Affinage

DKK2

Dickkopf-related protein 2 · UniProt Q9UBU2

Length
259 aa
Mass
28.4 kDa
Annotated
2026-06-09
69 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DKK2 is a secreted cysteine-rich, intrinsically disordered protein (PMID:31212691) that acts as a context-dependent modulator of Wnt signaling and a regulator of tissue patterning, differentiation, and tumor immune evasion (PMID:16672341, PMID:29431745). In most developmental and tumor-suppressive contexts it antagonizes canonical Wnt/β-catenin signaling through the Wnt co-receptors LRP5/6, binding LRP6 and preventing its phosphorylation (PMID:28180900); this Wnt-antagonist activity drives corneal versus epidermal fate specification of the ocular surface epithelium (PMID:16672341), specifies hairless plantar skin by regionally restraining Wnt/β-catenin activity (PMID:30509557), and is required redundantly with DKK1 to limit myocardial proliferation during epicardial development (PMID:20439124). In the developing eye DKK2 is an essential transcriptional target of PITX2, itself induced by retinoic acid signaling, establishing a RA→PITX2→DKK2 axis that represses ectopic Wnt activation in periocular tissue (PMID:18367164, PMID:20122913). DKK2 also promotes terminal osteoblast differentiation and mineralization, an effect not fully explained by its Wnt-antagonist function (PMID:16056226). The protein's signaling output is strikingly context-specific: in Xenopus neural crest specification DKK2 acts as a positive regulator of Wnt/β-catenin via LRP6 and β-catenin in a GSK3β-independent manner (PMID:30035713), whereas in the adult hippocampus it suppresses Wnt/PCP signaling through the JNK effector to support context discrimination and adult neurogenesis (PMID:41125965). In tumor immune evasion DKK2 secreted by tumor cells acts on cytotoxic lymphocytes via LRP5 to block STAT5 nuclear localization independently of LRP6 and β-catenin, suppressing NK and CD8+ T cell activity; its blockade enhances PD-1 immunotherapy (PMID:29431745), and a parallel NAT10/ac4C-stabilized DKK2→LRP6→AKT-mTOR axis impairs CD8+ T cell cytotoxicity through cholesterol accumulation (PMID:41542770). DKK2 expression is controlled transcriptionally by C/EBPβ (PMID:26656471) and silenced epigenetically by promoter methylation in multiple cancers (PMID:19755393, PMID:22964660), and it is post-transcriptionally repressed by several microRNAs (PMID:27542661, PMID:27501171).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2005 High

    Established that DKK2 is not merely a Wnt antagonist but a positive driver of terminal osteoblast differentiation, raising the possibility of Wnt-independent activity.

    Evidence Dkk2 knockout mice and cultured osteoblast rescue with exogenous Dkk2

    PMID:16056226

    Open questions at the time
    • Molecular mechanism of the Wnt-independent terminal-differentiation effect undefined
    • Receptor mediating the osteoblast effect not identified
  2. 2006 High

    Defined DKK2 as a fate-determining Wnt antagonist, showing its loss converts corneal epithelium into keratinizing epidermis with hair follicles.

    Evidence Dkk2 knockout mice with histology and immunohistochemistry

    PMID:16672341

    Open questions at the time
    • Direct demonstration of LRP5/6 engagement in this tissue not shown
    • Downstream target genes of the repressed Wnt program not mapped
  3. 2008 High

    Placed DKK2 genetically downstream of the PITX2 homeodomain factor in neural crest, defining a transcriptional circuit with negative feedback during eye development.

    Evidence Dkk2 and Pitx2 knockout mice, Wnt reporter analysis

    PMID:18367164

    Open questions at the time
    • Direct PITX2 binding to the DKK2 locus not demonstrated here
    • Mechanism of feedback to PITX2 unresolved
  4. 2010 High

    Extended the upstream circuit by showing retinoic acid drives PITX2 to induce DKK2, establishing a RA→PITX2→DKK2 Wnt-repressive axis in periocular mesenchyme.

    Evidence Raldh1/Raldh3 double null mice, ChIP, EMSA, in situ hybridization

    PMID:20122913

    Open questions at the time
    • Whether RA also directly regulates DKK2 independent of PITX2 untested
    • Spatiotemporal contribution of each node not dissected
  5. 2010 Medium

    Demonstrated functional redundancy of DKK2 with DKK1 in restraining myocardial proliferation during epicardial specification.

    Evidence Dkk1/Dkk2 single and double null mice, histology

    PMID:20439124

    Open questions at the time
    • Receptor and downstream effectors in heart not defined
    • Degree of unique versus redundant DKK2 contribution unresolved
  6. 2009 Medium

    Identified DKK2 as a methylation-silenced gene whose re-expression is growth-suppressive in renal and ovarian carcinoma, supporting a tumor-suppressor role tied to Wnt target downregulation.

    Evidence Demethylation, ChIP, stable overexpression with viability/apoptosis/cell-cycle assays in RCC and ovarian cells

    PMID:19755393 PMID:22964660

    Open questions at the time
    • Causality of methylation in primary tumors not fully established
    • Single-lab overexpression readouts
  7. 2012 Medium

    Revealed a context-dependent oncogenic role, showing DKK2 promotes Ewing sarcoma metastatic outgrowth, contrasting its tumor-suppressive role elsewhere.

    Evidence RNAi knockdown plus orthotopic xenograft and gene expression analysis

    PMID:23204234

    Open questions at the time
    • Receptor/signaling basis of pro-metastatic activity not defined
    • MMP1 mediation only correlative
  8. 2013 Medium

    Distinguished DKK2 from DKK1 as a pro-angiogenic factor, showing it enhances tumor vascularity and growth in vivo.

