DKK1

Summary

DKK1 (dickkopf Wnt signaling pathway inhibitor 1, HGNC:2891) is a protein-coding gene on chromosome 10q21.1, encoding Dickkopf-related protein 1 (O94907). 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. In precision oncology, DKK1 NUCLEAR EXPRESSION is associated with resistance to Levoleucovorin + Oxaliplatin + Fluorouracil + Irinotecan in Colorectal Cancer (CIViC Level B).

This gene encodes a member of the dickkopf family of proteins. Members of this family are secreted proteins characterized by two cysteine-rich domains that mediate protein-protein interactions. The encoded protein binds to the LRP6 co-receptor and inhibits beta-catenin-dependent Wnt signaling. This gene plays a role in embryonic development and may be important in bone formation in adults. Elevated expression of this gene has been observed in numerous human cancers and this protein may promote proliferation, invasion and growth in cancer cell lines.

Source: NCBI Gene 22943 — RefSeq curated summary.

At a glance

• GWAS associations: 28
• Clinical variants (ClinVar): 50 total
• Phenotypes (HPO): 50
• Druggable target: yes
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• MANE Select transcript: NM_012242

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2891
Approved symbol	DKK1
Name	dickkopf Wnt signaling pathway inhibitor 1
Location	10q21.1
Locus type	gene with protein product
Status	Approved
Aliases	SK, DKK-1
Ensembl gene	ENSG00000107984
Ensembl biotype	protein_coding
OMIM	605189
Entrez	22943

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding_CDS_not_defined, 1 protein_coding

ENST00000373970, ENST00000467359, ENST00000476752, ENST00000494277

RefSeq mRNA: 1 — MANE Select: NM_012242 NM_012242

CCDS: CCDS7246

Canonical transcript exons

ENST00000373970 — 4 exons

Exon	Start	End
ENSE00000704914	52314923	52315085
ENSE00001160616	52314281	52314677
ENSE00001462031	52316554	52317657
ENSE00003628542	52316295	52316435

Expression profiles

Bgee: expression breadth ubiquitous, 195 present calls, max score 99.69.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 150.7315 / max 4780.6564, expressed in 1300 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
104938	148.5127	1288
104940	1.1261	219
104939	0.9906	401
104941	0.1022	66

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
decidua	UBERON:0002450	99.69	gold quality
endometrium epithelium	UBERON:0004811	98.37	gold quality
stromal cell of endometrium	CL:0002255	98.17	gold quality
placenta	UBERON:0001987	94.00	gold quality
mucosa of urinary bladder	UBERON:0001259	93.02	gold quality
lower esophagus mucosa	UBERON:0035834	87.86	gold quality
epithelium of esophagus	UBERON:0001976	84.53	gold quality
esophagus squamous epithelium	UBERON:0006920	84.22	gold quality
urinary bladder	UBERON:0001255	83.52	gold quality
tibia	UBERON:0000979	83.02	gold quality
endocervix	UBERON:0000458	81.54	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.51	gold quality
sperm	CL:0000019	81.03	gold quality
skin of leg	UBERON:0001511	80.95	gold quality
vagina	UBERON:0000996	80.26	gold quality
cervix squamous epithelium	UBERON:0006922	80.07	gold quality
cervix epithelium	UBERON:0004801	78.94	gold quality
subcutaneous adipose tissue	UBERON:0002190	78.52	gold quality
male germ cell	CL:0000015	78.44	gold quality
skin of abdomen	UBERON:0001416	77.61	gold quality
cranial nerve II	UBERON:0000941	77.06	gold quality
ectocervix	UBERON:0012249	77.03	gold quality
endometrium	UBERON:0001295	76.90	gold quality
epithelial cell of pancreas	CL:0000083	76.89	gold quality
uterine cervix	UBERON:0000002	76.22	gold quality
zone of skin	UBERON:0000014	75.25	gold quality
mammalian vulva	UBERON:0000997	72.77	gold quality
squamous epithelium	UBERON:0006914	72.72	gold quality
gall bladder	UBERON:0002110	72.28	gold quality
skin of hip	UBERON:0001554	71.18	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-MTAB-7052	yes	11225.13
E-HCAD-24	yes	4555.45
E-GEOD-109979	yes	1635.62
E-GEOD-124472	yes	1202.80
E-MTAB-8495	yes	906.93
E-MTAB-6701	yes	141.80
E-MTAB-6678	yes	26.56
E-MTAB-7249	no	466.98
E-MTAB-8060	no	52.29
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

5 targets.

