DACT2

Summary

DACT2 (dishevelled binding antagonist of beta catenin 2, HGNC:21231) is a protein-coding gene on chromosome 6q27, encoding Dapper homolog 2 (Q5SW24). Involved in regulation of intracellular signaling pathways during development.

Predicted to enable several functions, including beta-catenin binding activity; delta-catenin binding activity; and protein kinase C binding activity. Predicted to be involved in several processes, including epithelial cell morphogenesis; inner medullary collecting duct development; and negative regulation of nodal signaling pathway. Predicted to act upstream of or within hematopoietic progenitor cell differentiation. Predicted to be active in cytoplasm.

Source: NCBI Gene 168002 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 178 total — 5 pathogenic
• MANE Select transcript: NM_214462

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21231
Approved symbol	DACT2
Name	dishevelled binding antagonist of beta catenin 2
Location	6q27
Locus type	gene with protein product
Status	Approved
Aliases	bA503C24.7, DAPPER2
Ensembl gene	ENSG00000164488
Ensembl biotype	protein_coding
OMIM	608966
Entrez	168002

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000366795, ENST00000366796, ENST00000607983, ENST00000610183

RefSeq mRNA: 3 — MANE Select: NM_214462 NM_001286350, NM_001286351, NM_214462

CCDS: CCDS47519, CCDS69241, CCDS75554

Canonical transcript exons

ENST00000366795 — 4 exons

Exon	Start	End
ENSE00001084726	168310168	168310446
ENSE00001356933	168311152	168311284
ENSE00001356939	168319388	168319777
ENSE00001442635	168306904	168309098

Expression profiles

Bgee: expression breadth ubiquitous, 149 present calls, max score 89.05.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2754 / max 45.0437, expressed in 123 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
76735	0.1983	89
76737	0.0581	24
76736	0.0190	7

Top tissues by expression

240 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
placenta	UBERON:0001987	89.05	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.76	gold quality
putamen	UBERON:0001874	82.69	gold quality
nucleus accumbens	UBERON:0001882	81.86	gold quality
caudate nucleus	UBERON:0001873	81.60	gold quality
apex of heart	UBERON:0002098	78.14	gold quality
decidua	UBERON:0002450	74.56	gold quality
minor salivary gland	UBERON:0001830	72.01	gold quality
skin of leg	UBERON:0001511	71.74	gold quality
skin of abdomen	UBERON:0001416	71.19	gold quality
mouth mucosa	UBERON:0003729	70.75	gold quality
zone of skin	UBERON:0000014	70.38	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	70.17	gold quality
saliva-secreting gland	UBERON:0001044	70.04	gold quality
cartilage tissue	UBERON:0002418	69.84	silver quality
right adrenal gland cortex	UBERON:0035827	68.99	gold quality
right atrium auricular region	UBERON:0006631	68.54	gold quality
right lobe of liver	UBERON:0001114	68.47	gold quality
cardiac atrium	UBERON:0002081	68.36	gold quality
prostate gland	UBERON:0002367	66.92	gold quality
mucosa of transverse colon	UBERON:0004991	66.34	gold quality
oocyte	CL:0000023	66.07	gold quality
body of pancreas	UBERON:0001150	64.27	gold quality
mammary duct	UBERON:0001765	64.22	gold quality
endometrium	UBERON:0001295	64.17	gold quality
layer of synovial tissue	UBERON:0007616	63.98	silver quality
adult mammalian kidney	UBERON:0000082	63.90	gold quality
nipple	UBERON:0002030	63.85	gold quality
lower esophagus mucosa	UBERON:0035834	63.80	gold quality
skin of hip	UBERON:0001554	63.42	silver quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-7008	yes	120.37
E-ANND-3	yes	4.73

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NKX2-5, PITX2

miRNA regulators (miRDB)

19 targeting DACT2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-609	99.82	64.26	505
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-671-5P	99.52	67.11	1277
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-6873-5P	98.45	66.14	1417
HSA-MIR-1262	98.17	66.52	757
HSA-MIR-4701-3P	98.17	66.25	788
HSA-MIR-6736-5P	98.17	66.43	760
HSA-MIR-4652-5P	96.46	64.22	553
HSA-MIR-6741-5P	93.86	63.06	437
HSA-MIR-4749-5P	92.16	62.26	179