    Evidence Adenoviral and endothelial-specific transgenic DKK2 in melanoma and retinopathy models

    PMID:24091497

    Open questions at the time
    • Endothelial receptor and signaling pathway not identified
    • Relationship to Wnt antagonism unclear
  9. 2011 Medium

    Linked DKK2 loss to fibrotic transformation, showing DKK2 supplementation suppresses pro-fibrotic genes in hepatic stellate cells via canonical Wnt.

    Evidence Sept4 knockout mice, exogenous Dkk2, LEF/TCF luciferase reporter

    PMID:21763422

    Open questions at the time
    • Direct DKK2 receptor engagement not shown
    • Single-lab epistasis
  10. 2015 Medium

    Defined transcriptional and post-transcriptional control of DKK2 by C/EBPβ and miR-27a, including a promoter variant altering C/EBPβ binding.

    Evidence ChIP, EMSA, promoter mutagenesis, miR-27a gain/loss, proliferation assays

    PMID:26656471

    Open questions at the time
    • Physiological context of this regulation beyond CHO cells limited
    • Functional impact of the promoter variant in vivo untested
  11. 2016 Medium

    Identified multiple microRNAs (miR-154, miR-221, miR-187-5p) as direct repressors of DKK2 that activate Wnt/β-catenin in fibrosis, chemoresistance, and leukemia.

    Evidence Dual-luciferase/3'-UTR validation with rescue in cardiac fibroblasts, esophageal adenocarcinoma, and B-ALL cells, plus xenografts

    PMID:27296949 PMID:27501171 PMID:27542661

    Open questions at the time
    • Receptor-level mechanism downstream of DKK2 in each context not dissected
    • Some validations in single cell lines
  12. 2016 Medium

    Confirmed dose-dependent DKK2 antagonism of Wnt3a in hepatocellular carcinoma and linked a low-activity promoter haplotype to reduced DKK2 and unchecked Wnt signaling.

    Evidence Wnt3a dose-response, promoter reporter haplotype analysis, LOH and sequencing in HCC

    PMID:25826080 PMID:27203079

    Open questions at the time
    • Broader Dkk2-dependent oncogenic network only correlative
    • Causality of haplotype in carcinogenesis not proven
  13. 2018 High

    Uncovered a Wnt-β-catenin-independent immune-evasion mechanism: tumor-secreted DKK2 acts via LRP5 to block STAT5 nuclear localization and suppress cytotoxic lymphocytes.

    Evidence Genetic and antibody ablation of DKK2 in mouse tumors, LRP5/LRP6 dissection, STAT5 localization and NK/CD8+ readouts

    PMID:29431745

    Open questions at the time
    • Structural basis of LRP5-selective signaling not resolved
    • How LRP5 engagement controls STAT5 trafficking mechanistically undefined
  14. 2018 High

    Demonstrated that DKK2 can act as a positive Wnt regulator in a GSK3β-independent manner, establishing genuine context dependence of its signaling output.

    Evidence Xenopus morpholino knockdown with Lrp6/β-catenin rescue and GSK3β inhibitor experiments

    PMID:30035713

    Open questions at the time
    • Molecular switch determining antagonist versus agonist activity unknown
    • Generality beyond neural crest untested
  15. 2018 High

    Established DKK2 as a regional Wnt suppressor specifying hairless skin, with loss permitting ectopic functional hair follicle formation.

    Evidence Conditional/constitutive Dkk2 knockout mice with Wnt reporters and histology

    PMID:30509557

    Open questions at the time
    • Upstream regulators restricting DKK2 to plantar skin not identified
    • Receptor mediating regional Wnt restriction not shown directly
  16. 2020 High

    Defined a NAT10/ac4C post-transcriptional mechanism stabilizing DKK2 mRNA, with secreted DKK2 driving LRP6–AKT-mTOR–cholesterol-dependent CD8+ T cell dysfunction.

    Evidence Nat10 conditional knockout, scRNA-seq/multi-omics, ac4C analysis, DKK2 neutralization, AKT-mTOR and cholesterol assays in CRC models

    PMID:41542770

    Open questions at the time
    • Reconciliation of LRP6-dependent versus LRP5-dependent immune mechanisms unresolved
    • Direct DKK2-LRP6 binding step in T cells not structurally defined
  17. 2022 Medium

    Showed circCELF1 controls DKK2 via miR-636 sponging and FTO-dependent m6A reduction, integrating circular RNA and epitranscriptomic control in cardiac fibrosis.

    Evidence RIP/m6A analysis, luciferase, and functional assays in cardiac fibroblasts plus AMI mouse model

    PMID:35132536

    Open questions at the time
    • DKK2 receptor in cardiac fibroblasts not defined
    • Relative contribution of the two regulatory arms unquantified
  18. 2023 Medium

    Linked DKK2 to neurodegeneration, showing microglial upregulation near amyloid plaques and an anti-synaptic effect on hippocampal neurons, while flagging a human-mouse discrepancy.

    Evidence AD/ALS mouse models, in situ hybridization, recombinant DKK2 on rat hippocampal neurons with spine quantification

    PMID:36599670

    Open questions at the time
    • Absence of microglial DKK2 upregulation in human AD cortex unexplained
    • Receptor mediating anti-synaptic effect not identified
  19. 2024 Medium

    Positioned DKK2 as a Kremen1 ligand in aortic valve calcification, integrating it into an m6A/circHIPK3/miR-182-5p regulatory network.

