DKK3

Summary

DKK3 (dickkopf Wnt signaling pathway inhibitor 3, HGNC:2893) is a protein-coding gene on chromosome 11p15.3, encoding Dickkopf-related protein 3 (Q9UBP4). Antagonizes canonical Wnt signaling by inhibiting LRP5/6 interaction with Wnt and by forming a ternary complex with the transmembrane protein KREMEN that promotes internalization of LRP5/6.

This gene encodes a protein that is a member of the dickkopf family. The secreted protein contains two cysteine rich regions and is involved in embryonic development through its interactions with the Wnt signaling pathway. The expression of this gene is decreased in a variety of cancer cell lines and it may function as a tumor suppressor gene. Alternative splicing results in multiple transcript variants encoding the same protein.

Source: NCBI Gene 27122 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 61 total — 2 likely-pathogenic
• Phenotypes (HPO): 1
• MANE Select transcript: NM_001018057

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2893
Approved symbol	DKK3
Name	dickkopf Wnt signaling pathway inhibitor 3
Location	11p15.3
Locus type	gene with protein product
Status	Approved
Aliases	REIC, RIG, CRRL
Ensembl gene	ENSG00000050165
Ensembl biotype	protein_coding
OMIM	605416
Entrez	27122

Gene structure

Transcript identifiers

Ensembl transcripts: 68 — 58 protein_coding, 7 protein_coding_CDS_not_defined, 3 retained_intron

ENST00000326932, ENST00000396505, ENST00000525493, ENST00000525927, ENST00000526218, ENST00000527132, ENST00000528188, ENST00000529338, ENST00000530694, ENST00000531309, ENST00000532372, ENST00000532873, ENST00000533813, ENST00000533900, ENST00000534479, ENST00000534511, ENST00000683431, ENST00000903515, ENST00000903516, ENST00000903517, ENST00000903518, ENST00000903519, ENST00000903520, ENST00000903521, ENST00000903522, ENST00000903523, ENST00000903524, ENST00000903525, ENST00000903526, ENST00000903527, ENST00000931290, ENST00000931291, ENST00000931292, ENST00000931293, ENST00000931294, ENST00000958789, ENST00000958790, ENST00000958791, ENST00000958792, ENST00000958793, ENST00000958794, ENST00000958795, ENST00000958796, ENST00000958797, ENST00000958798, ENST00000958799, ENST00000958800, ENST00000958801, ENST00000958802, ENST00000958803, ENST00000958804, ENST00000958805, ENST00000958806, ENST00000958807, ENST00000958808, ENST00000958809, ENST00000958810, ENST00000958811, ENST00000958812, ENST00000958813, ENST00000958814, ENST00000958815, ENST00000958816, ENST00000958817, ENST00000958818, ENST00000958819, ENST00000958820, ENST00000958821

RefSeq mRNA: 4 — MANE Select: NM_001018057 NM_001018057, NM_001330220, NM_013253, NM_015881

CCDS: CCDS7808, CCDS81555

Canonical transcript exons

ENST00000683431 — 7 exons

Exon	Start	End
ENSE00003479992	11968395	11968487
ENSE00003488247	12002300	12002437
ENSE00003566360	11998696	11998779
ENSE00003573226	11966954	11967098
ENSE00003657382	11965809	11965965
ENSE00003920150	12008370	12008626
ENSE00003920631	11963036	11964686

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 99.96.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 87.8498 / max 1757.7294, expressed in 1285 samples.

FANTOM5 promoters (18 alternative TSS)

Promoter ID	TPM avg	Samples expressed
118690	46.5351	1197
118699	28.2115	1227
118697	4.0655	907
118691	1.7918	688
118702	1.3862	143
118700	1.0894	642
118698	1.0041	555
118694	0.8649	477
118695	0.6038	235
118693	0.5678	283