Target	Regulation
CCND1	Activation
EGR1	Activation
FOS	Activation
KLF10	Activation
NAB2	Activation

Upstream regulators (CollecTRI, top): APP, ASCL1, ATF4, CTNNB1, DLX5, EOMES, EWSR1, EZH2, FLI1, FOXO1, FOXO3, GATA6, ID2, JUN, KLF9, LEF1, MESP1, MSC, MSX1, MSX2, MYC, MYCN, NANOG, NFATC4, NKX2-5, OTX2, PAX6, PGR, POU5F1, SALL1, SOX2, SP7, SUZ12, TBX18, TBXT, TCF7L2, TP53, TWIST1, TWIST2, ZFP42

miRNA regulators (miRDB)

81 targeting DKK1, 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-126-5P	100.00	72.71	3180
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-613	99.91	71.50	1710

Literature-anchored findings (GeneRIF, showing 40)

• overexpression sensitizes brain tumor cells to apoptosis after DNA alkylation damage; may link WNT and p53 pathways (PMID:11840333)
• Analysis of individual Dkk domains & chimeric Dkks shows that the carboxy-terminal domains of both Dkk1 & 2 associate with LRP6 & are necessary & sufficient for Wnt8 inhibition. The NH2-terminal of Dkk1 plays an inhibitory role in Dkk-LRP interactions. (PMID:12167704)
• dickkopf-1 has a critical role in reentry into the cell cycle of human adult stem cells from bone marrow (PMID:12740383)
• Recombinant DKK1 inhibits the differentiation of osteoblastic precursor cells (PMID:14695408)
• Data show that DKK1 decreass melanocyte function, probably through beta-catenin-mediated regulation of microphthalmia-associated transcription factor activity, which in turn modulates the growth and differentiation of melanocytes. (PMID:15117970)
• Induction of DKK1 contributes to the pathological cascade triggered by beta-amyloid and is critically involved in the process of tau phosphorylation. (PMID:15229249)
• Together, our data suggest that Dkk-1 may be able to antagonize Wnt signaling and exert its tumor suppressive effects through beta-catenin-independent non-canonical pathways (i.e., the Wnt/JNK pathway). (PMID:15451431)
• Data show that FGF20 and DKK1 appear to be direct targets for beta-catenin/TCF transcriptional regulation via LEF/TCF-binding sites, and are expressed early in Xenopus embryogenesis under the control of the Wnt signaling pathway. (PMID:15592430)
• DKK-1 expression decreases in human colon tumors, suggesting that DKK-1 acts as a tumor suppressor gene in this neoplasia; the Wnt/beta-catenin pathway is downregulated by the induction of DKK-1 expression, a mechanism that is lost in colon cancer (PMID:15592505)
• We found that Dkk1-Fz5, but not Dkk3-Fz5, potently synergized with LRP6 to activate signaling in a dishevelled-dependent manner. (PMID:15694380)
• These data suggest that HBM mutant proteins can transit to the cell surface in sufficient quantity to transduce Wnt signal and that the likely mechanism for the HBM mutations’ physiologic effects is via reduced affinity to and inhibition by DKK1. (PMID:15923613)
• Marrow stromal cell-conditioned medium promotes the proliferation of Dickkopf-1-secreting multiple myeloma cells. (PMID:16293576)
• DKK-1 promoter was selectively hypermethylated in advanced colorectal neoplasms (PMID:16491118)
• loss of DKK expression plays a role in development or progression of malignant melanoma (PMID:16568085)
• reduction of DKK-1 levels after autologous stem cell transplantation may correlate with the normalization of osteoblast function (PMID:16646053)
• The involvement of Dkk1 in human but not murine adipogenesis indicates that inter-species differences exist in the molecular control of this process. (PMID:16763196)
• Dkk-1 and Dkk-4 may potentially be involved in the development of different injuries in response to pathological gastroesophageal acid reflux.Dickkopf homologs in squamous mucosa of esophagitis patients are overexpressed in Barrett’s esophagus. (PMID:16863544)
• The demonstration that DKK1 inhibits Wnt signaling in neurons and causes neuronal death supports the hypothesis that inhibition of the canonical Wnt pathway contributes to the pathophysiology of neurodegenerative disorders. (PMID:16919965)
• Together, our data indicate the possible correlation between Dkk-1 and human placental choriocarcinoma and suggest potential applications of Dkk-1 in treatment of human placental choriocarcinomas. (PMID:17026960)
• DKK1 is a key player in multiple myeloma bone disease (PMID:17068150)
• These results further clarify the mechanism by which DKK1 suppresses melanocyte density and differentiation, and help explain why DKK1-rich palmoplantar epidermis is paler than non-palmoplantar epidermis via mesenchymal-epithelial interactions. (PMID:17159916)
• Dickkopf-1 is a master regulator of joint remodeling. (PMID:17237793)
• DKK1 as a potential prognostic and diagnostic marker for cohorts of breast cancer patients with poor prognosis. Dickkopf-1 may also become a relevant candidate target for immunotherapy of different cancers. (PMID:17245340)
• Oxidative stress response regulates DKK1 expression through the JNK signaling cascade in multiple myeloma plasma cells. (PMID:17255354)
• Inappropriate histone modifications might deregulate DKK1 expression in medulloblastoma tumorigenesis and block its tumor-suppressive activity. (PMID:17329407)
• Calcitriol activates the transcription of the DKK-1 gene, probably in an indirect way that is associated to the promotion of a differentiated phenotype in colon cancer cells. (PMID:17449905)
• DKK1 and SFRP1 inhibit the transformed phenotype of breast cancer cell lines, and DKK1 inhibits tumor formation. (PMID:17485441)
• MYCN might stimulate cell proliferation by inhibiting the expression of DKK1. DKK1 might exert part of its growth suppressive effect by induction of SYNPO2 expression. (PMID:17643814)
• data strongly suggests that dihydrotestosterone-inducible DKK-1 is involved in dihydrotestosterone-driven balding (PMID:17657240)
• concludes that bone-derived prostate cell line that produces osteoblastic lesions induces new bone formation through Wnt canonical signaling, that LRP5 mediates this effect, and that DKK1 is involved in the balance between bone formation and resorption (PMID:17700537)
• In 60 multiple myeloma patients checked, it was found that among the Wnt inhibitors, Dickkopf-1 and secreted frizzled-related protein-3 were produced by multiple myeloma cells. (PMID:17702698)
• Increased Dickkopf-1 expression is associated with breast cancer bone metastases (PMID:17876334)
• findings further elucidate why human skin is thicker and paler on the palms and soles than on the trunk through topographical and site-specific differences in the secretion of DKK1 by dermal fibroblasts that affects the overlying epidermis. (PMID:17984176)
• Data demonstrate that systemic levels of Dkk-1 are elevated in osteosarcoma (OS) and may serve as a prognostic or diagnostic marker for evaluation of OS. (PMID:17987039)
• DKK-1 mediated tumor suppressor effect is independent of beta-catenin dependent transcription and a CamKII pathway contributes to DKK-1 signaling (PMID:18157634)
• Significant association with late-onset Alzheimer’s disease for 4 SNPs: rs1881747 near DKK1, rs2279420 in ANK3, rs2306402 in CTNNA3, and rs5030882 in CXXC6 in 1,160 cases and 1,389 controls. (PMID:18163421)
• Dkk1 inhibits this process and may be a key factor regulating pre-osteoblast differentiation and myeloma bone disease (PMID:18294945)
• MesP1 drives vertebrate cardiovascular differentiation through Dkk-1-mediated blockade of Wnt-signalling (PMID:18297060)
• DKK1 may play a key role in the development of osteolytic bone lesions in multiple myeloma by directly interrupting Wnt3a-regulated differentiation of osteoblasts (PMID:18305214)
• Using a large series of myeloma patients, we could show for the first time a correlation between DKK-1 serum concentration and the amount of lytic bone disease, indicating that DKK-1 is an important factor for the extent of bone disease (PMID:18331598)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Dkk1	ENSMUSG00000024868
rattus_norvegicus	Dkk1	ENSRNOG00000048688