    Evidence m6A analysis, RNA stability, valve interstitial cell osteogenesis, CAVD mouse model

    PMID:38945954

    Open questions at the time
    • Direct DKK2-Kremen1 binding not biochemically resolved here
    • Quantitative contribution to calcification phenotype limited
  20. 2025 High

    Demonstrated that DKK2 suppresses Wnt/PCP signaling via JNK in the adult hippocampus, with haploinsufficiency impairing context discrimination and neurogenesis rescued by JNK inhibition.

    Evidence Dkk2+/- and Dkk2-/- mice, hippocampal slice signaling assays, DKK2 administration, JNK inhibitor rescue, behavior and neurogenesis quantification

    PMID:41125965

    Open questions at the time
    • Receptor mediating Wnt/PCP suppression in hippocampus not defined
    • Dose-specific divergence between β-catenin and PCP effects mechanistically unexplained

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular switch that determines whether DKK2 antagonizes or activates Wnt signaling, and selects between LRP5- and LRP6-dependent outputs across tissues, remains undefined.
  • No structural model reconciling LRP5/LRP6/Kremen1 engagement across contexts
  • Determinants of antagonist-versus-agonist behavior unknown
  • Cell-type-specific receptor expression governing output not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0098772 molecular function regulator activity 4
Localization
GO:0005576 extracellular region 3
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 2
Partners
KREMEN1LRP5LRP6MIC3