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	99.96	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.94	gold quality
middle temporal gyrus	UBERON:0002771	99.92	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.87	gold quality
lateral globus pallidus	UBERON:0002476	99.84	gold quality
right atrium auricular region	UBERON:0006631	99.81	gold quality
entorhinal cortex	UBERON:0002728	99.78	gold quality
tendon of biceps brachii	UBERON:0008188	99.78	gold quality
substantia nigra pars compacta	UBERON:0001965	99.75	gold quality
vena cava	UBERON:0004087	99.75	gold quality
choroid plexus epithelium	UBERON:0003911	99.73	gold quality
stromal cell of endometrium	CL:0002255	99.69	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.68	gold quality
pons	UBERON:0000988	99.67	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	99.67	gold quality
CA1 field of hippocampus	UBERON:0003881	99.67	gold quality
medial globus pallidus	UBERON:0002477	99.65	gold quality
parietal lobe	UBERON:0001872	99.64	gold quality
globus pallidus	UBERON:0001875	99.64	gold quality
postcentral gyrus	UBERON:0002581	99.64	gold quality
nucleus accumbens	UBERON:0001882	99.63	gold quality
descending thoracic aorta	UBERON:0002345	99.63	gold quality
putamen	UBERON:0001874	99.62	gold quality
orbitofrontal cortex	UBERON:0004167	99.62	gold quality
superior vestibular nucleus	UBERON:0007227	99.57	gold quality
Brodmann (1909) area 46	UBERON:0006483	99.56	gold quality
medulla oblongata	UBERON:0001896	99.52	gold quality
inferior olivary complex	UBERON:0002127	99.52	gold quality
thoracic aorta	UBERON:0001515	99.51	gold quality
dorsal root ganglion	UBERON:0000044	99.50	gold quality

Single-cell (SCXA)

Detected in 15 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-GEOD-137537	yes	3886.94
E-MTAB-7316	yes	2882.47
E-CURD-114	yes	68.92
E-HCAD-35	yes	40.88
E-MTAB-8410	yes	35.95
E-HCAD-10	yes	32.91
E-HCAD-11	yes	32.07
E-GEOD-135922	yes	21.95
E-MTAB-8142	yes	12.78
E-GEOD-84465	yes	12.60
E-CURD-46	yes	11.41
E-GEOD-130148	yes	4.00
E-MTAB-7037	no	976.66
E-MTAB-11121	no	826.03
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI1, IRX1, MYCN, NKX3-1, PAX6

miRNA regulators (miRDB)

88 targeting DKK3, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-579-3P	99.86	71.66	3628

Literature-anchored findings (GeneRIF, showing 40)