Protein

Protein identifiers

Dickkopf-related protein 1 — O94907 (reviewed: O94907)

Alternative names: SK

All UniProt accessions (2): O94907, I1W660

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. Inhibits the pro-apoptotic function of KREMEN1 in a Wnt-independent manner, and has anti-apoptotic activity.

Subunit / interactions. Interacts with LRP6. Interacts (via the C-terminal Cys-rich domain) with LRP5 (via beta-propeller regions 3 and 4); the interaction, enhanced by MESD and or KREMEN, antagonizes Wnt-mediated signaling. Forms a ternary complex with LRP6 and KREM1. Interacts with KREM1.

Subcellular location. Secreted.

Tissue specificity. Placenta.

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

Similarity. Belongs to the dickkopf family.

RefSeq proteins (1): NP_036374* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006796	Dickkopf_N	Domain
IPR039863	DKK1-4	Family
IPR047304	Dkk1_Cys2	Domain
IPR047305	Dkk1_N	Domain
IPR048499	DIKK1/2/4_C-subdom2	Domain
IPR048500	DIKK1/2/4_C-subdom1	Domain

Pfam: PF04706, PF21479, PF21481

UniProt features (23 total): disulfide bond 10, strand 5, helix 2, region of interest 2, glycosylation site 2, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
3SOQ	X-RAY DIFFRACTION	1.9
3S2K	X-RAY DIFFRACTION	2.8
3S8V	X-RAY DIFFRACTION	3.1
5FWW	X-RAY DIFFRACTION	3.5
5GJE	ELECTRON MICROSCOPY	21

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O94907-F1	70.68	0.38

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 (10): 127–138, 189–201, 195–210, 200–237, 220–245, 239–263, 85–97, 91–111, 114–128, 121–133

