DKK4

Summary

DKK4 (dickkopf Wnt signaling pathway inhibitor 4, HGNC:2894) is a protein-coding gene on chromosome 8p11.21, encoding Dickkopf-related protein 4 (Q9UBT3). 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. Activity of this protein is modulated by binding to the Wnt co-receptor and the co-factor kremen 2.

Source: NCBI Gene 27121 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 45 total — 1 pathogenic
• MANE Select transcript: NM_014420

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2894
Approved symbol	DKK4
Name	dickkopf Wnt signaling pathway inhibitor 4
Location	8p11.21
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000104371
Ensembl biotype	protein_coding
OMIM	605417
Entrez	27121

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000220812

RefSeq mRNA: 1 — MANE Select: NM_014420 NM_014420

CCDS: CCDS6130

Canonical transcript exons

ENST00000220812 — 4 exons

Exon	Start	End
ENSE00000692528	42374063	42374359
ENSE00000692530	42374761	42374913
ENSE00000692532	42375680	42375830
ENSE00001324582	42376935	42377229

Expression profiles

Bgee: expression breadth ubiquitous, 108 present calls, max score 92.18.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1399 / max 32.1051, expressed in 42 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
92900	0.1399	42

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	92.18	silver quality
endometrium epithelium	UBERON:0004811	87.18	silver quality
paraflocculus	UBERON:0005351	79.32	silver quality
frontal pole	UBERON:0002795	78.80	gold quality
middle frontal gyrus	UBERON:0002702	78.14	silver quality
Brodmann (1909) area 10	UBERON:0013541	76.02	gold quality
buccal mucosa cell	CL:0002336	75.63	silver quality
cerebellar hemisphere	UBERON:0002245	69.93	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	69.83	gold quality
cerebellar cortex	UBERON:0002129	69.76	gold quality
cerebellum	UBERON:0002037	67.80	gold quality
right hemisphere of cerebellum	UBERON:0014890	66.93	gold quality
palpebral conjunctiva	UBERON:0001812	65.15	silver quality
esophagus mucosa	UBERON:0002469	64.65	gold quality
esophagus squamous epithelium	UBERON:0006920	62.78	silver quality
esophagus	UBERON:0001043	62.41	gold quality
lower esophagus mucosa	UBERON:0035834	62.06	gold quality
islet of Langerhans	UBERON:0000006	61.25	gold quality
hair follicle	UBERON:0002073	61.06	gold quality
nasal cavity mucosa	UBERON:0001826	60.34	gold quality
lower esophagus	UBERON:0013473	60.19	gold quality
lower esophagus muscularis layer	UBERON:0035833	60.06	gold quality
duodenum	UBERON:0002114	58.23	gold quality
cerebellar vermis	UBERON:0004720	57.34	gold quality
decidua	UBERON:0002450	56.55	gold quality
thymus	UBERON:0002370	55.30	gold quality
vagina	UBERON:0000996	54.50	gold quality
adenohypophysis	UBERON:0002196	53.76	gold quality
oral cavity	UBERON:0000167	53.73	silver quality
esophagogastric junction muscularis propria	UBERON:0035841	52.21	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-109979	yes	3368.45
E-ANND-3	yes	2.94

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1, GLI1, HNF4A, LEF1, MYOD1, VDR

Literature-anchored findings (GeneRIF, showing 25)