• REIC gene expression was decreased in 14 of 24 fresh non-small cell lung cancer specimens (58%) compared to that in corresponding non-cancerous tissue. (PMID:11814687)
• Transfection of Dkk-3 and dominant-negative LRP5 into osteosarcoma cells significantly reduces invasion capacity and cell motility. (PMID:15087387)
• Dkk-3/REIC functions as a suppressor for human tumor growth (PMID:15516983)
• Down-regulation of Dickkopf 3 in elderly schizophrenic subjects. (PMID:15998302)
• loss of DKK expression plays a role in development or progression of malignant melanoma (PMID:16568085)
• The methylation level of DKK3 protein was significantly higher and mRNA level wassignificantly lower in bladder tumor than in bladder mucosa. (PMID:16609023)
• Loss of Dkk-3 expression resulting in impairment of glandular structure and uncontrolled prostate epithelial cell (PrEC) proliferation, both of which are crucial for prostate cancer progression. (PMID:16751809)
• These data show that DKK3 and WNT4 have multiple actions on steroidogenesis in adrenocortical cells, including effects on overall steroidogenesis (aldosterone and cortisol biosynthesis) and distinct effects on steroidogenic enzyme mRNA levels. (PMID:16981135)
• Dkk-3 mRNA and protein are clearly present in adult human pancreatic islets. (PMID:17347849)
• Stable overexpression of murine Dkk-3 in B16F10 cells significantly increased microvessel density in a melanoma model. We postulate a novel function of Dkk-3 in endothelial cells as a differentiation factor involved in remodeling the tumor vasculature. (PMID:18033687)
• Ectopic expression of Dkk3 in lung cancer cells with Dkk3 hypermethylation induced apoptosis and inhibited TCF-4 activity as well as nuclear accumulation of beta-catenin and expression of TCF-4 targets c-Myc and cyclin D1 (PMID:18048388)
• High DKK3 expression in benign ganglioneuromas and down-regulation of DKK3 by MYCN in neuroblastoma might contribute to the strongly different clinical behavior of both neuroblastic tumor types. MYCN expression is inversely correlated with that of DKK3. (PMID:18059033)
• Dkk-3 expression in normal epithelium of the prostate is lost during benign and malignant transformation and differentiation. The loss of expression is counterbalanced by upregulation of Dkk-3 expression in the blood vessels of the remodeled tissue. (PMID:18247400)
• REIC/Dkk-3 plays a pivotal role in the biology of human malignant glioma and suggests that REIC/Dkk-3 is a promising candidate for molecular target therapy. (PMID:18443132)
• Down-regulation of the Dkks associated to promoter hypermethylation appears to be frequently involved in gastrointestinal tumorigenesis. (PMID:18461655)
• REIC/Dkk-3 overexpression downregulates P-glycoprotein in multidrug-resistant MCF7/ADR cells and induces apoptosis in breast cancer (PMID:18654608)
• Aberrant methylation of the DKK3 promoter downregulates mRNA & protein expression in human breast cancer development. It may be a tumor suppressor in normal breast tissue. (PMID:18826564)
• both ATF3 and Smad were crucially and synergistically involved in down-regulation of Id-1, which regulated JNK phosphorylation in REIC/Dkk-3-induced apoptosis. (PMID:18922905)
• Dkk3 is a negative regulator of beta-catenin and its downregulation contributes to an activation of the beta-catenin signaling pathway (PMID:19003969)
• Epigenetic silencing of the Dkk-3 gene by promoter methylation was a common event in gastric cancer and was associated with a poor outcome in such patients. (PMID:19051296)
• Dkk-3 can play a role in head and neck squamous cell carcinoma (HNSCC) carcinogenesis with unknown mechanism. Allelic loss at Dkk-3 locus may also be used as a novel prognostic biomarker in HNSCC. (PMID:19192722)
• These results indicate that adenovirus-REIC has another arm against human cancer, an indirect host-mediated effect because of overproduction of IL-7 by mis-targeted normal human fibroblasts, in addition to its direct effect on cancer cells. (PMID:19279003)
• assessment of Dkk3 and AFP may be useful in the diagnosis of hepatic tumors. (PMID:19437037)
• Elevated Dkk-3 levels are specifically associated with Alzheimer’s disease (AD) and may serve as a potential non-invasive AD biomarker in plasma. (PMID:19457090)
• DKK-3 expression in tumor endothelium: a novel prognostic marker of pancreatic adenocarcinomas. (PMID:19493271)
• Data suggest that aberrant promoter methylation and decreased expression of DKK-3 and WIF-1 may be an important mechanism in hepatocellular carcinoma, and may be useful for early diagnosis and therapy of HCC. (PMID:19496188)
• Wnt antagonist genes WIF1 and DKK3 show a very similar frequency of promoter methylation in human breast cancer, but only DKK3 methylation proves as a novel prognostic marker (PMID:19570204)
• Loss of DKK3 by methylation is associated with breast cancer. (PMID:19859801)
• DKK3 is preferentially expressed by human bulge cells, compared to differentiated hair follicle keratinocytes (PMID:20050020)
• Results indicate that DKK3 acts as an antiapoptotic molecule by decreasing the intracellular level of reactive oxygen species. (PMID:20514419)
• DKK3 mRNA expression was reduced in 63% (35 of 56) of tumors compared with normal ovarian samples (PMID:20532910)
• genetic variation of DKK3 may modify severity of autosomal dominant polycystic kidney disease resulting from PKD1 mutations. (PMID:20616171)
• Upregulation of Dkk-3 expression in esophageal squamous cell carcinoma may contribute to tumor invasion and metastasis. (PMID:20627041)
• Dkk-3 protein detection using enzyme-linked immunosorbent assay as molecular markers can contribute to detection and diagnosis of gynecological cancer, especially for ovarian cancer and endometrial cancer. (PMID:20666943)
• This study suggests that a cause of catenin delocalization in oral cancer could be due to WNT pathway activation, by epigenetic alterations of SFRP-1, SFRP-2, SFRP-4, SFRP-5, WIF-1, DKK-3 genes (PMID:20811686)
• Dkk3+ megakaryocytes correlated with microvessel density in PV and PMF; Dkk3 might be involved in the pathogenesis of myeloproliferative neoplasms. (PMID:20978717)
• REIC/Dkk-3 may play a role in regulating the morphological process of normal tissue architecture through an autocrine and/or paracrine manner. (PMID:21042718)
• Analyzed the internalization of Cy3-labeled recombinant REIC/Dkk-3 protein. Among the cell lines screened, mouse induced pluripotent stem (iPS) cells showed a unique pattern of internalization. (PMID:21042779)
• Dkk-3 is expressed in human and mouse epidermis at the interface of upper spinous layer and granular layer. Dkk-3 expression is down-regulated in the hyperproliferative epidermis including skin cancers and non-cancerous proliferative diseases. (PMID:21323747)
• data demonstrate that MYCN-regulated miRNAs are able to modulate the expression of the tumor suppressor DKK3 in neuroblastoma (PMID:21572098)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	dkk3b	ENSDARG00000070683
danio_rerio	dkk3a	ENSDARG00000103591
mus_musculus	Dkk3	ENSMUSG00000030772
rattus_norvegicus	Dkk3	ENSRNOG00000016343