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 DKK2 has a role in terminal osteoblast differentiation and mineralized matrix formation. Canonical Wnts upregulate Dkk2 expression in osteoblasts, and Dkk2 expression after peak Wnt7b expression induces a phenotype resembling terminal osteoblast differentiation leading to mineralization. Dkk2-null osteoblasts are poorly mineralized upon osteogenic induction, and exogenous Dkk2 partially rescues osteogenic marker expression. Effects on terminal differentiation may not be entirely mediated by its Wnt antagonistic activity, as FRP3 (another Wnt antagonist) differs from Dkk2 in rescuing the deficiency. Dkk2 knockout mice, cultured osteoblast differentiation models, exogenous Dkk2 overexpression/rescue, osteoid quantification Nature genetics High 16056226
2006 Dkk2-mediated repression of the Wnt/β-catenin pathway (via interaction with Wnt co-receptor Lrp5/6) is essential to promote differentiation of corneal epithelial progenitor cells into a non-keratinizing stratified epithelium. Loss of Dkk2 results in complete transformation of corneal epithelium into a stratified keratinizing epithelium with epidermal markers and hair follicles, demonstrating Dkk2 determines corneal versus epidermal fate of ocular surface epithelium. Dkk2 knockout mice, immunohistochemistry, histological analysis of corneal transformation Development (Cambridge, England) High 16672341
2008 Dkk2 is an essential downstream transcriptional target of the PITX2 homeodomain transcription factor in neural crest during eye development. Loss of DKK2 leads to ectopic activation of canonical Wnt signaling in central ocular surface ectoderm and underlying mesenchyme, ectopic conjunctival goblet cells and eyelash follicles in central structures, ectopic blood vessels in periocular mesenchyme, and persistently high PITX2 expression (evidence for a negative feedback loop). Dkk2 knockout and Pitx2 knockout mice, immunohistochemistry, Wnt reporter analysis Developmental biology High 18367164
2010 Retinoic acid (RA) signaling in perioptic mesenchyme induces Pitx2, which in turn induces Dkk2 to repress Wnt/β-catenin signaling during eye development. Raldh1/Raldh3 double null mice deficient for ocular RA synthesis show downregulation of both Pitx2 and Dkk2 in perioptic mesenchyme, and upregulation of Axin2 (Wnt readout). A DR5 RA response element upstream of Pitx2 binds RA receptors (confirmed by ChIP and gel mobility shift assay). Raldh1/Raldh3 double null mice, chromatin immunoprecipitation (ChIP), gel mobility shift assay, in situ hybridization Developmental biology High 20122913
2009 DKK2 is epigenetically silenced by promoter methylation in renal cell carcinoma. Stable overexpression of DKK2 in RCC cells decreases cell viability, increases apoptosis, and reduces S/G2-M phase cells, with corresponding decreases in Bcl2 and cyclin D1 expression. ChIP assays showed decreased acetyl-H3, acetyl-H4, and dimethylated H3K4, and increased dimethylated H3K9, at the DKK2 locus in RCC cell lines. 5-Aza-2'-deoxycytidine treatment, chromatin immunoprecipitation (ChIP), stable DKK2 transfection, cell viability, colony formation, apoptosis, cell cycle assays Clinical cancer research Medium 19755393
2009 Silencing Dkk2 (but not Dkk1) reduces the stimulatory effects of microstructured titanium (SLA and modSLA) surfaces on osteoblast differentiation; exogenous Dkk2 (but not Dkk1) restores these effects. Antibodies to Dkk2 specifically block substrate-dependent changes, demonstrating autocrine action. This indicates a major role for Dkk2 and Wnt/Ca2+-dependent signaling in late-stage osteoblast differentiation on microstructured and hydrophilic surfaces. Stable Dkk1/Dkk2 siRNA silencing in MG63 cells, exogenous rhDkk1/rhDkk2 addition, neutralizing antibodies, osteoblast differentiation assays on titanium surfaces Biomaterials Medium 20004015
2010 Dkk1 and Dkk2 together regulate epicardial specification during mouse heart development. Single Dkk1 or Dkk2 null mice show no discernible heart phenotype, but double null embryos die perinatally and show ventricular septal defects, myocardial and epicardial hyperplasia, and broadened Connexin 43 expression in proepicardial precursors, demonstrating that Dkk1 and Dkk2 redundantly inhibit Wnt signaling to regulate early myocardial proliferation. Dkk1/Dkk2 double null mice, histology, immunohistochemistry International journal of cardiology Medium 20439124
2012 DKK2 overexpression in ovarian cancer cell lines suppresses malignant cell growth and invasion, and decreases downstream Wnt signaling targets β-catenin, c-Myc, and cyclin D1. DKK2 also decreases matrix metalloproteinase-2 and focal adhesion kinase expression, consistent with inhibition of cell migration and invasion. DKK2 is epigenetically silenced by promoter methylation in ovarian carcinoma. DKK2 transfection/overexpression in SKOV3 and ES-2 cell lines, methylation-specific PCR, Western blotting, invasion assays Carcinogenesis Medium 22964660
2012 DKK2 is a pro-metastatic gene in Ewing sarcoma that is critical for malignant cell outgrowth in vitro and in an orthotopic xenograft mouse model. DKK2 expression correlates with invasiveness, potentially mediated through MMP1. DKK2 differentially regulates CXCR4, PTHrP, RUNX2, TGFβ1, HIF1α, JAG1, IL6, and VEGF (genes associated with homing, invasion, osteolysis). DKK2 suppression simultaneously increased neuronal differentiation potential while decreasing chondrogenic and osteogenic differentiation. RNA interference in Ewing sarcoma cells, orthotopic xenograft mouse model, invasion assays, gene expression analysis Cancer research Medium 23204234
2013 DKK2 enhances angiogenesis while DKK1 inhibits it in normal and tumor tissues. In B16F10 melanoma-bearing mice, adenovirus-expressing DKK2 increased tumor growth, vascular density, perfusion, and pericyte coverage, while DKK1 showed opposite effects. Endothelial-specific DKK2 transgenic mice confirmed increased tumor growth. DKK2 also showed opposite results to DKK1 in a murine model of oxygen-induced retinopathy. Adenovirus-mediated DKK2 overexpression in B16F10 melanoma model, endothelial-specific DKK2 transgenic mice, in vivo retinopathy model Angiogenesis Medium 24091497