Glycosylation sites (2): 61, 256

Function

Pathways and Gene Ontology

Reactome pathways

4 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
R-HSA-2892245	POU5F1 (OCT4), SOX2, NANOG repress genes related to differentiation

MSigDB gene sets: 533 (showing top): GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, HORIUCHI_WTAP_TARGETS_DN, GOBP_BODY_MORPHOGENESIS, BROWNE_HCMV_INFECTION_6HR_DN, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_NEGATIVE_REGULATION_OF_STRIATED_MUSCLE_CELL_DIFFERENTIATION, DACOSTA_UV_RESPONSE_VIA_ERCC3_XPCS_DN, GOBP_SYNAPSE_ASSEMBLY

GO Biological Process (47): negative regulation of transcription by RNA polymerase II (GO:0000122), cell morphogenesis (GO:0000902), mesoderm formation (GO:0001707), hair follicle development (GO:0001942), regulation of receptor internalization (GO:0002090), heart induction (GO:0003129), heart valve development (GO:0003170), endocardial cushion development (GO:0003197), learning or memory (GO:0007611), positive regulation of gene expression (GO:0010628), negative regulation of neuron projection development (GO:0010977), negative regulation of Wnt signaling pathway (GO:0030178), negative regulation of ossification (GO:0030279), embryonic limb morphogenesis (GO:0030326), negative regulation of BMP signaling pathway (GO:0030514), forebrain development (GO:0030900), response to retinoic acid (GO:0032526), endodermal cell differentiation (GO:0035987), negative regulation of mesodermal cell fate specification (GO:0042662), regulation of endodermal cell fate specification (GO:0042663), negative regulation of apoptotic process (GO:0043066), regulation of neuron apoptotic process (GO:0043523), positive regulation of Wnt signaling pathway, calcium modulating pathway (GO:0045813), positive regulation of JNK cascade (GO:0046330), regulation of synaptic transmission, glutamatergic (GO:0051966), canonical Wnt signaling pathway (GO:0060070), limb development (GO:0060173), face morphogenesis (GO:0060325), negative regulation of SMAD protein signal transduction (GO:0060392), motor learning (GO:0061743), negative regulation of canonical Wnt signaling pathway (GO:0090090), Wnt signaling pathway involved in somitogenesis (GO:0090244), synapse pruning (GO:0098883), regulation of dopaminergic neuron differentiation (GO:1904338), negative regulation of Wnt-Frizzled-LRP5/6 complex assembly (GO:1904723), positive regulation of midbrain dopaminergic neuron differentiation (GO:1904958), negative regulation of presynapse assembly (GO:1905607), positive regulation of Wnt signaling pathway, planar cell polarity pathway (GO:2000096), negative regulation of cardiac muscle cell differentiation (GO:2000726), endoderm formation (GO:0001706)

GO Molecular Function (5): growth factor activity (GO:0008083), co-receptor binding (GO:0039706), receptor antagonist activity (GO:0048019), low-density lipoprotein particle receptor binding (GO:0050750), protein binding (GO:0005515)

GO Cellular Component (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), early endosome membrane (GO:0031901)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Signaling by WNT	1
TCF dependent signaling in response to WNT	1
Signaling by WNT in cancer	1
Transcriptional regulation of pluripotent stem cells	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure development	3
heart development	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
anatomical structure morphogenesis	1
formation of primary germ layer	1
mesoderm morphogenesis	1
hair cycle process	1
skin epidermis development	1
receptor internalization	1
regulation of receptor-mediated endocytosis	1
organ induction	1
heart field specification	1
regulation of heart morphogenesis	1
mesenchyme development	1
behavior	1
cognition	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
regulation of neuron projection development	1
neuron projection development	1
negative regulation of cell projection organization	1
negative regulation of signal transduction	1
Wnt signaling pathway	1
regulation of Wnt signaling pathway	1
ossification	1
regulation of ossification	1
negative regulation of multicellular organismal process	1
limb morphogenesis	1
embryonic appendage morphogenesis	1
BMP signaling pathway	1
regulation of BMP signaling pathway	1
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
negative regulation of cellular response to growth factor stimulus	1
brain development	1
response to lipid	1
response to oxygen-containing compound	1
endoderm formation	1

Protein interactions and networks

STRING

2980 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DKK1	LRP6	O75581	999
DKK1	LRP5	O75197	999
DKK1	KREMEN1	Q96MU8	999
DKK1	KREMEN2	Q8NCW0	998
DKK1	CKAP4	Q07065	977
DKK1	SOST	Q9BQB4	958
DKK1	DKK3	Q9UBP4	947
DKK1	CTNNB1	P35222	939
DKK1	WNT3A	P56704	908
DKK1	WNT1	P04628	900
DKK1	WIF1	Q9Y5W5	882
DKK1	SFRP1	Q8N474	874
DKK1	FRZB	Q92765	869
DKK1	AXIN2	Q9Y2T1	865
DKK1	WNT6	Q9Y6F9	847