Protein

Protein identifiers

Dickkopf-related protein 3 — Q9UBP4 (reviewed: Q9UBP4)

All UniProt accessions (5): Q9UBP4, E9PHY3, E9PKK9, E9PKW6, F6SYF8

UniProt curated annotations — full annotation on UniProt →

Function. Antagonizes canonical Wnt signaling by inhibiting LRP5/6 interaction with Wnt and by forming a ternary complex with the transmembrane protein KREMEN that promotes internalization of LRP5/6. DKKs play an important role in vertebrate development, where they locally inhibit Wnt regulated processes such as antero-posterior axial patterning, limb development, somitogenesis and eye formation. In the adult, Dkks are implicated in bone formation and bone disease, cancer and Alzheimer disease.

Subunit / interactions. Interacts with LRP5 and LRP6.

Subcellular location. Secreted.

Tissue specificity. Highest expression in heart, brain, and spinal cord.

Post-translational modifications. N- and O-glycosylated.

Domain organisation. The C-terminal cysteine-rich domain mediates interaction with LRP5 and LRP6.

Similarity. Belongs to the dickkopf family.

RefSeq proteins (4): NP_001018067, NP_001317149, NP_037385, NP_056965 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006796	Dickkopf_N	Domain
IPR039863	DKK1-4	Family
IPR047300	Dkk3_Cys2	Domain
IPR047301	Dkk3_N	Domain

Pfam: PF04706

UniProt features (18 total): glycosylation site 6, disulfide bond 4, region of interest 3, sequence variant 2, signal peptide 1, chain 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UBP4-F1	74.08	0.29

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (4): 208–220, 214–231, 219–265, 241–273

Glycosylation sites (6): 121, 204, 26, 28, 96, 106

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 294 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, GOBP_GLUCOCORTICOID_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, GOBP_C21_STEROID_HORMONE_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_STEROID_METABOLIC_PROCESS, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_NEGATIVE_REGULATION_OF_LIPID_BIOSYNTHETIC_PROCESS, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, GOBP_NEGATIVE_REGULATION_OF_ALCOHOL_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY

GO Biological Process (11): anatomical structure morphogenesis (GO:0009653), Wnt signaling pathway (GO:0016055), regulation of transforming growth factor beta receptor signaling pathway (GO:0017015), adrenal gland development (GO:0030325), negative regulation of aldosterone biosynthetic process (GO:0032348), negative regulation of DNA-templated transcription (GO:0045892), negative regulation of canonical Wnt signaling pathway (GO:0090090), negative regulation of anti-Mullerian hormone signaling pathway (GO:1902613), negative regulation of cortisol biosynthetic process (GO:2000065), multicellular organism development (GO:0007275), negative regulation of Wnt signaling pathway (GO:0030178)

GO Molecular Function (3): co-receptor binding (GO:0039706), receptor antagonist activity (GO:0048019), protein binding (GO:0005515)

