WNT5A (wingless-type MMTV integration site family, member 5A)

2008-06-01   Masaru Katoh 

Genetics, Cell Biology Section, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan





WNT5A gene at chromosome 3p14.3 and WNT5B gene at chromosome 12p13.33 are paralogs within the human genome.
Atlas Image
Schematic representation of WNT5A gene.
Atlas Image
Alignment of mammalian WNT5A and WNT5B orthologs. N-terminal signal peptide (double over-line), conserved Cys residues (+), and Asn-linked glycosylation sites are shown.


WNT5A gene consists of 5 exons. First methionine is located in exon 1, while stop codon in exon 5. dbSNP rs655731, located within exon 5 of the human WNT5A gene, is a synonymous SNP corresponding to codon 263.


WNT5A is preferentially upregulated in gastric cancer, and melanoma, but downregulated in breast cancer, colorectal cancer, and acute lymphocytic leukemia.
Wnt5a is upregulated by IL6 family cytokines through gp130 in cultured cardiomyocytes, by TGFbeta in mammary epithelial cells, and by TNFalpha in gastric cancer cells. WNT5A upregulation in primary tumor is in part due to stromal expression based on tumor-stromal interaction, while WNT5A downregulation in primary tumor is in part due to epigenetic silencing induced by promoter CpG hypermethylation.



Mature WNT5A protein with conserved Cys residues is a secreted-type glycoprotein.


WNT5A mRNA is relatively abundantly expressed in salivary gland, bladder, uterus, placenta, and fetal kidney.


Naive WNT5A protein is synthesized in the endoplasmic reticulum. Mature WNT5A protein with lipid modifications and glycosylations enters the trans-Golgi network for secretion from the cell surface.


WNT5A signals are transduced to the canonical and non-canonical WNT signaling cascades. WNT5A signaling through Frizzled-4 ( FZD4 ) or FZD5 receptor and LRP5 or LRP6 co-receptor leads to the stabilization and nuclear accumulation of beta-catenin for the transcriptional activation of target genes, such as MYC, CCND1, and FGF20. On the other hand, WNT5A signaling through Frizzled family receptor or ROR1 or ROR2 co-receptor leads to the activation of the non-canonical WNT signaling cascades, such as DAG - PKC, IP3 - NFAT, or IP3 - NLK signaling cascades. WNT5A-PKC signaling promotes invasion and metastasis of tumors through SNAI1 (Snail)-mediated epithelial-to-mesenchymal transition (EMT), while WNT5A-NLK signaling suppresses carcinogenesis through inhibition of the canonical WNT signaling cascade. Expression of WNT5A is associated with metastatic or aggressive phenotype in gastric cancer, melanoma, and osteosarcoma, but is associated with non-aggressive or better prognostic phenotype in breast cancer, colorectal cancer, and acute lymphocytic leukemia. Together these facts indicate that WNT5A induces oncogenic as well as tumor suppressive functions in a context-dependent manner.


Human WNT5A shows 98.7% total amino-acid identity with rodent Wnt5a, indicating that mammalian WNT5A orthologs are highly conserved. Among 19 WNT family members, WNT5A is most homologous to WNT5B.



WNT5A gene is located at human chromosome 3p14.3 around the susceptible locus of Zimmermann-Laband Syndrome; however, mutation of WNT5A gene has not been detected.


Wnt5a knockout mice show smaller somites and shortened presomitic mesoderm, abnormalities in the lungs with the foreshortened trachea, dysplasia of genitals, and ventricular septal defects.