IntAct

35 interactions, top by confidence:

A	B	Type	Score
LRP6	DKK1	psi-mi:“MI:0407”(direct interaction)	0.960
DKK1	LRP6	psi-mi:“MI:0915”(physical association)	0.960
LRP6	DKK1	psi-mi:“MI:0915”(physical association)	0.960
MDFI	DKK1	psi-mi:“MI:0915”(physical association)	0.710
DKK1	MDFI	psi-mi:“MI:0915”(physical association)	0.710
KREMEN1	DKK1	psi-mi:“MI:0915”(physical association)	0.670
KREMEN1	DKK1	psi-mi:“MI:0407”(direct interaction)	0.670
DKK1	LRP5	psi-mi:“MI:0914”(association)	0.640
	DKK1	psi-mi:“MI:0915”(physical association)	0.560
Lrp6	DKK1	psi-mi:“MI:0407”(direct interaction)	0.440
KRTAP10-1	DKK1	psi-mi:“MI:0915”(physical association)	0.370
DPP4	DKK1	psi-mi:“MI:0915”(physical association)	0.370
SMAD9	DKK1	psi-mi:“MI:0915”(physical association)	0.370
DKK1	TK2	psi-mi:“MI:0914”(association)	0.350

BioGRID (43): KRTAP10-1 (Two-hybrid), LRP6 (Affinity Capture-MS), LRP5 (Affinity Capture-MS), POTEI (Affinity Capture-MS), PSMD13 (Affinity Capture-MS), RBM45 (Affinity Capture-MS), PSMD6 (Affinity Capture-MS), TK2 (Affinity Capture-MS), FBLN1 (Affinity Capture-MS), AMZ2 (Affinity Capture-MS), DKK1 (Two-hybrid), CTNNB1 (Co-localization), TK2 (Affinity Capture-MS), RBM45 (Affinity Capture-MS), LRP6 (Affinity Capture-MS)

ESM2 similar proteins: A7E2Z9, B3MFC2, B3NSF6, B4GAN3, B4HNI3, B4J8Z9, B4KR21, B4LQ44, B4MQJ1, B4P641, B4QBL6, B5A5T4, B5E022, C6K2K4, D3ZTT2, O13157, O88745, O94907, P01216, P24387, P43446, P68241, P68242, Q01974, Q26492, Q5R7F5, Q5RH73, Q66IA6, Q6DGP8, Q6FHJ7, Q76KF0, Q7YRN1, Q86Y78, Q8BNJ6, Q8BPP5, Q8CGD2, Q8JIE9, Q8NC67, Q8NFY4, Q99445

Diamond homologs: O54908, O94907, Q8JFE6, Q8JFX8, Q8JFY0, Q8JFY1, Q8R413, Q8VEJ3, Q9QUN9, Q9QYZ8, Q9UBP4, Q9UBT3, Q9UBU2, Q8JFX9, D2Y2C0, D2Y2E0, D2Y2E1, D2Y2E2, D2Y2E3, D2Y2E4, D2Y2E5, D2Y2E6, D2Y2E7, P25687, P42890, P58294, P84909, Q14A28, Q2XXR7, Q2XXR8, Q5W280, Q863H5, Q8JFQ0, Q8JFY2, Q8R414, Q9HC23, Q9PW66, Q9QXU7

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
DKK1	down-regulates	LRP6	binding
DKK1	down-regulates	WNT3A
MYC	“down-regulates quantity by repression”	DKK1	“transcriptional regulation”
POU5F1	“down-regulates quantity by repression”	DKK1	“transcriptional regulation”
DKK1	up-regulates	KREMEN1	binding
DKK1	up-regulates	KREMEN2	binding
ASCL1	“down-regulates quantity by repression”	DKK1	“transcriptional regulation”
Amyloid_fibril_formation	“up-regulates activity”	DKK1
PTH1R	“down-regulates quantity”	DKK1

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	34
Likely benign	8
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

286 predictions. Top by Δscore:

Variant	Effect	Δscore
10:52314646:GGAA:G	donor_gain	1.0000
10:52314647:GAA:G	donor_gain	1.0000
10:52314674:CCAGG:C	donor_loss	1.0000
10:52314675:CAGGT:C	donor_loss	1.0000
10:52314676:AGGTG:A	donor_loss	1.0000
10:52314678:G:GA	donor_loss	1.0000
10:52314921:A:AG	acceptor_gain	1.0000
10:52314922:G:GA	acceptor_gain	1.0000
10:52314922:GCC:G	acceptor_gain	1.0000
10:52314922:GCCGT:G	acceptor_gain	1.0000
10:52315081:AAATG:A	donor_gain	1.0000
10:52315082:AATG:A	donor_gain	1.0000
10:52315082:AATGG:A	donor_loss	1.0000
10:52315083:ATG:A	donor_gain	1.0000
10:52315083:ATGG:A	donor_loss	1.0000
10:52315084:TG:T	donor_gain	1.0000
10:52315084:TGG:T	donor_loss	1.0000
10:52315085:GG:G	donor_gain	1.0000
10:52315085:GGTG:G	donor_loss	1.0000
10:52315086:G:GG	donor_gain	1.0000
10:52315087:T:A	donor_loss	1.0000
10:52316284:T:TA	acceptor_gain	1.0000
10:52316291:TTAG:T	acceptor_loss	1.0000
10:52316292:TAG:T	acceptor_loss	1.0000
10:52316293:A:AG	acceptor_gain	1.0000
10:52316293:A:G	acceptor_loss	1.0000
10:52316293:AG:A	acceptor_gain	1.0000
10:52316294:G:GA	acceptor_gain	1.0000
10:52316294:GG:G	acceptor_gain	1.0000
10:52316294:GGA:G	acceptor_gain	1.0000

AlphaMissense

1727 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:52316571:T:A	C189S	1.000
10:52316571:T:C	C189R	1.000
10:52316572:G:C	C189S	1.000
10:52316573:T:G	C189W	1.000
10:52316609:T:G	C201W	1.000
10:52316620:T:G	F205C	1.000
10:52316624:G:C	W206C	1.000
10:52316624:G:T	W206C	1.000
10:52316634:T:A	C210S	1.000
10:52316635:G:A	C210Y	1.000
10:52316635:G:C	C210S	1.000
10:52316636:T:G	C210W	1.000
10:52316639:A:C	K211N	1.000
10:52316639:A:T	K211N	1.000
10:52316664:T:A	C220S	1.000
10:52316664:T:C	C220R	1.000
10:52316665:G:C	C220S	1.000
10:52316666:T:G	C220W	1.000
10:52316706:T:C	F234L	1.000
10:52316706:T:G	F234V	1.000
10:52316707:T:C	F234S	1.000
10:52316707:T:G	F234C	1.000
10:52316708:C:A	F234L	1.000
10:52316708:C:G	F234L	1.000
10:52315040:T:A	C121S	0.999
10:52315041:G:C	C121S	0.999
10:52315058:T:A	C127S	0.999
10:52315059:G:C	C127S	0.999
10:52315060:C:G	C127W	0.999
10:52315076:T:A	C133S	0.999

dbSNP variants (sampled 300 via entrez): RS1001501247 (10:52313995 C>T), RS1001773362 (10:52313148 C>A), RS1001960589 (10:52313440 A>T), RS1003174787 (10:52315315 CT>C), RS1003721441 (10:52315578 T>C), RS1005190597 (10:52312696 A>G), RS1005190997 (10:52315881 C>A), RS1005625937 (10:52316071 G>T), RS1005894105 (10:52317560 G>A), RS1005968180 (10:52315762 A>C), RS1006454840 (10:52317697 T>A), RS1006667641 (10:52317907 CT>C,CTT), RS1006776053 (10:52312643 T>C), RS1007235475 (10:52313244 C>T), RS1007253996 (10:52318067 T>C)

Disease associations

OMIM: gene MIM:605189 | disease phenotypes: MIM:615436

GenCC curated gene-disease

Mondo (1): aortic aneurysm, familial thoracic 8 (MONDO:0014187)

Orphanet (0):

HPO phenotypes

50 total (30 of 50 shown, HPO-id order):

HPO	Term
HP:0000020	Urinary incontinence
HP:0000360	Tinnitus
HP:0000613	Photophobia
HP:0000639	Nystagmus
HP:0000651	Diplopia
HP:0000939	Osteoporosis
HP:0001288	Gait disturbance
HP:0001293	Cranial nerve compression
HP:0001324	Muscle weakness
HP:0001437	Abnormality of the musculature of the lower limbs
HP:0001605	Vocal cord paralysis
HP:0002015	Dysphagia
HP:0002066	Gait ataxia
HP:0002073	Progressive cerebellar ataxia
HP:0002196	Myelopathy
HP:0002315	Headache
HP:0002321	Vertigo
HP:0002331	Recurrent paroxysmal headache
HP:0002395	Lower limb hyperreflexia
HP:0002512	Brain stem compression
HP:0002516	Increased intracranial pressure
HP:0002650	Scoliosis
HP:0002653	Bone pain
HP:0002757	Recurrent fractures
HP:0002808	Kyphosis
HP:0002949	Fused cervical vertebrae
HP:0002953	Vertebral compression fracture
HP:0003396	Syringomyelia
HP:0003474	Somatic sensory dysfunction
HP:0003487	Babinski sign