GO Cellular Component (2): obsolete extracellular space (GO:0005615), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure development	2
negative regulation of alcohol biosynthetic process	2
developmental process	1
cell surface receptor signaling pathway	1
transforming growth factor beta receptor signaling pathway	1
regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
regulation of cellular response to transforming growth factor beta stimulus	1
endocrine system development	1
gland development	1
aldosterone biosynthetic process	1
regulation of aldosterone biosynthetic process	1
negative regulation of steroid hormone biosynthetic process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
negative regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
regulation of anti-Mullerian hormone signaling pathway	1
anti-Mullerian hormone receptor signaling pathway	1
negative regulation of glucocorticoid biosynthetic process	1
cortisol biosynthetic process	1
regulation of cortisol biosynthetic process	1
multicellular organismal process	1
negative regulation of signal transduction	1
Wnt signaling pathway	1
regulation of Wnt signaling pathway	1
protein binding	1
signaling receptor binding	1
signaling receptor inhibitor activity	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2290 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DKK3	DKK2	Q9UBU2	966
DKK3	LRP5	O75197	961
DKK3	DKK1	O94907	947
DKK3	WNT6	Q9Y6F9	865
DKK3	WNT2B	Q93097	858
DKK3	KREMEN1	Q96MU8	754
DKK3	SFRP1	Q8N474	749
DKK3	FZD8	Q9H461	745
DKK3	WIF1	Q9Y5W5	730
DKK3	WNT3A	P56704	726
DKK3	SFRP2	Q96HF1	725
DKK3	SFRP4	Q6FHJ7	698
DKK3	LRP6	O75581	682
DKK3	CTNNB1	P35222	674
DKK3	KREMEN2	Q8NCW0	667

IntAct

42 interactions, top by confidence:

A	B	Type	Score
SGTA	DKK3	psi-mi:“MI:0915”(physical association)	0.560
BAG6	DKK3	psi-mi:“MI:0915”(physical association)	0.560
KLF11	DKK3	psi-mi:“MI:0915”(physical association)	0.560
DNAJB6	DKK3	psi-mi:“MI:0915”(physical association)	0.560
DKK3	NME4	psi-mi:“MI:0914”(association)	0.530
CMA1	MANBA	psi-mi:“MI:0914”(association)	0.530
GPIHBP1	ADAM10	psi-mi:“MI:0914”(association)	0.530
TIMP3	ZZEF1	psi-mi:“MI:0914”(association)	0.530
DKK3		psi-mi:“MI:0915”(physical association)	0.490
DKK3	NEC1	psi-mi:“MI:0915”(physical association)	0.370
DKK3	HOXA1	psi-mi:“MI:0915”(physical association)	0.370
DKK3	NUFIP2	psi-mi:“MI:0915”(physical association)	0.370
IDH1	DKK3	psi-mi:“MI:0915”(physical association)	0.370
DKK3	APC	psi-mi:“MI:0915”(physical association)	0.370
AURKA	DKK3	psi-mi:“MI:0915”(physical association)	0.370
BCAR3	DKK3	psi-mi:“MI:0915”(physical association)	0.370
DKK3	CDH1	psi-mi:“MI:0915”(physical association)	0.370
DKK3	ESR2	psi-mi:“MI:0915”(physical association)	0.370
DKK3	PPM1D	psi-mi:“MI:0915”(physical association)	0.370
DKK3	SMAD4	psi-mi:“MI:0915”(physical association)	0.370
DKK3	MYO9A	psi-mi:“MI:0914”(association)	0.350
DKK3	HS3ST1	psi-mi:“MI:0914”(association)	0.350

BioGRID (112): DKK3 (Two-hybrid), DKK3 (Two-hybrid), DKK3 (Two-hybrid), DKK3 (Two-hybrid), DKK3 (Two-hybrid), DKK3 (Two-hybrid), DKK3 (Two-hybrid), UBA52 (Affinity Capture-MS), MYO5B (Affinity Capture-MS), TNIP2 (Affinity Capture-MS), CEP131 (Affinity Capture-MS), ATAD3C (Affinity Capture-MS), MYO5A (Affinity Capture-MS), GOSR2 (Affinity Capture-MS), ASPM (Affinity Capture-MS)

ESM2 similar proteins: O08999, O35485, O35806, O43278, O89103, O95428, P13207, P23943, P35054, P49765, P49766, P59383, P97766, P98153, P98154, Q00918, Q14766, Q14767, Q16610, Q28019, Q2Q0I9, Q2TAL6, Q3U515, Q4ZHG4, Q5BIR3, Q5HZW5, Q5NRP8, Q5NRQ0, Q61508, Q61810, Q62894, Q765Z5, Q7TQH7, Q7Z4F1, Q867D0, Q86T13, Q86VZ4, Q8BH27, Q8C8N3, Q8CB67