Literature-anchored findings (GeneRIF, showing 21)

• Nuclear beta-catenin was more frequently expressed in non-polypoid growth low grade colorectal neoplasms than in polypoid growth neoplasms. (PMID:18370954)
• Epigenetic regulation of DACT2 is a key component of the Wnt signalling pathway in human lung cancer. (PMID:22806826)
• Hypermethylation of Dact1 gene is associated with transitional cell carcinomas. (PMID:23244112)
• DACT2 suppresses hepatocellular carcinoma by inhibiting Wnt signaling in human hepatocellular carcinoma cells. (PMID:23449122)
• Reduced expression of DACT2 due to methylation-mediated gene silencing promotes hepatocellular carcinoma progression (PMID:23496880)
• Loss of DACT2 expression is associated with esophageal squamous cell carcinoma. (PMID:23803417)
• DACT2 acts as a functional tumor suppressor in colon cancer through inhibiting Wnt/beta-catenin signaling. Its methylation at early stages of colon carcinogenesis is an independent prognostic factor. (PMID:25023701)
• DACT2 suppresses papillary thyroid cancer proliferation and metastasis by inhibiting Wnt signaling. (PMID:25375359)
• This study demonstrated that Genes overexpressed in Pilomyxoid Astrocytoma vs. Pilocytic Astrocytoma, ranked according to fold-change, included developmental genes H19, DACT2,COL2A1; COL1A1 and IMP3. (PMID:25521223)
• There was no statistical difference between groups concerning DACT1 and DACT2 either in promoter hypermethylation or transcript levels. Age was associated with DACT2 promoter hypermethylation, especially over 56 years old. (PMID:25524937)
• DACT2 is frequently methylated in human esophageal cancer and its expression is regulated by promoter region methylation. DACT2 suppresses esophageal cancer growth by inhibiting Wnt signaling. (PMID:26919254)
• The rate of methylation of ZIC1, ZIC4, HHIP, and DACT2 in tumors was very high, while methylation of CXXC4 was low to moderate in OSCC and LSCC. (PMID:27553089)
• Results demonstrate that DACT2 functions as a tumor suppressor for breast cancer but was frequently disrupted epigenetically in this cancer. (PMID:27708215)
• The simultaneous methylation of DACT1 and DACT2 may play important roles in progression of ESCC and may serve as prognostic methylation biomarkers for ESCC patients. (PMID:28077137)
• DACT2 suppresses breast cancer cell growth both in vitro and in vivo. (PMID:28607412)
• Our findings provide a novel DACT2 demethylating stimulator to verify and expand previously established link between DACT2 and colorectal cancer (CRC), suggesting DACT2 demethylation is strongly correlated with CRC prognosis. (PMID:29199082)
• An association was found of DACT2 promoter methylation with advanced tumor stages. This gene has been suggested as a potential biomarker, however, more investigation is required to validate this function. (PMID:29745077)
• Studies suggested that DACT2 expression in nasopharyngeal carcinoma cells is restored by TET1 which demethylates its promotor region. (PMID:30075814)
• Results demonstrate that DACT2 is frequently inactivated epigenetically by CpG methylation in nasopharyngeal carcinoma (NPC), while it inhibits NPC cell proliferation and metastasis via suppressing beta-catenin/Cdc25c signaling. These findings suggest that DACT2 promoter methylation is a potential epigenetic biomarker for the detection of NPC. (PMID:30359298)
• Comparative exome sequencing reveals novel candidate genes for retinitis pigmentosa. (PMID:32454406)
• Different expression of DACT1, DACT2, and CYCLIN D1 genes in human colorectal cancer tissues and its association with clinicopathological characteristics. (PMID:37610179)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	dact2	ENSDARG00000056986
mus_musculus	Dact2	ENSMUSG00000048826
rattus_norvegicus	Dact2	ENSRNOG00000022921