GWAS associations

28 associations (top):

Study	Trait	p-value
GCST000561_4	Electrocardiographic traits	7.000000e-08
GCST000872_11	QRS duration	3.000000e-08
GCST002127_24	Periodontitis (Mean PAL)	5.000000e-06
GCST002333_5	Bone properties (heel)	5.000000e-15
GCST002335_5	Bone properties (heel)	1.000000e-08
GCST003598_17	QRS duration	7.000000e-08
GCST003598_44	QRS duration	1.000000e-07
GCST003844_12	QRS duration	4.000000e-08
GCST003871_11	QRS complex (Cornell)	2.000000e-14
GCST003872_8	QRS complex (12-leadsum)	3.000000e-06
GCST003989_2	Chin dimples	2.000000e-08
GCST003996_44	Monobrow	4.000000e-15
GCST006423_10	Fracture	1.000000e-32
GCST007006_8	Logical memory (delayed recall) in normal cognition	2.000000e-08
GCST009391_184	Metabolite levels	9.000000e-06
GCST009615_11	Triglyceride levels x loop diuretics use interaction	1.000000e-07
GCST010796_3630	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-20
GCST010796_3631	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-10
GCST010796_3632	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-12
GCST010796_3633	Electrocardiogram morphology (amplitude at temporal datapoints)	8.000000e-15
GCST010796_3634	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-17
GCST010796_3635	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-20
GCST010796_3636	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-19
GCST010796_3637	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-18
GCST010796_3638	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-15
GCST010796_3639	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-11
GCST010796_3640	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-09
GCST010796_3641	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0005054	QRS complex
EFO:0005654	velocity of sound measurement
EFO:0004514	bone quantitative ultrasound measurement
EFO:0007742	QRS amplitude
EFO:0007906	synophrys measurement
EFO:0004874	memory performance
EFO:0010476	dimethylglycine measurement
EFO:0004530	triglyceride measurement
EFO:0004327	electrocardiography

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3885562 (PROTEIN-PROTEIN INTERACTION), CHEMBL6024 (SINGLE PROTEIN)

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
DKK1 NUCLEAR EXPRESSION	Levoleucovorin + Oxaliplatin + Fluorouracil + Irinotecan	Colorectal Cancer	Resistance	CIViC B	EID824

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2241529	DKK1		0.00	0

ChEMBL bioactivities

34 potent at pChembl≥5 of 34 total, top 34 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.10	IC50	0.8	nM	CHEMBL4576027
9.10	IC50	0.8	nM	CHEMBL4474010
9.10	IC50	0.8	nM	CHEMBL4466053
9.10	IC50	0.8	nM	CHEMBL4586339
9.10	IC50	0.8	nM	CHEMBL4462757
9.10	IC50	0.8	nM	CHEMBL4579843
9.10	IC50	0.8	nM	CHEMBL4576557
9.10	IC50	0.8	nM	CHEMBL4470464
9.10	IC50	0.8	nM	CHEMBL4451479
9.10	IC50	0.8	nM	CHEMBL4590623
9.10	IC50	0.8	nM	CHEMBL4542030
9.10	IC50	0.8	nM	CHEMBL4467961
9.10	IC50	0.8	nM	CHEMBL4460731
9.10	IC50	0.8	nM	CHEMBL4576841
9.10	IC50	0.8	nM	CHEMBL4572229
9.10	IC50	0.8	nM	CHEMBL4536339
9.10	IC50	0.8	nM	CHEMBL4447719
9.10	IC50	0.8	nM	CHEMBL4556608
9.10	IC50	0.8	nM	CHEMBL4439893
9.10	IC50	0.8	nM	CHEMBL4458139
9.10	IC50	0.8	nM	CHEMBL4461936
9.10	IC50	0.8	nM	CHEMBL4528967
9.10	IC50	0.8	nM	CHEMBL4531218
9.10	IC50	0.8	nM	CHEMBL4541777
9.10	IC50	0.8	nM	CHEMBL4585933
7.40	IC50	40	nM	CHEMBL4439204
7.40	IC50	40	nM	CHEMBL4590101
6.33	Kd	470	nM	CHEMBL1162107
6.20	EC50	630	nM	CHEMBL570667
6.00	EC50	1000	nM	CHEMBL570666
6.00	EC50	1000	nM	CHEMBL569046
5.72	EC50	1900	nM	CHEMBL569986
5.11	EC50	7800	nM	CHEMBL569998
5.01	EC50	9800	nM	CHEMBL571525