Diamond homologs: O54908, O94907, Q8JFE6, Q8JFX8, Q8JFY0, Q8JFY1, Q8R413, Q8VEJ3, Q9QUN9, Q9QYZ8, Q9UBP4, Q9UBT3, Q9UBU2, P0CJ13, Q90839, Q9QZL9, Q9UK85

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
IRX1	“down-regulates quantity by repression”	DKK3	“transcriptional regulation”
hsa-miR-183-5p	“down-regulates quantity by repression”	DKK3	“post transcriptional regulation”
hsa-miR-582-3p	“down-regulates quantity by repression”	DKK3	“post transcriptional regulation”
hsa-miR-92a-3p	“down-regulates quantity by repression”	DKK3	“post transcriptional regulation”
hsa-miR-92b-5p	“down-regulates quantity by repression”	DKK3	“post transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	2
Uncertain significance	44
Likely benign	3
Benign	2

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1255591	NM_001018057.2(DKK3):c.1006dup (p.Glu336fs)	Likely pathogenic
1255592	NM_001018057.2(DKK3):c.952C>T (p.Arg318Cys)	Likely pathogenic

SpliceAI

1386 predictions. Top by Δscore:

Variant	Effect	Δscore
11:11964682:TGTGG:T	acceptor_gain	1.0000
11:11964687:C:CC	acceptor_gain	1.0000
11:11968392:CAC:C	donor_loss	1.0000
11:11968393:A:AC	donor_gain	1.0000
11:11968393:AC:A	donor_gain	1.0000
11:11968393:ACCAT:A	donor_gain	1.0000
11:11968394:C:CC	donor_gain	1.0000
11:11968394:CC:C	donor_gain	1.0000
11:11968394:CCAT:C	donor_gain	1.0000
11:11968394:CCATC:C	donor_gain	1.0000
11:11968483:CACTC:C	acceptor_gain	1.0000
11:11968484:ACTC:A	acceptor_gain	1.0000
11:11968485:CTC:C	acceptor_gain	1.0000
11:11968485:CTCC:C	acceptor_gain	1.0000
11:11968486:TC:T	acceptor_gain	1.0000
11:11968486:TCCT:T	acceptor_gain	1.0000
11:11968487:CC:C	acceptor_gain	1.0000
11:11968488:C:CC	acceptor_gain	1.0000
11:11968488:CTGG:C	acceptor_loss	1.0000
11:11968499:C:CT	acceptor_gain	1.0000
11:11998694:A:AC	donor_gain	1.0000
11:11998695:C:CC	donor_gain	1.0000
11:12002295:CTTA:C	donor_loss	1.0000
11:12002296:TTA:T	donor_loss	1.0000
11:12002297:TACCT:T	donor_loss	1.0000
11:12002299:C:CT	donor_loss	1.0000
11:12002438:C:CC	acceptor_gain	1.0000
11:11964511:C:CA	donor_gain	0.9900
11:11964683:GTGG:G	acceptor_gain	0.9900
11:11964684:TGG:T	acceptor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000043135 (11:11981176 A>G), RS1000334677 (11:12007732 G>A), RS1000358880 (11:11969477 C>T), RS1000545838 (11:11968638 T>C), RS1000579917 (11:11968405 C>A,G,T), RS1000595262 (11:11985277 C>G,T), RS1000703340 (11:11975574 G>A), RS1000720369 (11:12011709 A>G), RS1000753289 (11:11962886 G>A), RS1000878869 (11:12008005 G>T), RS1000926946 (11:11964175 G>A), RS1000945839 (11:11979676 C>A), RS1001049387 (11:11979758 T>G), RS1001147373 (11:11965757 T>A,C), RS1001175843 (11:11997624 G>A)

Disease associations

OMIM: gene MIM:605416 | disease phenotypes: MIM:174050

GenCC curated gene-disease

Mondo (2): autosomal dominant polycystic kidney disease (MONDO:0004691), autosomal dominant polycystic liver disease (MONDO:0000447)

Orphanet (2): Autosomal dominant polycystic kidney disease (Orphanet:730), Isolated polycystic liver disease (Orphanet:2924)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0006557	Polycystic liver disease