• chromosome 8 mapping by FISH (PMID:11701963)
• DKK4 may play a role in schizophrenia pathogenesis (PMID:17553464)
• DICKKOPF-4 is induced by TCF/beta-catenin and upregulated in human colon cancer, promotes tumour cell invasion and angiogenesis. (PMID:18408752)
• Down-regulation of the Dkks associated to promoter hypermethylation appears to be frequently involved in gastrointestinal tumorigenesis. (PMID:18461655)
• DKK4 is an important negative regulator of colon cancer cell growth. (PMID:19059704)
• Dickkopf-4 and -2 are significantly upregulated in most colorectal tumors (PMID:19659606)
• DKK1 and DKK4 proteins are expressed in the lung epithelium in idiopathic pulmonary fibrosis (PMID:20650998)
• Polymorphism of DKK4 was significantly associated with brain volume in Chinese individuals. (PMID:21341386)
• The TR/DKK4/Wnt/beta-catenin cascade influences the proliferation and migration of hepatoma cells during the metastasis process and support a tumor suppressor role of the thyroid hormone receptor. (PMID:21994129)
• TFAP2E hypermethylation is associated with clinical nonresponsiveness to chemotherapy in colorectal cancer. Functional assays confirm that TFAP2E-dependent resistance is mediated through DKK4. (PMID:22216841)
• Our findings suggest a potential tumour suppressive role of DKK4 as well as that of an important regulator of HCC. (PMID:22249261)
• Found the unique expression of the Wnt antagonist DKK4 in SW480APC, but not parental SW480 cell-derived exosomes. Upregulation of DKK4 in SW480APC cells was confirmed by RT-PCR, immunoblotting, and immunogold electron microscopy. (PMID:22740476)
• It would appear that deregulation of the WNT pathway by overexpression of DKK4 may further impair WNT signaling and lead to Anorectal malformations. (PMID:23108157)
• rs3923086 in AXIN2 and rs3763511 in DKK4 that did not show any association in the overall population were significantly associated with early on-set and estrogen receptor negative breast cancers, respectively. (PMID:23516639)
• DKK4 upregulated by T3/TR antagonizes the Wnt signal pathway to suppress tumor cell progression (PMID:23958302)
• The recurrence of benign tumors of mammary gland occurred predominantly in women-carriers of mutant alleles with polymorphism rs8190924 of gene GSR and AA rs3763511of gene DKK4. (PMID:26419038)
• DKK4 may have function on the development and progression of pancreatic cancer. (PMID:26880586)
• in NOD/SCID mice supplemented with high glucose, HepG2 xenografted tumors grew rapidly in which elevated levels of beta-catenin, c-Myc and decreased levels of DKK4 were detected. Knockdown of DKK4 by shRNA promotes proliferation of HCC cells in NG, which is suppressed by treating cells exogenously with recombinant DKK4 protein. Our in vitro and in vivo results indicate an important functional role of DKK4 in glucose fa… (PMID:27272409)
• DKK4 expression is significantly upregulated in human masticatory mucosa during wound healing (PMID:28005267)
• We found that TCF7L1 recruits the C-terminal binding protein (CtBP) and histone deacetylase 1 (HDAC1) to the DKK4 promoter to repress DKK4 gene expression. In the absence of TCF7L1, TCF7L2 and beta-catenin occupancy at the DKK4 promoter is stimulated and DKK4 expression is increased. These findings uncover a critical role for TCF7L1 in repressing DKK4 gene expression to promote the oncogenic potential of CRCs. (PMID:28450117)
• Our results indicated that DKK4 might be contributed to predicting EOC progression and prognosis. DKK4 could promote the invasion of EOC through JNK activation. (PMID:28666421)
• Data suggest a critical role of dickkopf 4 (DKK4) in docetaxel resistance of the lung adenocarcinoma A549 (A549/DTX) cells. (PMID:28981599)
• Dkk4 CRD2 mediates high-affinity binding to both the E1E2 region of low-density lipoprotein receptor-related protein 6 (LRP6 E1E2) and the Kremen1 (Krm1) extracellular domain. (PMID:29925589)
• The data implied that DLX3 regulated Wnt/beta-catenin pathway through histone modification of DKK4 during the osteogenic differentiation of bone marrow mesenchymal stem cells. (PMID:31202458)
• Sensitization of hepatocellular carcinoma cells towards doxorubicin and sorafenib is facilitated by glucosedependent alterations in reactive oxygen species, P-glycoprotein and DKK4. (PMID:32713860)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Dkk4	ENSMUSG00000031535
rattus_norvegicus	Dkk4	ENSRNOG00000019267

Protein

Protein identifiers

Dickkopf-related protein 4 — Q9UBT3 (reviewed: Q9UBT3)

All UniProt accessions (1): Q9UBT3

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. Expressed in cerebellum, T-cells, esophagus and lung.

Post-translational modifications. Appears to be not glycosylated. Can be proteolytically processed by a furin-like protease.

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

Similarity. Belongs to the dickkopf family.

RefSeq proteins (1): NP_055235* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006796	Dickkopf_N	Domain
IPR039863	DKK1-4	Family
IPR047299	Dkk4_Cys2	Domain
IPR048499	DIKK1/2/4_C-subdom2	Domain
IPR048500	DIKK1/2/4_C-subdom1	Domain

Pfam: PF04706, PF21479, PF21481

UniProt features (22 total): strand 6, disulfide bond 5, region of interest 3, chain 2, turn 2, signal peptide 1, sequence conflict 1, helix 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
5O57	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UBT3-F1	73.72	0.45

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 (5): 176–202, 196–218, 145–157, 151–166, 156–194

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-201681	TCF dependent signaling in response to WNT
R-HSA-3772470	Negative regulation of TCF-dependent signaling by WNT ligand antagonists
R-HSA-5339717	Signaling by LRP5 mutants