Implicated in

Entity name
Poor prognosis
Entity name
Gastric cancer
Poor prognosis
Entity name
Poor prognosis
Entity name
Breast cancer
Better prognosis
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Colorectal cancer
Better prognosis
Better prognosis


Pubmed IDLast YearTitleAuthors
91606671997A role for the Wnt gene family in hematopoiesis: expansion of multilineage progenitor cells.Austin TW et al
90999601997Expression and hormone regulation of Wnt2, 3, 4, 5a, 7a, 7b and 10b in normal human endometrium and endometrial carcinoma.Bui TD et al
127892832003Gene-expression profiling in human cutaneous melanoma.Carr KM et al
155924302005FGF-20 and DKK1 are transcriptional targets of beta-catenin and FGF-20 is implicated in cancer and development.Chamorro MN et al
179863842008Wnt5a-mediated non-canonical Wnt signalling regulates human endothelial cell proliferation and migration.Cheng CW et al
82882271993Molecular cloning of the human proto-oncogene Wnt-5A and mapping of the gene (WNT5A) to chromosome 3p14-p21.Clark CC et al
82977891993Wnt-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.Dealy CN et al
168805142006Wnt-5a/Ca2+-induced NFAT activity is counteracted by Wnt-5a/Yes-Cdc42-casein kinase 1alpha signaling in human mammary epithelial cells.Dejmek J et al
174260202007The Wnt5A/protein kinase C pathway mediates motility in melanoma cells via the inhibition of metastasis suppressors and initiation of an epithelial to mesenchymal transition.Dissanayake SK et al
153279982004Signals through gp130 upregulate Wnt5a and contribute to cell adhesion in cardiac myocytes.Fujio Y et al
182870272008Antisera induced by infusions of autologous Ad-CD154-leukemia B cells identify ROR1 as an oncofetal antigen and receptor for Wnt5a.Fukuda T et al
160837172005Expression pattern of Wnt signaling components in the adult intestine.Gregorieff A et al
97279771998Identification of c-MYC as a target of the APC pathway.He TC et al
90543601997A member of the Frizzled protein family mediating axis induction by Wnt-5A.He X et al
76279531995Aberrant expression of the growth factor Wnt-5A in human malignancy.Iozzo RV et al
118096892002Loss of Wnt-5a protein is associated with early relapse in invasive ductal breast carcinomas.Jönsson M et al
172032012007STAT3-induced WNT5A signaling loop in embryonic stem cells, adult normal tissues, chronic persistent inflammation, rheumatoid arthritis and cancer (Review).Katoh M et al
162732602005WNT/PCP signaling pathway and human cancer (review).Katoh M et al
98159761995Wnt5a cloning, expression, and up-regulation in human primary breast cancers.Lejeune S et al
166028272006Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context.Mikels AJ et al
82758671993Xwnt-5A: a maternal Wnt that affects morphogenetic movements after overexpression in embryos of Xenopus laevis.Moon RT et al
128396242003The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a/JNK signalling pathway.Oishi I et al
182986552008Activation of Wnt signalling in stroma from pancreatic cancer identified by gene expression profiling.Pilarsky C et al
165696992006Wnt 5a signaling is critical for macrophage-induced invasion of breast cancer cell lines.Pukrop T et al
178980012007Wnt5a is required for proper mammary gland development and TGF-beta-mediated inhibition of ductal growth.Roarty K et al
121658122002Expression 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.Saitoh T et al
119566592002Frequent up-regulation of WNT5A mRNA in primary gastric cancer.Saitoh T et al
90734551997Modulation of embryonic intracellular Ca2+ signaling by Wnt-5A.Slusarski DC et al
102013721999Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells.Tetsu O et al
120868642002Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma.Weeraratna AT et al
184209332008Wnt5a control of cell polarity and directional movement by polarized redistribution of adhesion receptors.Witze ES et al
80653591994Differential transformation of mammary epithelial cells by Wnt genes.Wong GT et al
100213401999A Wnt5a pathway underlies outgrowth of multiple structures in the vertebrate embryo.Yamaguchi TP et al
181722522008WNT5A exhibits tumor-suppressive activity through antagonizing the Wnt/beta-catenin signaling, and is frequently methylated in colorectal cancer.Ying J et al
179921212007Expression of Wnt5a and its downstream effector beta-catenin in uveal melanoma.Zuidervaart W et al

Other Information

Locus ID:

