2CID 2009505.
• 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. PMID 11956659.
• 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. PMID 12086864.
• 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. PMID 12165812.
• 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. PMID 12244165.
• Thrasivoulou C, Millar M, Ahmed A (December 2013). "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. doi:10.1074/jbc.M112.437913. PMC 3861617. PMID 24158438.
• Ishitani T, Kishida S, Hyodo-Miura J, Ueno N, Yasuda J, Waterman M, Shibuya H, Moon RT, Ninomiya-Tsuji J, Matsumoto K (January 2003). "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. doi:10.1128/MCB.23.1.131-139.2003. PMC 140665. PMID 12482967.
• Hocevar BA, Mou F, Rennolds JL, Morris SM, Cooper JA, Howe PH (June 2003). "Regulation of the Wnt signaling pathway by disabled-2 (Dab2)". The EMBO Journal. 22 (12): 3084–94. doi:10.1093/emboj/cdg286. PMC 162138. PMID 12805222.
• 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. PMC 11160266. PMID 12841867. S2CID 46098300.
• Glinsky GV, Glinskii AB, Stephenson AJ, Hoffman RM, Gerald WL (March 2004). "Gene expression profiling predicts clinical outcome of prostate cancer". The Journal of Clinical Investigation. 113 (6): 913–23. doi:10.1172/JCI20032. PMC 362118. PMID 15067324.
• 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. PMID 15389636. S2CID 35609184.
• 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. PMID 15592517.
• 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. PMID 15735754. S2CID 10356112.
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• Genes on human chromosome 3