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001525_32	Visceral fat	4.000000e-06
GCST001692_7	Response to taxane treatment (docetaxel)	7.000000e-06
GCST002120_6	Metabolite levels (Dihydroxy docosatrienoic acid)	8.000000e-06
GCST003808_1	Non-response to selective serotonin reuptake inhibitors and depression	5.000000e-07
GCST006297_2	Response to perphenazine in schizophrenia	3.000000e-06
GCST006585_2777	Blood protein levels	5.000000e-08
GCST006585_653	Blood protein levels	9.000000e-06
GCST011616_49	Cortical volume	6.000000e-12
GCST012226_342	Waist circumference adjusted for body mass index	3.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005275	dihydroxy docosatrienoic acid measurement
EFO:0005658	response to selective serotonin reuptake inhibitor
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D016891	Polycystic Kidney, Autosomal Dominant	C12.050.351.968.419.403.875.500; C12.200.777.419.403.875.500; C12.950.419.403.875.500; C16.131.077.717.500; C16.320.184.625.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

70 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, increases methylation	9
sodium arsenite	affects expression, affects cotreatment, decreases expression, increases abundance, increases expression	3
Tobacco Smoke Pollution	affects expression, decreases expression, increases expression	3
chloropicrin	decreases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	2
Arsenic	increases abundance, affects methylation, affects cotreatment, decreases expression	2
Benzo(a)pyrene	increases methylation, affects methylation, decreases methylation, increases expression	2
Doxorubicin	affects response to substance, increases expression	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
aristolochic acid I	increases expression	1
bisphenol F	affects cotreatment, increases expression	1
sotorasib	affects cotreatment, decreases expression	1
sporidesmin	decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
propionaldehyde	increases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
sulforaphane	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
pentanal	increases expression	1
avobenzone	increases expression	1
casticin	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	increases expression	1
trametinib	affects cotreatment, decreases expression	1
(+)-JQ1 compound	increases expression, decreases reaction	1
NVP-BKM120	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00414440	PHASE4	COMPLETED	Efficacy, Safety and Tolerability of Everolimus in Preventing End-stage Renal Disease in Patients With Autosomal Dominant Polycystic Kidney Disease
NCT03273413	PHASE4	ACTIVE_NOT_RECRUITING	Statin Therapy in Patients With Early Stage ADPKD
NCT03949894	PHASE4	COMPLETED	Evaluating the Safety and effectivenesS in Adult KorEaN Patients Treated With Tolvaptan for Management of Autosomal domInAnt poLycystic Kidney Disease
NCT00309283	PHASE3	COMPLETED	Somatostatin in Polycystic Kidney: a Long-term Three Year Follow up Study
NCT00346918	PHASE3	COMPLETED	Sirolimus (Rapamune®) for Autosomal Dominant Polycystic Kidney Disease (ADPKD)
NCT00428948	PHASE3	COMPLETED	Tolvaptan Phase 3 Efficacy and Safety Study in Autosomal Dominant Polycystic Kidney Disease (ADPKD)
NCT01022424	PHASE3	COMPLETED	A Long-term Administration Study of OPC-41061 in Patients With Autosomal Dominant Polycystic Kidney Disease (ADPKD) (2) [Extension of Study 156-05-002]
NCT01214421	PHASE3	COMPLETED	Tolvaptan Extension Study in Participants With ADPKD
NCT01377246	PHASE3	COMPLETED	Somatostatin In Patients With Autosomal Dominant Polycystic Kidney Disease And Moderate To Severe Renal Insufficiency
NCT01616927	PHASE3	UNKNOWN	Study of Lanreotide to Treat Polycystic Kidney Disease
NCT01853553	PHASE3	COMPLETED	Mineralocorticoid Antagonism and Endothelial Dysfunction in Autosomal Dominant Polycystic Kidney Disease (ADPKD)