2013 miR-21 promotes oral cancer invasion via the Wnt/β-catenin pathway by directly targeting DKK2. Knockdown of miR-21 in SCC25 cells decreases invasion potential with upregulation of DKK2, as confirmed by Matrigel invasion assay and Western blotting. LNA probe knockdown of miR-21 in SCC25 cells, Matrigel invasion assay, Western blotting Pathology oncology research Low 23999978
2014 Dkk2/Frzb in the dermal papillae regulates feather regeneration and axis formation. Lentiviral overexpression, shRNA knockdown, or antibody neutralization of Dkk2/Frzb results in dual feather axis formation. Wnt signaling is required for maintenance of dermal papilla marker gene expression and feather regeneration, but excessive Wnt signaling (from Dkk2/Frzb loss) delays regeneration and reduces pulp formation. Lentiviral overexpression and shRNA knockdown of Dkk2/Frzb in avian feather follicles, antibody neutralization, in vivo feather regeneration assays Developmental biology Medium 24463139
2016 miR-154 directly targets DKK2 (confirmed by dual-luciferase assay) in cardiac fibroblasts. miR-154 inhibits DKK2 expression, leading to increased β-catenin, α-SMA, and collagens I and III, and increased cardiac fibroblast proliferation, migration, and reduced apoptosis. DKK2 siRNA recapitulates these effects; DKK2 overexpression reverses them. Co-transfection of DKK2 overexpression with miR-154 mimics shows mutual functional counteraction. Dual-luciferase assay, miR-154 mimic/inhibitor transfection, DKK2 siRNA, DKK2 overexpression, Western blot, cardiac fibroblast proliferation/migration/apoptosis assays Cell biology international Medium 27542661
2016 miR-221 directly targets DKK2 in esophageal adenocarcinoma cells (confirmed as target gene). Knockdown of miR-221 in 5-FU resistant cells results in reduced proliferation, increased apoptosis, restored chemosensitivity, and inactivation of the Wnt/β-catenin pathway mediated by altered DKK2 expression, as well as slower xenograft tumor growth in nude mice. miR-221 knockdown in 5-FU resistant cell lines, xenograft mouse model, qRT-PCR, immunohistochemistry, miR-221 target validation Annals of surgery Medium 27501171
2016 Increased liver carcinogenesis in Dkk2-deleted (Dkk2-/-) mice treated with DEN/Phenobarbital, and spontaneous atypia in untreated Dkk2-/- livers. Transcriptome analysis reveals a Dkk2-dependent genetic network involving Wnt/β-catenin but also multiple additional oncogenic factors (Pdgf-b, Gdf-15, Hnf4a). Dkk2-/- tumor cells show significant deregulation of stemness genes with enhanced colony-forming properties. Dkk2 knockout mice, DEN/Phenobarbital hepatocarcinogenesis model, whole transcriptome analysis, colony-forming assays Oncotarget Medium 25826080
2016 DKK2 functions in the Wnt/β-catenin signaling pathway as an antagonist of Wnt3a in a dose-dependent manner, inhibiting Wnt3a-induced cell proliferation in HuH-7 hepatocellular carcinoma cells. An HCC-associated DKK2 promoter haplotype (TAGC) shows the lowest promoter activity, and its retention in LOH is associated with reduced DKK2 transcription, contributing to unchecked Wnt/β-catenin signaling in HCC. Wnt3a stimulation with DKK2 dose-response in HuH-7 cells, reporter assay for promoter haplotypes, LOH analysis, sequencing of 47 HCC cases PLoS genetics Medium 27203079
2018 DKK2, secreted by tumor cells (intestinal tumor cells with APC loss or melanoma cells with PTEN loss), acts on cytotoxic lymphocytes via LRP5 to inhibit STAT5 signaling by impeding STAT5 nuclear localization, independently of LRP6 and the Wnt-β-catenin pathway. Genetic or antibody-mediated ablation of DKK2 activates NK cells and CD8+ T cells in tumors, impedes tumor progression, and enhances the effects of PD-1 blockade. DKK2 genetic ablation and antibody blockade in mouse tumor models, LRP5/LRP6 mechanistic dissection, STAT5 nuclear localization assays, NK and CD8+ T cell activation readouts Nature medicine High 29431745
2018 Dkk2 is required for neural crest specification in Xenopus, functioning as a positive regulator of Wnt/β-catenin signaling (not an antagonist in this context). Dkk2 depletion causes loss of neural crest progenitors, rescued by Lrp6 or β-catenin expression. Dkk2 overexpression expands neural crest territory. Mechanistically, Dkk2 mediates neural crest-inducing activity through Lrp6 and β-catenin in a GSK3β-independent manner (unlike Wnt8). Xenopus morpholino knockdown of Dkk2, mRNA rescue with Lrp6 or β-catenin, overexpression experiments, GSK3β inhibitor experiments eLife High 30035713
2018 DKK2 is endogenously expressed in plantar skin and suppresses hair follicle development, specifying hairless skin. Genetic deletion of Dkk2 permits formation of fully functional plantar hair follicles with sebaceous glands, stem cell compartment, and regenerative capacity. In Dkk2-null plantar skin, Wnt/β-catenin signaling activity is initially broadly elevated and gradually becomes patterned, mimicking follicular development. Dkk2 conditional/constitutive knockout mice, Wnt reporter assays, histology, immunofluorescence Cell reports High 30509557
2011 In hepatic stellate cells (HSCs), downregulation of Dkk2 links loss of Sept4 to myofibroblastic transformation. Supplementation of Dkk2 suppresses pro-fibrotic genes (α-smooth muscle actin, collagen genes) and induces anti-fibrotic gene Smad7 in Sept4-/- HSCs, acting via the canonical Wnt pathway as measured by lymphoid enhancer-binding factor/TCF-luciferase reporter assay. Sept4 knockout mice, DNA microarray, qRT-PCR, exogenous Dkk2 supplementation, LEF/TCF-luciferase reporter assay Biochimica et biophysica acta Medium 21763422
2011 Reduced DKK2 expression (caused by DKK2 promoter methylation) is associated with loss of tumour patterning in CYLD-defective tumours (cylindroma to spiradenoma transition). RNA interference-mediated silencing of DKK2 in cylindroma primary cell cultures increases colony formation, cell viability, and anchorage-independent growth. RNAi silencing of DKK2 in primary cylindroma cells, genome-wide transcriptomic analysis, methylation analysis, morphometric analysis The Journal of pathology Medium 21598248
2015 C/EBPβ directly binds and activates the DKK2 promoter (confirmed by ChIP and EMSA), and miR-27a negatively regulates DKK2 expression (confirmed by mutation analysis and miR-27a overexpression/inhibition experiments). A spontaneous promoter variant (DKK2 c.-1130 T>C) changes C/EBPβ binding affinity. miR-27a suppresses CHO cell proliferation by down-regulating DKK2 gene expression. ChIP, EMSA, deletion fragment/mutation analysis, C/EBPβ overexpression and RNAi, miR-27a overexpression and inhibition, RTCA xCELLigence proliferation assay Scientific reports Medium 26656471