Paralogs (2): DACT1 (ENSG00000165617), DACT3 (ENSG00000197380)

Protein

Protein identifiers

Dapper homolog 2 — Q5SW24 (reviewed: Q5SW24)

Alternative names: Dapper antagonist of catenin 2

All UniProt accessions (1): Q5SW24

UniProt curated annotations — full annotation on UniProt →

Function. Involved in regulation of intracellular signaling pathways during development. Negatively regulates the Nodal signaling pathway, possibly by promoting the lysosomal degradation of Nodal receptors, such as TGFBR1. May be involved in control of the morphogenetic behavior of kidney ureteric bud cells by keeping cells epithelial and restraining their mesenchymal character. May play an inhibitory role in the re-epithelialization of skin wounds by attenuating TGF-beta signaling.

Subunit / interactions. Can form homodimers and heterodimers with DACT1 or DACT3. Interacts with CSNK1D, PKA catalytic subunit, PKC-type kinase, CSNK2B, DVL1, DVL2, DVL3, VANGL1, VANGL2, TGFBR1, CTNNB1, CTNND2, CTNND1, LEF1, TCF7, TCF7L1 and HDAC1.

Domain organisation. The C-terminal PDZ-binding motif may mediate interaction with the PDZ domains of DSH (Dishevelled) family proteins.

Similarity. Belongs to the dapper family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q5SW24-1	1	yes
Q5SW24-2	2
Q5SW24-3	3
Q5SW24-4	4

RefSeq proteins (3): NP_001273279, NP_001273280, NP_999627* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR024843	Dapper	Family

Pfam: PF15268

UniProt features (19 total): region of interest 4, compositionally biased region 4, splice variant 4, sequence variant 2, sequence conflict 2, chain 1, coiled-coil region 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5SW24-F1	50.81	0.04

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 78 (showing top): GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_REGULATION_OF_TRANSMEMBRANE_RECEPTOR_PROTEIN_SERINE_THREONINE_KINASE_SIGNALING_PATHWAY, GOBP_ACTIVIN_RECEPTOR_SIGNALING_PATHWAY, GOBP_EPITHELIAL_CELL_MORPHOGENESIS, chr6q27, GOBP_COLLECTING_DUCT_DEVELOPMENT, GOBP_SKIN_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_RECEPTOR_PROTEIN_SERINE_THREONINE_KINASE_SIGNALING_PATHWAY, GOBP_REGULATION_OF_ACTIVIN_RECEPTOR_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_CELL_ADHESION, GOMF_BETA_CATENIN_BINDING, GOMF_PROTEIN_KINASE_C_BINDING, ER_Q6_02

GO Biological Process (6): hematopoietic progenitor cell differentiation (GO:0002244), epithelial cell morphogenesis (GO:0003382), negative regulation of cell adhesion (GO:0007162), skin development (GO:0043588), inner medullary collecting duct development (GO:0072061), negative regulation of nodal signaling pathway (GO:1900108)

GO Molecular Function (6): protein kinase C binding (GO:0005080), beta-catenin binding (GO:0008013), transcription factor binding (GO:0008134), protein kinase A binding (GO:0051018), delta-catenin binding (GO:0070097), protein binding (GO:0005515)

GO Cellular Component (1): cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	4
hemopoiesis	1
cell differentiation	1
cell morphogenesis	1
epithelial cell development	1
cell adhesion	1
regulation of cell adhesion	1
negative regulation of cellular process	1
animal organ development	1
collecting duct development	1
negative regulation of activin receptor signaling pathway	1
nodal signaling pathway	1
regulation of nodal signaling pathway	1
protein kinase binding	1
binding	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

604 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DACT2	DACT3	Q96B18	924
DACT2	CTNNB1	P35222	693
DACT2	ACVR1B	P36896	629
DACT2	DVL1	O14640	569
DACT2	FRMD1	Q8N878	566
DACT2	TGFBR1	P36897	557
DACT2	KIF25	Q9UIL4	557
DACT2	DYNLT2	Q8IZS6	543
DACT2	CCDC188	H7C350	521
DACT2	WDR27	A2RRH5	516
DACT2	SMOC2	Q9H3U7	493
DACT2	PHF10	Q8WUB8	462
DACT2	HMG20B	Q9P0W2	459
DACT2	BIN3	Q9NQY0	457
DACT2	JADE3	Q92613	450