MSigDB gene sets: 134 (showing top): MODULE_52, GOBP_EPITHELIUM_DEVELOPMENT, MORF_MSH3, MODULE_45, MORF_BRCA1, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, MODULE_16, GOBP_REGULATION_OF_HAIR_CYCLE, GOBP_REGULATION_OF_HAIR_FOLLICLE_DEVELOPMENT, MODULE_66, MODULE_118, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, MODULE_379, GOBP_CANONICAL_WNT_SIGNALING_PATHWAY, MORF_FANCG

GO Biological Process (5): Wnt signaling pathway (GO:0016055), negative regulation of Wnt signaling pathway (GO:0030178), negative regulation of hair follicle placode formation (GO:0061170), negative regulation of canonical Wnt signaling pathway (GO:0090090), multicellular organism development (GO:0007275)

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)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Signaling by WNT	1
TCF dependent signaling in response to WNT	1
Signaling by WNT in cancer	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell surface receptor signaling pathway	1
negative regulation of signal transduction	1
Wnt signaling pathway	1
regulation of Wnt signaling pathway	1
negative regulation of hair follicle development	1
hair follicle placode formation	1
regulation of hair follicle placode formation	1
negative regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
multicellular organismal process	1
anatomical structure development	1
protein binding	1
signaling receptor binding	1
signaling receptor inhibitor activity	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

838 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DKK4	LRP5	O75197	997
DKK4	LRP6	O75581	994
DKK4	KREMEN1	Q96MU8	945
DKK4	WNT6	Q9Y6F9	860
DKK4	WNT2B	Q93097	826
DKK4	FRZB	Q92765	823
DKK4	FZD8	Q9H461	788
DKK4	WIF1	Q9Y5W5	786
DKK4	SFRP1	Q8N474	772
DKK4	WNT3A	P56704	744
DKK4	KREMEN2	Q8NCW0	701
DKK4	CTNNB1	P35222	699
DKK4	SOSTDC1	Q6X4U4	687
DKK4	FURIN	P09958	678
DKK4	SOST	Q9BQB4	654

IntAct

16 interactions, top by confidence:

A	B	Type	Score
TSPO2	DKK4	psi-mi:“MI:0915”(physical association)	0.560
ITGAM	DKK4	psi-mi:“MI:0915”(physical association)	0.560
GIMAP5	DKK4	psi-mi:“MI:0915”(physical association)	0.560
DKK4	OPTN	psi-mi:“MI:0915”(physical association)	0.560
DKK4	LRP5	psi-mi:“MI:0914”(association)	0.530
TSPO2	DKK4	psi-mi:“MI:0915”(physical association)	0.000
ITGAM	DKK4	psi-mi:“MI:0915”(physical association)	0.000
GIMAP5	DKK4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (11): RNPEPL1 (Affinity Capture-MS), LRP5 (Affinity Capture-MS), CUL1 (Affinity Capture-MS), IDE (Affinity Capture-MS), TSPO2 (Two-hybrid), ITGAM (Two-hybrid), GIMAP5 (Two-hybrid), RNPEPL1 (Affinity Capture-MS), LRP5 (Affinity Capture-MS), UBR2 (Affinity Capture-MS), DKK4 (Affinity Capture-RNA)

ESM2 similar proteins: A6NCL2, D3ZTT2, O19131, O46655, O70280, P01177, P01178, P01179, P01180, P01183, P01185, P01186, P03973, P13389, P19438, P22298, P22934, P25118, P35454, P35455, P50555, P58658, P58659, Q02509, Q14AE4, Q32LD3, Q3URS3, Q5T700, Q68US5, Q6UWE3, Q6UWL2, Q6V9X0, Q6WN34, Q76LW6, Q86Y78, Q8BPP5, Q8BVP6, Q8N6Q3, Q8VEA6, Q8WXA2

Diamond homologs: O54908, O94907, Q8JFE6, Q8JFX8, Q8JFY0, Q8JFY1, Q8R413, Q8VEJ3, Q9QUN9, Q9QYZ8, Q9UBP4, Q9UBT3, Q9UBU2, Q8JFX9, D2Y2E1, D2Y2E2, D2Y2E3, D2Y2E6, D2Y2E7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	39
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3245574	NC_000008.10:g.(?42129619)(42329908_?)del	Pathogenic

SpliceAI

311 predictions. Top by Δscore:

Variant	Effect	Δscore
8:42374759:AC:A	donor_gain	1.0000
8:42374760:CC:C	donor_gain	1.0000
8:42374794:T:TA	donor_gain	1.0000
8:42374911:CAT:C	acceptor_gain	1.0000
8:42376929:CCTTA:C	donor_loss	1.0000
8:42376930:CTTAC:C	donor_loss	1.0000
8:42376931:TTACC:T	donor_loss	1.0000
8:42376932:TACCT:T	donor_loss	1.0000
8:42376933:A:AC	donor_gain	1.0000
8:42376933:A:AG	donor_loss	1.0000
8:42376933:ACCTT:A	donor_gain	1.0000
8:42376934:C:CC	donor_gain	1.0000
8:42376934:CCTT:C	donor_gain	1.0000
8:42376934:CCTTC:C	donor_gain	1.0000
8:42376937:T:A	donor_gain	1.0000
8:42374764:T:TA	donor_gain	0.9900
8:42374910:ACATC:A	acceptor_loss	0.9900
8:42374913:TCT:T	acceptor_loss	0.9900
8:42374914:C:CA	acceptor_loss	0.9900
8:42374915:T:A	acceptor_loss	0.9900
8:42375674:GCTC:G	donor_loss	0.9900
8:42375676:T:TC	donor_loss	0.9900
8:42375677:C:CC	donor_loss	0.9900
8:42375678:A:AT	donor_loss	0.9900
8:42375679:C:CA	donor_loss	0.9900
8:42375829:CC:C	acceptor_gain	0.9900
8:42375830:CC:C	acceptor_gain	0.9900
8:42375831:C:CA	acceptor_loss	0.9900
8:42375832:T:A	acceptor_loss	0.9900
8:42376933:AC:A	donor_gain	0.9900

AlphaMissense

1458 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:42374203:A:C	F191C	0.999
8:42374202:G:C	F191L	0.997
8:42374202:G:T	F191L	0.997
8:42374204:A:G	F191L	0.997
8:42374289:C:A	W162C	0.997
8:42374289:C:G	W162C	0.997
8:42374274:C:A	K167N	0.994
8:42374274:C:G	K167N	0.994
8:42374278:C:G	C166S	0.992
8:42374279:A:T	C166S	0.992
8:42374278:C:T	C166Y	0.990
8:42374194:C:G	C194S	0.989
8:42374195:A:T	C194S	0.989
8:42374293:A:C	F161C	0.989
8:42374248:C:G	C176S	0.988
8:42374249:A:T	C176S	0.988
8:42374323:C:T	C151Y	0.988
8:42374277:A:C	C166W	0.987
8:42374305:C:T	C157Y	0.987
8:42374204:A:C	F191V	0.986
8:42374323:C:G	C151S	0.986
8:42374324:A:T	C151S	0.986
8:42374341:C:G	C145S	0.986
8:42374342:A:T	C145S	0.986
8:42374278:C:A	C166F	0.985
8:42374304:A:C	C157W	0.985
8:42374305:C:G	C157S	0.985
8:42374306:A:T	C157S	0.985
8:42374322:A:C	C151W	0.985
8:42374188:C:T	C196Y	0.984

dbSNP variants (sampled 300 via entrez): RS1000007418 (8:42381332 A>C), RS1000159463 (8:42374564 G>A), RS1000166049 (8:42387110 C>T), RS1000306647 (8:42393060 C>G), RS1000310780 (8:42381023 T>A,C), RS1000356617 (8:42393028 T>C), RS1000443456 (8:42392749 C>A,G), RS1000463643 (8:42386816 T>C), RS1000720408 (8:42391887 A>C,G,T), RS1000901769 (8:42385591 G>A), RS1000980085 (8:42379386 G>C,T), RS1001114010 (8:42382832 G>A), RS1001116233 (8:42375988 C>T), RS1001143368 (8:42382583 G>A,C), RS1001339008 (8:42386681 G>A)

Disease associations

OMIM: gene MIM:605417 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases abundance, decreases methylation, increases methylation, affects cotreatment, decreases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	increases expression, increases methylation	2
ethyl-p-hydroxybenzoate	increases expression	1
ceric oxide	decreases expression, increases abundance, affects cotreatment	1
CGP 52608	increases reaction, affects binding	1
deguelin	increases expression	1
K 7174	decreases expression	1
theaflavin-3,3’-digallate	affects expression	1
Air Pollutants	affects cotreatment, decreases expression, increases abundance	1
Amphotericin B	increases expression	1
Calcitriol	decreases reaction, increases expression	1
Fluorouracil	increases expression	1
Hydrogen Peroxide	increases secretion	1
Mustard Gas	increases expression	1
Quercetin	decreases expression	1
Tamoxifen	decreases expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Urethane	decreases expression	1
Valproic Acid	affects expression	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

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