2019 DKK2 is an intrinsically disordered protein (IDP) that can be stabilized by fusion to lysyl-tRNA synthetase (LysRS, an RNA-binding protein). The DKK2-LysRS fusion is expressed as a soluble, functional protein; removal of LysRS by site-specific protease cleavage causes insoluble aggregation. Functional competence was confirmed by in vitro Wnt signaling reporter assay, HUVEC tube formation assay, and in vivo Matrigel plug assay. DKK2-LysRS fusion protein expression, protease cleavage, Wnt signaling reporter assay in vitro, HUVEC tube formation assay, Matrigel plug assay in vivo International journal of molecular sciences Medium 31212691
2020 Dkk2 mRNA levels in skeletal muscle (soleus) are increased by hindlimb unloading and decreased by hypergravity in mice. Serum Dkk2 levels are negatively correlated with trabecular bone mineral density and positively correlated with RANKL mRNA in tibia. Shear stress suppresses Dkk2 mRNA in C2C12 cells via cyclooxygenase signaling. Dkk2 suppresses osteogenic gene expression (ALP activity, mineralization) and increases RANKL mRNA in osteoblasts in vitro. Hindlimb unloading mouse model, DNA microarray, serum Dkk2 ELISA, shear stress on C2C12 cells, cyclooxygenase inhibitor treatment, in vitro osteoblast assays International journal of molecular sciences Medium 32268570
2020 NAT10 stabilizes DKK2 mRNA via N4-acetylcytosine (ac4C) modification, leading to high DKK2 protein expression. Secreted DKK2 engages LRP6 receptors to activate AKT-mTOR signaling, inducing cholesterol accumulation in CD8+ T cells and impairing their cytotoxicity. Nat10 ablation or DKK2 neutralization restored CD8+ T cell function and synergized with anti-PD-1 therapy in syngeneic CRC mouse models. Nat10 conditional knockout mice (MC38/CT-26 syngeneic models), single-cell RNA-seq, multi-omics integration, ac4C mRNA modification analysis, DKK2 neutralization, AKT-mTOR signaling assays, cholesterol accumulation measurement in CD8+ T cells The Journal of clinical investigation High 41542770
2022 circCELF1 enhances DKK2 expression in cardiac fibroblasts by two mechanisms: (1) acting as a sponge for miR-636, preventing miR-636 from suppressing DKK2; and (2) upregulating FTO expression, which reduces m6A modification of DKK2 mRNA and inhibits miR-636 binding to DKK2. circCELF1/miR-636/DKK2 pathway regulates CF viability, activation, apoptosis, and migration; DKK2 knockdown promotes myocardial fibrosis, and DKK2 or miR-636 inhibitors reduce MF in AMI mice. RIP and RT-qPCR for m6A modification of DKK2, luciferase assays, CCK-8, Western blot, flow cytometry, Transwell assay in cardiac fibroblasts, AMI mouse model Journal of cardiovascular translational research Medium 35132536
2023 DKK2 in Alzheimer's disease mouse models is upregulated in disease-associated microglia (DAM/ARM), with DAM/ARM Dkk2 microglia preferentially accumulating near β-amyloid plaques. Recombinant DKK2 treatment of rat hippocampal primary neurons blocked WNT7a-induced dendritic spine and synapse formation, indicating an anti-synaptic effect. However, no microglial DKK2 upregulation was detected in postmortem human AD frontal cortex. APP/PS1 and APP AD mouse models, SOD1 ALS mouse model, in situ hybridization for Dkk2 mRNA in microglia, recombinant DKK2 treatment of rat hippocampal neurons, dendritic spine/synapse quantification eNeuro Medium 36599670
2024 miR-182-5p suppresses DKK2 expression, which is the ligand of Kremen1 (Krm1), a negative regulator of the Wnt/β-catenin pathway. In aortic valve calcification, DDX5 recruits METTL3 to promote m6A modification of circHIPK3, which increases stability of Krm1 mRNA; miR-182-5p-mediated DKK2 suppression attenuates Krm1-mediated inhibition of Wnt signaling, promoting aortic valve calcification. m6A modification analysis, RNA stability assays, in vitro osteogenic stimulation of valve interstitial cells, CAVD mouse model, in vivo circHIPK3 overexpression Experimental & molecular medicine Medium 38945954
2025 DKK2 contributes to hippocampal function by suppressing Wnt/PCP signaling. Complete loss of Dkk2 enhances both Wnt/β-catenin and Wnt/PCP (planar cell polarity) signaling in the hippocampus, while haploinsufficiency primarily enhances Wnt/PCP signaling. In hippocampal slices, DKK2 suppresses Wnt3a-mediated Wnt/β-catenin and Wnt5a-mediated Wnt/PCP signaling. Dkk2+/- mice show impaired context discrimination and reduced adult hippocampal neurogenesis; chronic JNK inhibition (JNK is a Wnt/PCP effector) rescues both phenotypes. Dkk2+/- and Dkk2-/- mice, hippocampal slice electrophysiology/signaling assays, DKK2 chronic intracranial administration, JNK inhibitor rescue, behavioral assays, adult neurogenesis quantification Neuropsychopharmacology High 41125965
2017 Human serum albumin (HSA) was identified as a highly effective fusion partner for DKK2 that significantly improves expression, biochemical properties, and pharmacokinetics. Amino acid substitutions in DKK2 designed to decrease heparan sulfate binding further improved PK in rodents. HSA-DKK2 variants retain canonical Wnt inhibitor activity, as shown by their ability to bind to and prevent phosphorylation of the Wnt co-receptor LRP6. HSA-DKK2 fusion protein engineering, LRP6 binding assay, LRP6 phosphorylation assay, pharmacokinetic studies in rodents, heparan sulfate binding mutagenesis Protein engineering, design & selection Medium 28180900
2016 miR-187-5p directly targets the 3'-UTR of DKK2, inhibiting DKK2 expression in Nalm-6 B cells and leading to inappropriate activation of Wnt/β-catenin signaling, increased cell proliferation, and suppression of apoptosis in B-cell ALL. 3'-UTR reporter assay, miR-187-5p overexpression, cell proliferation and apoptosis assays, Wnt/β-catenin pathway readout Oncology research Low 27296949
2016 DKK2 directly interacts with Toxoplasma gondii micronemal protein MIC3, identified by yeast two-hybrid screen and confirmed by additional protein-protein interaction tests. The tandem repeat EGF domains of MIC3 are critical for mediating interactions with DKK2. Yeast two-hybrid screen, protein-protein interaction confirmation assays Parasitology research Low 27053129