IntAct

3 interactions, top by confidence:

A	B	Type	Score
DACT2	SMCHD1	psi-mi:“MI:0915”(physical association)	0.400
DACT2	MLYCD	psi-mi:“MI:0914”(association)	0.350

BioGRID (17): CAMK2D (Affinity Capture-MS), CAMK2G (Affinity Capture-MS), DACT2 (Reconstituted Complex), VHL (Affinity Capture-Western), CYSRT1 (Two-hybrid), DACT2 (Proximity Label-MS), ZBTB20 (Affinity Capture-MS), WDR48 (Affinity Capture-MS), DAK (Affinity Capture-MS), MLYCD (Affinity Capture-MS), SMEK1 (Affinity Capture-MS), IQSEC1 (Affinity Capture-MS), SEL1L3 (Affinity Capture-MS), DACT2 (Affinity Capture-MS), NARS2 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A1B0GUS0, A0A5F9ZHS7, A7E346, A7MB34, A8MZG2, B2RU40, D4A9R4, O08574, O75593, P0C1Z6, P0CG20, Q0VG99, Q0ZCJ7, Q17QH7, Q29RM2, Q2KIS6, Q2M2S6, Q2M3G4, Q2NL68, Q32LE6, Q3U1J1, Q5JXC2, Q5R815, Q5SW24, Q61660, Q63247, Q6NZ36, Q6PBC9, Q6ZN01, Q6ZRI6, Q7TN08, Q7Z591, Q80VF6, Q86WR7, Q8BG26, Q8BP99, Q8BXQ8, Q8IYS4, Q8N9Y4, Q8NAV2

Diamond homologs: Q5SW24, Q66KC9, Q673G8, Q6QZN6, Q7TN08, Q8JJ48, Q8QG92, Q8R4A3, Q9NYF0, Q0PHV7, Q96B18

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
DACT2	down-regulates	TGFBR1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

178 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	0
Uncertain significance	149
Likely benign	19
Benign	3

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
150709	GRCh38/hg38 6q27(chr6:167963618-170597678)x1	Pathogenic
1527319	GRCh37/hg19 6q26-27(chr6:161047873-170919482)	Pathogenic
1527327	GRCh37/hg19 6q27(chr6:167317903-170919482)	Pathogenic
202226	GRCh37/hg19 6q26-27(chr6:162865436-170901287)x3	Pathogenic
685707	GRCh37/hg19 6q27(chr6:166607593-170919482)x1	Pathogenic

SpliceAI

629 predictions. Top by Δscore:

Variant	Effect	Δscore
6:168308946:C:A	donor_gain	1.0000
6:168309096:CAC:C	acceptor_gain	1.0000
6:168309099:CT:C	acceptor_loss	1.0000
6:168309100:T:A	acceptor_loss	1.0000
6:168311147:GGTAC:G	donor_loss	1.0000
6:168311148:GTAC:G	donor_loss	1.0000
6:168311149:TA:T	donor_loss	1.0000
6:168311150:ACCTG:A	donor_loss	1.0000
6:168311151:CCTG:C	donor_loss	1.0000
6:168311280:CGGGA:C	acceptor_gain	1.0000
6:168311281:GGGA:G	acceptor_gain	1.0000
6:168311282:GGA:G	acceptor_gain	1.0000
6:168311283:GA:G	acceptor_gain	1.0000
6:168311284:AC:A	acceptor_loss	1.0000
6:168311285:C:CC	acceptor_gain	1.0000
6:168311285:CTG:C	acceptor_loss	1.0000
6:168311286:T:C	acceptor_loss	1.0000
6:168319382:CCTTA:C	donor_loss	1.0000
6:168319383:CTTAC:C	donor_loss	1.0000
6:168319384:TTACC:T	donor_loss	1.0000
6:168319385:TACCA:T	donor_loss	1.0000
6:168319387:CCAG:C	donor_gain	1.0000
6:168309094:ATCAC:A	acceptor_gain	0.9900
6:168309095:TCAC:T	acceptor_gain	0.9900
6:168309096:CACC:C	acceptor_gain	0.9900
6:168309099:C:CC	acceptor_gain	0.9900
6:168309106:C:CT	acceptor_gain	0.9900
6:168310166:ACC:A	donor_loss	0.9900
6:168310444:AGC:A	acceptor_gain	0.9900
6:168310445:GC:G	acceptor_gain	0.9900