NCBI: 7474
MIM: 164975
HGNC: 12784
Ensembl: ENSG00000114251


dbSNP: 7474
ClinVar: 7474
TCGA: ENSG00000114251


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
mTOR signaling pathwayKEGGko04150
Wnt signaling pathwayKEGGko04310
Axon guidanceKEGGko04360
Basal cell carcinomaKEGGko05217
mTOR signaling pathwayKEGGhsa04150
Wnt signaling pathwayKEGGhsa04310
Axon guidanceKEGGhsa04360
Pathways in cancerKEGGhsa05200
Basal cell carcinomaKEGGhsa05217
HTLV-I infectionKEGGko05166
HTLV-I infectionKEGGhsa05166
Hippo signaling pathwayKEGGhsa04390
Hippo signaling pathwayKEGGko04390
Proteoglycans in cancerKEGGhsa05205
Proteoglycans in cancerKEGGko05205
Signaling pathways regulating pluripotency of stem cellsKEGGhsa04550
Signaling pathways regulating pluripotency of stem cellsKEGGko04550
Wnt signalingKEGGhsa_M00677
Wnt signalingKEGGM00677
Signal TransductionREACTOMER-HSA-162582
Signaling by GPCRREACTOMER-HSA-372790
GPCR ligand bindingREACTOMER-HSA-500792
Class B/2 (Secretin family receptors)REACTOMER-HSA-373080
Signaling by WntREACTOMER-HSA-195721
WNT ligand biogenesis and traffickingREACTOMER-HSA-3238698
TCF dependent signaling in response to WNTREACTOMER-HSA-201681
Negative regulation of TCF-dependent signaling by WNT ligand antagonistsREACTOMER-HSA-3772470
Beta-catenin independent WNT signalingREACTOMER-HSA-3858494
PCP/CE pathwayREACTOMER-HSA-4086400
Asymmetric localization of PCP proteinsREACTOMER-HSA-4608870
WNT5A-dependent internalization of FZD4REACTOMER-HSA-5099900
WNT5A-dependent internalization of FZD2, FZD5 and ROR2REACTOMER-HSA-5140745
Ca2+ pathwayREACTOMER-HSA-4086398
Vesicle-mediated transportREACTOMER-HSA-5653656
Membrane TraffickingREACTOMER-HSA-199991
Clathrin-mediated endocytosisREACTOMER-HSA-8856828
Cargo recognition for clathrin-mediated endocytosisREACTOMER-HSA-8856825
Breast cancerKEGGko05224
Breast cancerKEGGhsa05224


Pubmed IDYearTitleCitations
120868642002Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma.277
124829672003The TAK1-NLK mitogen-activated protein kinase cascade functions in the Wnt-5a/Ca(2+) pathway to antagonize Wnt/beta-catenin signaling.174
150673242004Gene expression profiling predicts clinical outcome of prostate cancer.171
174260202007The Wnt5A/protein kinase C pathway mediates motility in melanoma cells via the inhibition of metastasis suppressors and initiation of an epithelial to mesenchymal transition.140
165696992006Wnt 5a signaling is critical for macrophage-induced invasion of breast cancer cell lines.133
165696992006Wnt 5a signaling is critical for macrophage-induced invasion of breast cancer cell lines.133
166012432006The Wingless homolog WNT5A and its receptor Frizzled-5 regulate inflammatory responses of human mononuclear cells induced by microbial stimulation.132
181744552008Wnt5A/CaMKII signaling contributes to the inflammatory response of macrophages and is a target for the antiinflammatory action of activated protein C and interleukin-10.113
184209332008Wnt5a control of cell polarity and directional movement by polarized redistribution of adhesion receptors.107
199109232010Wnt5a regulates distinct signalling pathways by binding to Frizzled2.104


Masaru Katoh

WNT5A (wingless-type MMTV integration site family, member 5A)

Atlas Genet Cytogenet Oncol Haematol. 2008-06-01

Online version: http://atlasgeneticsoncology.org/gene/42825/wnt5a-(wingless-type-mmtv-integration-site-family-member-5a)