Source papers

Stage 0 corpus · 69 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Dkk2 has a role in terminal osteoblast differentiation and mineralized matrix formation. Nature genetics 265 16056226
2006 Dkk2 plays an essential role in the corneal fate of the ocular surface epithelium. Development (Cambridge, England) 124 16672341
2020 The lncRNA-GAS5/miR-221-3p/DKK2 Axis Modulates ABCB1-Mediated Adriamycin Resistance of Breast Cancer via the Wnt/β-Catenin Signaling Pathway. Molecular therapy. Nucleic acids 122 32160712
2018 DKK2 imparts tumor immunity evasion through β-catenin-independent suppression of cytotoxic immune-cell activation. Nature medicine 109 29431745
2008 The canonical Wnt signaling antagonist DKK2 is an essential effector of PITX2 function during normal eye development. Developmental biology 108 18367164
2013 MicroRNA-21 promotes oral cancer invasion via the Wnt/β-catenin pathway by targeting DKK2. Pathology oncology research : POR 103 23999978
2010 Retinoic acid signaling in perioptic mesenchyme represses Wnt signaling via induction of Pitx2 and Dkk2. Developmental biology 85 20122913
2009 Wnt antagonist gene DKK2 is epigenetically silenced and inhibits renal cancer progression through apoptotic and cell cycle pathways. Clinical cancer research : an official journal of the American Association for Cancer Research 78 19755393
2016 miR-221 Mediates Chemoresistance of Esophageal Adenocarcinoma by Direct Targeting of DKK2 Expression. Annals of surgery 69 27501171
2009 The roles of Wnt signaling modulators Dickkopf-1 (Dkk1) and Dickkopf-2 (Dkk2) and cell maturation state in osteogenesis on microstructured titanium surfaces. Biomaterials 57 20004015
2012 DKK2 mediates osteolysis, invasiveness, and metastatic spread in Ewing sarcoma. Cancer research 54 23204234
2012 Epigenetic silencing of DKK2 and Wnt signal pathway components in human ovarian carcinoma. Carcinogenesis 52 22964660
2018 MiR-27a targets DKK2 and SFRP1 to promote reosseointegration in the regenerative treatment of peri-implantitis. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 41 30151888
2013 Distinct roles of DKK1 and DKK2 in tumor angiogenesis. Angiogenesis 41 24091497
2014 Dkk2/Frzb in the dermal papillae regulates feather regeneration. Developmental biology 38 24463139
2010 Dkk1 and Dkk2 regulate epicardial specification during mouse heart development. International journal of cardiology 37 20439124
2009 MSX1 induces the Wnt pathway antagonist genes DKK1, DKK2, DKK3, and SFRP1 in neuroblastoma cells, but does not block Wnt3 and Wnt5A signalling to DVL3. Cancer letters 37 19815336
2022 circCELF1 Inhibits Myocardial Fibrosis by Regulating the Expression of DKK2 Through FTO/m6A and miR-636. Journal of cardiovascular translational research 36 35132536
2018 Dkk2 promotes neural crest specification by activating Wnt/β-catenin signaling in a GSK3β independent manner. eLife 33 30035713
2016 MiR-154 directly suppresses DKK2 to activate Wnt signaling pathway and enhance activation of cardiac fibroblasts. Cell biology international 33 27542661
2013 MicroRNA-222 promotes tumorigenesis via targeting DKK2 and activating the Wnt/β-catenin signaling pathway. FEBS letters 32 23587485
2005 Comparative genomics on DKK2 and DKK4 orthologs. International journal of molecular medicine 31 16077958
2021 Mesenchymal Stem Cell-Derived Extracellular Vesicles Inhibit Osteoporosis via MicroRNA-27a-Induced Inhibition of DKK2-Mediated Wnt/β-Catenin Pathway. Inflammation 30 34676493
2020 miR‑483‑3p promotes the osteogenesis of human osteoblasts by targeting Dikkopf 2 (DKK2) and the Wnt signaling pathway. International journal of molecular medicine 30 32945363
2007 WNT antagonist, DKK2, is a Notch signaling target in intestinal stem cells: augmentation of a negative regulation system for canonical WNT signaling pathway by the Notch-DKK2 signaling loop in primates. International journal of molecular medicine 29 17143565
2018 Regional Control of Hairless versus Hair-Bearing Skin by Dkk2. Cell reports 27 30509557
2020 Roles of Dkk2 in the Linkage from Muscle to Bone during Mechanical Unloading in Mice. International journal of molecular sciences 26 32268570
2016 miR-187-5p Regulates Cell Growth and Apoptosis in Acute Lymphoblastic Leukemia via DKK2. Oncology research 23 27296949
2011 Downregulation of the Wnt antagonist Dkk2 links the loss of Sept4 and myofibroblastic transformation of hepatic stellate cells. Biochimica et biophysica acta 20 21763422
2020 MiR-128 promotes osteogenic differentiation of bone marrow mesenchymal stem cells in rat by targeting DKK2. Bioscience reports 19 31985779
2011 Transition from cylindroma to spiradenoma in CYLD-defective tumours is associated with reduced DKK2 expression. The Journal of pathology 18 21598248
2010 A systematic gene-based screen of chr4q22-q32 identifies association of a novel susceptibility gene, DKK2, with the quantitative trait of alcohol dependence symptom counts. Human molecular genetics 14 20332099
2019 Up-regulation of long non-coding RNA AWPPH inhibits proliferation and invasion of gastric cancer cells via miR-203a/DKK2 axis. Human cell 13 31489578
2024 Spatial Multi-omics Reveals the Role of the Wnt Modulator, Dkk2, in Palatogenesis'. Journal of dental research 12 38910391
2024 Noncoding RNA regulates the expression of Krm1 and Dkk2 to synergistically affect aortic valve lesions. Experimental & molecular medicine 12 38945954