PubChem BioAssay actives

7 with measured affinity, of 26 total; 7 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
7-(dimethylamino)-3,4-dioxo-10H-phenoxazine-1-carboxylic acid	1894739: Inhibition of human LRP6-DKK1 interaction by binding to LRP6 incubated for 1 hr by SPR analysis	kd	0.4700	uM
[1-(4-naphthalen-2-ylpyrimidin-2-yl)piperidin-4-yl]methanamine	446072: Inhibition of Dkk1-mediated Wnt/beta-casein signaling in osteosarcoma cells assessed as potentiation of TCF-luciferase response	ec50	0.6300	uM
4-[(4-naphthalen-2-ylpyrimidin-2-yl)amino]benzenesulfonamide	446072: Inhibition of Dkk1-mediated Wnt/beta-casein signaling in osteosarcoma cells assessed as potentiation of TCF-luciferase response	ec50	1.0000	uM
1-(4-naphthalen-2-ylpyrimidin-2-yl)piperidin-4-amine	446072: Inhibition of Dkk1-mediated Wnt/beta-casein signaling in osteosarcoma cells assessed as potentiation of TCF-luciferase response	ec50	1.0000	uM
N-[[1-(4-naphthalen-2-ylpyrimidin-2-yl)piperidin-4-yl]methyl]acetamide	446072: Inhibition of Dkk1-mediated Wnt/beta-casein signaling in osteosarcoma cells assessed as potentiation of TCF-luciferase response	ec50	1.9000	uM
4-[[4-(5-methylthiophen-2-yl)pyrimidin-2-yl]amino]benzenesulfonamide	446072: Inhibition of Dkk1-mediated Wnt/beta-casein signaling in osteosarcoma cells assessed as potentiation of TCF-luciferase response	ec50	7.8000	uM
4-[methyl-[4-(5-methylthiophen-2-yl)pyrimidin-2-yl]amino]benzenesulfonamide	446072: Inhibition of Dkk1-mediated Wnt/beta-casein signaling in osteosarcoma cells assessed as potentiation of TCF-luciferase response	ec50	9.8000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases methylation, increases expression	8
Tetrachlorodibenzodioxin	decreases expression, decreases reaction	7
Valproic Acid	affects cotreatment, decreases expression, affects expression	7
Progesterone	affects response to substance, affects cotreatment, increases expression, decreases reaction	6
Particulate Matter	decreases expression, increases abundance, affects cotreatment, affects expression, increases expression	6
methylmercuric chloride	affects cotreatment, decreases expression, increases expression	4
sodium arsenite	decreases expression, increases abundance	4
(+)-JQ1 compound	decreases expression	4
Estradiol	affects cotreatment, increases expression, decreases expression	4
Hydrogen Peroxide	decreases expression, decreases reaction, affects expression, increases expression	4
Cyclosporine	decreases expression, increases expression	4
Aflatoxin B1	affects expression, decreases methylation, increases expression, increases methylation	4
Decitabine	affects expression, affects methylation, decreases methylation, increases expression	3
Ethanol	increases abundance, decreases activity, decreases reaction, decreases expression, affects cotreatment	3
Silicon Dioxide	decreases expression, increases expression	3
bisphenol A	affects expression, decreases expression	2
cobaltous chloride	decreases expression	2
potassium chromate(VI)	affects cotreatment, decreases expression, increases expression	2
cupric chloride	increases expression, decreases expression	2
perfluorooctane sulfonic acid	affects expression, affects reaction, affects methylation, decreases expression	2
perfluoro-n-nonanoic acid	decreases expression	2
Glyphosate	decreases expression, increases expression	2
Air Pollutants	decreases expression, increases abundance	2
Cadmium	increases expression	2
Carbamazepine	affects expression	2
Dexamethasone	affects response to substance, decreases reaction, affects binding, increases reaction, increases expression	2
Fluorouracil	affects response to substance, decreases expression	2
Folic Acid	affects expression, increases expression	2
Methotrexate	decreases response to substance, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3751509	Binding	Inhibition of DKK1/LRP6 (unknown origin) expressed in HEK293 cells assessed as inhibition of DKK1/LRP6 interaction at 100 uM after 2 hrs by immunofluorescence method	Synthesis and evaluation of gallocyanine dyes as potential agents for the treatment of Alzheimer’s disease and related neurodegenerative tauopathies. — Eur J Med Chem

Cellosaurus cell lines

5 cell lines: 3 cancer cell line, 1 transformed cell line, 1 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D7GA	Ubigene HEK293T DKK1 KO	Transformed cell line	Female
CVCL_E0BS	Ubigene HeLa DKK1 KO	Cancer cell line	Female
CVCL_F1SC	HyCyte NCI-N87 KO-hDKK1	Cancer cell line	Male
CVCL_UM34	WAe001-A-21	Embryonic stem cell	Male
CVCL_WN67	MOSJ-Dkk1	Cancer cell line	Female

Clinical trials (associated diseases)

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