AlphaMissense

4949 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:168308926:G:C	S277R	0.998
6:168308926:G:T	S277R	0.998
6:168308928:T:G	S277R	0.998
6:168310442:A:C	F128L	0.997
6:168310442:A:T	F128L	0.997
6:168310444:A:G	F128L	0.997
6:168311156:G:C	S125R	0.994
6:168311156:G:T	S125R	0.994
6:168311158:T:G	S125R	0.994
6:168308899:G:C	S286R	0.993
6:168308899:G:T	S286R	0.993
6:168308901:T:G	S286R	0.993
6:168307486:C:A	K757N	0.991
6:168307486:C:G	K757N	0.991
6:168311165:G:C	S122R	0.990
6:168311165:G:T	S122R	0.990
6:168311167:T:G	S122R	0.990
6:168307468:G:C	F763L	0.989
6:168307468:G:T	F763L	0.989
6:168307470:A:G	F763L	0.989
6:168308909:G:T	A283D	0.988
6:168308890:A:C	F289L	0.987
6:168308890:A:T	F289L	0.987
6:168308892:A:G	F289L	0.987
6:168307478:A:G	I760T	0.985
6:168311223:A:G	I103T	0.984
6:168310443:A:G	F128S	0.983
6:168307504:C:A	K751N	0.982
6:168307504:C:G	K751N	0.982
6:168310430:G:C	S132R	0.982

dbSNP variants (sampled 300 via entrez): RS1000054867 (6:168308852 G>A,C,T), RS1000084367 (6:168301920 T>C), RS1000269047 (6:168300681 A>G), RS1000298391 (6:168300823 A>C), RS1000304177 (6:168313005 C>T), RS1000454644 (6:168301737 T>A,C), RS1000523183 (6:168304641 C>G,T), RS1000628454 (6:168301546 G>A), RS1000632332 (6:168301746 G>T), RS1000775521 (6:168296814 G>A), RS1000861021 (6:168306624 G>C,T), RS1000874805 (6:168292563 G>A), RS1000921587 (6:168298226 T>C), RS1000986536 (6:168292814 A>T), RS1000995321 (6:168320111 T>C)

Disease associations

OMIM: gene MIM:608966 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002063_4	Sexual dimorphism in anthropometric traits	3.000000e-06
GCST007637_17	Diffusing capacity of carbon monoxide	5.000000e-06
GCST010653_12	Thyroid stimulating hormone levels	1.000000e-11
GCST012145_21	Ferritin levels	9.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005951	sexual dimorphism
EFO:0009369	diffusing capacity of the lung for carbon monoxide
EFO:0004459	ferritin measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases methylation, increases mutagenesis	2
beta-lapachone	decreases expression	1
mono-(2-ethylhexyl)phthalate	increases methylation, increases abundance	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	affects methylation, increases methylation	1
aflatoxin B2	increases methylation	1
ICG 001	decreases expression	1
abrine	increases expression	1
bisphenol S	decreases methylation	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Decitabine	affects methylation, affects expression	1
Microplastics	decreases expression, increases abundance	1
Air Pollutants	decreases expression, increases abundance	1
Citrulline	increases expression	1
Diethylhexyl Phthalate	increases abundance, increases methylation	1
Hydralazine	affects cotreatment, increases expression	1
Methapyrilene	affects methylation, increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Polystyrenes	decreases expression, increases abundance	1
Silicon Dioxide	decreases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	decreases expression	1
Valproic Acid	affects cotreatment, increases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.