2025 Fusobacterium mortiferum and its metabolite 5-aminovaleric acid promote the development of colorectal cancer in obese individuals through Wnt/β-catenin pathway by DKK2. Gut microbes 11 40340623
2021 Echogenic, Ultrasound-Sensitive Chitosan Nanodroplets for Spatiotemporally Controlled DKK-2 Gene Delivery to Prostate Cancer Cells. International journal of nanomedicine 11 33488078
2020 DKK2 blockage-mediated immunotherapy enhances anti-angiogenic therapy of Kras mutated colorectal cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 11 32559853
2023 ARHGAP9 knockdown promotes lung adenocarcinoma metastasis by activating Wnt/β-catenin signaling pathway via suppressing DKK2. Genomics 10 37454937
2024 Integrated analysis strategy of genome-wide functional gene mining reveals DKK2 gene underlying meat quality in Shaziling synthesized pigs. BMC genomics 9 38178019
2020 Dickkopf-2 (DKK2) as Context Dependent Factor in Patients with Esophageal Adenocarcinoma. Cancers 9 32075129
2016 Identification of host proteins, Spata3 and Dkk2, interacting with Toxoplasma gondii micronemal protein MIC3. Parasitology research 9 27053129
2023 Microglial Expression of the Wnt Signaling Modulator DKK2 Differs between Human Alzheimer's Disease Brains and Mouse Neurodegeneration Models. eNeuro 8 36599670
2021 CircCNIH4 inhibits gastric cancer progression via regulating DKK2 and FRZB expression and Wnt/β-catenin pathway. Journal of biological research (Thessalonike, Greece) 8 34364402
2015 The transcription factor ccaat/enhancer binding protein β (C/EBPβ) and miR-27a regulate the expression of porcine Dickkopf2 (DKK2). Scientific reports 8 26656471
2016 Increased liver carcinogenesis and enrichment of stem cell properties in livers of Dickkopf 2 (Dkk2) deleted mice. Oncotarget 7 25826080
2016 Selective Retention of an Inactive Allele of the DKK2 Tumor Suppressor Gene in Hepatocellular Carcinoma. PLoS genetics 7 27203079
2021 Dickkopf (Dkk)-2 is a beige fat-enriched adipokine to regulate adipogenesis. Biochemical and biophysical research communications 6 33647798
2020 Rational design of peptides for identification of linear epitopes and generation of neutralizing monoclonal antibodies against DKK2 for cancer therapy. Antibody therapeutics 5 32391516
2020 Methylation Assessment of Two DKK2 and DKK4 Genes in Oral Squamous Cell Carcinoma Patients. Iranian journal of public health 4 33346226
2020 Role of Dkk2 in the Muscle/bone Interaction of Androgen-Deficient Mice. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association 4 33352594
2019 Stabilization of Intrinsically Disordered DKK2 Protein by Fusion to RNA-Binding Domain. International journal of molecular sciences 4 31212691
2025 From traditional medicine to targeted therapy: Structure-activity relationship-guided optimization of scorpion toxin DKK2 for pain-associated sodium channel blockade. Journal of ethnopharmacology 3 40615098
2017 Engineering potent long-acting variants of the Wnt inhibitor DKK2. Protein engineering, design & selection : PEDS 3 28180900
2026 Targeting the N-acetyltransferase 10/DKK2 axis enhances CD8+ T cell antitumor activity in colorectal cancer models. The Journal of clinical investigation 2 41542770
2024 Spatial Multiomics Reveal the Role of Wnt Modulator, Dkk2, in Palatogenesis. bioRxiv : the preprint server for biology 2 37292772
2024 DKK2 promotes the progression of oral squamous cell carcinoma through the PI3K/AKT signaling pathway. Aging 2 38795388
2022 Promoter methylation analysis of DKK2 may be a potential biomarker for early detection of cervical cancer. Asian biomedicine : research, reviews and news 2 37551167
2013 Polymorphisms of the bovine DKK2 and their associations with body measurement traits and meat quality traits in Qinchuan cattle. Molecular biology reports 2 24057189
2025 DKK2 contributes to context discrimination and adult hippocampal neurogenesis by suppressing Wnt/PCP signaling. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 1 41125965
2024 Downregulated DKK2 may serve as a molecular mechanism of high-fat diet-induced myocardial injury via Wnt/β-catenin pathway. Life sciences 1 39667489
2023 The effect of 1,25-dihydroxyvitamin D3 on the Wnt signaling pathway in bovine intestinal epithelial cells is mediated by the DKK2 (dickkopf2) Wnt antagonist. The Journal of steroid biochemistry and molecular biology 1 37149202
2021 RNAM EXPRESSION AND DNA METHYLATION OF DKK2 GENE IN COLORECTAL CÂNCER. Arquivos de gastroenterologia 1 33909798
2019 Low Serum Levels of DKK2 Predict Incident Low-Impact Fracture in Older Women. JBMR plus 1 31372588
2013 Association study of DKK2 polymorphisms with alcohol dependence and alcohol-related harm. Alcoholism, clinical and experimental research 1 24117450
2026 Mesenchymal stem cell-derived exosomes promote scalp rejuvenation through type XVII collagen regulation via the miR-21-5p/DKK2/Wnt pathway. Frontiers in cell and developmental biology 0 42099389
2022 Accumulated X-ray irradiation induces miR-187-5p upregulation mediating fibrotic buccal mucosal fibroblasts activities via DKK2. Journal of dental sciences 0 37404627
2021 Retraction statement: MicroRNA-222 promotes tumorigenesis via targeting DKK2 and activating the Wnt/β-catenin signaling pathway. FEBS letters 0 34048597
2021 Generation of a DKK2 homozygous knockout human embryonic stem cell line using the CRISPR/Cas9 system. Stem cell research 0 34856466

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