NCT02115659	PHASE3	UNKNOWN	Triptolide-Containing Formulation as Treatment for Autosomal Dominant Polycystic Kidney Disease (ADPKD)
NCT02134899	PHASE3	COMPLETED	The Efficacy of Everolimus in Reducing Total Native Kidney Volume in Polycystic Kidney Disease Transplanted Recipients
NCT02160145	PHASE3	COMPLETED	Efficacy and Safety of Tolvaptan in Subjects With Chronic Kidney Disease Between Late Stage 2 to Early Stage 4 Due to Autosomal Dominant Polycystic Kidney Disease
NCT02964273	PHASE3	COMPLETED	Safety, Pharmacokinetics, Tolerability and Efficacy of Tolvaptan in Children and Adolescents With ADPKD (Autosomal Dominant Polycystic Kidney Disease)
NCT03764605	PHASE3	UNKNOWN	Metformin vs Tolvaptan for Treatment of Autosomal Dominant Polycystic Kidney Disease
NCT03918447	PHASE3	TERMINATED	A Trial of Bardoxolone Methyl in Patients With ADPKD - FALCON
NCT04064346	PHASE3	TERMINATED	Efficacy and Safety of Lixivaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease
NCT04152837	PHASE3	TERMINATED	Safety of Lixivaptan in Subjects Previously Treated With Tolvaptan for Autosomal Dominant Polycystic Kidney Disease
NCT04939935	PHASE3	RECRUITING	Implementation of Metformin theraPy to Ease Decline of Kidney Function in Polycystic Kidney Disease (IMPEDE-PKD)
NCT05373264	PHASE3	RECRUITING	HYDROchlorothiazide to PROTECT Polycystic Kidney Disease Patients and Improve Their Quality of Life
NCT00841568	PHASE2	COMPLETED	A Long-term Administration Study of OPC-41061 in Patients With Autosomal Dominant Polycystic Kidney Disease (ADPKD) [Extension of Study 156-04-001]
NCT01210560	PHASE2	COMPLETED	Dose-finding Study of New Tolvaptan Formulation in Subjects With ADPKD
NCT01336972	PHASE2	COMPLETED	Short-term Renal Hemodynamic Effects of Tolvaptan in Subjects With Autosomal Dominant Polycystic Kidney Disease (ADPKD)
NCT01451827	PHASE2	COMPLETED	8-Week Study of Tolvaptan Dose Forms in Autosomal Dominant Polycystic Kidney Disease (ADPKD)
NCT01670110	PHASE2	COMPLETED	Pasireotide LAR in Severe Polycystic Liver Disease
NCT01932450	PHASE2	UNKNOWN	Radiofrequency Ablation for ADPKD Blood Pressure and Disease Progression Control
NCT02527863	PHASE2	COMPLETED	Effect of the Aquaretic Tolvaptan on Nitric Oxide System
NCT02616055	PHASE2	TERMINATED	Long-Term Treatment and Follow up of Subjects Completing 24 Months of Treatment With Tesevatinib on Study KD019-101
NCT03203642	PHASE2	COMPLETED	Study of the Efficacy and Safety of Tesevatinib in Subjects With ADPKD
NCT03487913	PHASE2	COMPLETED	The ELiSA Study - Evaluation of Lixivaptan in Subjects With Autosomal Dominant Polycystic Kidney Disease
NCT03541447	PHASE2	COMPLETED	Tolvaptan-Octreotide LAR Combination in ADPKD
NCT04284657	PHASE2	COMPLETED	Pravastatin and Alkali Therapy in Patients With Autosomal Dominant Polycystic Kidney Disease
NCT04578548	PHASE2	TERMINATED	A Study to Evaluate the Effects of GLPG2737 in Participants With Autosomal Dominant Polycystic Kidney Disease (ADPKD)
NCT05190744	PHASE2	COMPLETED	Probenecid (PB) to Treat Hereditary Nephrogenic Diabetes Insipidus (NDI), ADPKD Treated With Tolvaptan, and Severely Polyuric Patients With Previous Lithium Administration
NCT05870007	PHASE2	ENROLLING_BY_INVITATION	Atorvastatin and Alkali Therapy in Patients With Autosomal Dominant Polycystic Kidney Disease
NCT06100133	PHASE2	UNKNOWN	Treat Autosomal Dominant Polycystic Kidney Disease With Oral Ketone Ester?
NCT06289998	PHASE2	ACTIVE_NOT_RECRUITING	Study of Tamibarotene in Patients With ADPKD
NCT06435858	PHASE2	RECRUITING	Short-term Effects of an SGLT2 Inhibitor on Divalent Ions in Autosomal Dominant Polycystic Kidney Disease
NCT06800651	PHASE2	RECRUITING	Trial of JMKX003142 in Participants With Rapidly Progressive Autosomal Dominant Polycystic Kidney Disease (ADPKD)