Affinage

DKK2

Dickkopf-related protein 2 · UniProt Q9UBU2

Length
259 aa
Mass
28.4 kDa
Annotated
2026-04-28
68 papers in source corpus 27 papers cited in narrative 27 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DKK2 is a secreted, context-dependent modulator of Wnt signaling that functions primarily as an antagonist of the canonical Wnt/β-catenin pathway by binding LRP5/6 co-receptors, but can also activate β-catenin signaling through a GSK3β-independent mechanism during neural crest specification (PMID:30035713, PMID:16672341, PMID:28180900). In development, DKK2 suppresses canonical Wnt signaling to specify corneal epithelial fate, maintain plantar skin hairlessness, regulate heart morphogenesis, and promote terminal osteoblast differentiation and mineralization, acting downstream of transcriptional regulators including PITX2 and retinoic acid signaling (PMID:16672341, PMID:30509557, PMID:16056226, PMID:18367164, PMID:20122913). In the adult brain, DKK2 sustains hippocampal neurogenesis by suppressing Wnt/PCP-JNK signaling and blocks WNT7a-induced synaptogenesis (PMID:41125965, PMID:36599670). In the tumor microenvironment, DKK2 mediates immune evasion through two distinct receptor axes: an LRP5-STAT5 pathway that suppresses NK and CD8⁺ T cell cytotoxicity, and an LRP6-AKT-mTOR-cholesterol pathway—driven by NAT10-mediated ac4C stabilization of DKK2 mRNA—that impairs CD8⁺ T cell function in colorectal cancer (PMID:29431745, PMID:41542770).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2005 High

    Establishing that DKK2 is not merely a Wnt antagonist but a positive regulator of terminal osteoblast differentiation resolved the paradox of why a Wnt inhibitor is upregulated during bone formation.

    Evidence Dkk2-null mice exhibited osteopenia with unmineralized osteoids; exogenous Dkk2 drove osteoblast cultures toward terminal differentiation

    PMID:16056226

    Open questions at the time
    • Whether DKK2 acts through canonical Wnt inhibition or a non-canonical pathway in osteoblasts was not resolved
    • The direct receptor interaction mediating osteoblast effects was not identified
  2. 2006 High

    Demonstrating that Dkk2 loss converts corneal epithelium to epidermal fate established DKK2 as a Wnt/β-catenin antagonist essential for corneal identity, revealing a tissue fate-switching function.

    Evidence Dkk2-knockout mice showed complete transformation of corneal epithelium into keratinizing skin-like epithelium

    PMID:16672341

    Open questions at the time
    • Whether DKK2 acts cell-autonomously in corneal progenitors or via paracrine signaling from mesenchyme was unclear
    • The specific Wnt ligands antagonized in this context were not identified
  3. 2008 High

    Placing DKK2 as a direct transcriptional target of PITX2 that suppresses Wnt signaling in periocular mesenchyme defined the RA→PITX2→DKK2 regulatory cascade governing anterior eye development.

    Evidence Pitx2- and Dkk2-deficient mice showed epistatic relationships; Raldh1/3 double-null mice lost both Pitx2 and Dkk2 expression with ectopic Wnt activation

    PMID:18367164 PMID:20122913

    Open questions at the time
    • Whether DKK2 has PITX2-independent roles in other periocular tissues was not tested
    • Direct ChIP for PITX2 on the Dkk2 promoter was not shown
  4. 2009 Medium

    Identifying DKK2 promoter hypermethylation as an epigenetic silencing mechanism in renal cell carcinoma positioned DKK2 as a tumor suppressor whose loss permits unchecked Wnt/β-catenin signaling.

    Evidence Methylation-specific analysis and ChIP for histone marks at the DKK2 locus in RCC; DKK2 re-expression increased apoptosis and reduced proliferation

    PMID:19755393

    Open questions at the time
    • Epigenetic silencing was shown in one tumor type; generalizability across cancers was not established
    • No in vivo tumor suppression experiment was performed
  5. 2010 Medium

    Revealing that Dkk1 and Dkk2 redundantly restrict myocardial proliferation explained why single knockouts lacked cardiac phenotypes and defined a shared Wnt-inhibitory role in heart development.

    Evidence Dkk1/Dkk2 double-null mice displayed myocardial and epicardial hyperplasia with ventricular septal defects

    PMID:20439124

    Open questions at the time
    • The individual contributions of Dkk1 vs Dkk2 could not be separated
    • Downstream effectors in cardiac progenitors were not identified
  6. 2013 Medium

    Showing that DKK2 enhances angiogenesis—opposite to DKK1—established a functional divergence between DKK family members in vascular biology.

    Evidence Adenoviral DKK2 expression and endothelial-specific DKK2 transgenic mice increased tumor vascular density and pericyte coverage in melanoma models

    PMID:24091497

    Open questions at the time
    • The receptor and signaling pathway mediating DKK2's pro-angiogenic effect was not identified
    • Whether the effect is Wnt-dependent or Wnt-independent was not determined
  7. 2015 Medium

    Identifying C/EBPβ as a direct transcriptional activator of DKK2 and miR-27a as a post-transcriptional repressor defined key regulatory nodes controlling DKK2 expression levels.

    Evidence ChIP and EMSA confirmed C/EBPβ binding at four DKK2 promoter sites; miR-27a directly targeted the DKK2 3′UTR

    PMID:26656471

    Open questions at the time
    • Studies were performed on porcine DKK2; conservation in human was assumed but not directly validated
    • Physiological contexts where C/EBPβ regulation is critical were not defined
  8. 2017 Medium

    Biochemical demonstration that DKK2 directly binds LRP6 and prevents its phosphorylation established the molecular mechanism of Wnt co-receptor blockade.

    Evidence Direct LRP6 binding and phosphorylation inhibition assays with purified HSA-DKK2 fusion proteins and heparan sulfate binding mutants

    PMID:28180900

    Open questions at the time
    • Whether LRP5 and LRP6 are engaged with different affinities was not resolved
    • Structural basis of the DKK2-LRP6 interaction was not determined
  9. 2018 High

    Three concurrent discoveries fundamentally expanded DKK2 biology: (1) DKK2 suppresses anti-tumor immunity via LRP5-STAT5 independently of β-catenin; (2) DKK2 activates β-catenin through LRP6 in a GSK3β-independent manner during neural crest specification; (3) DKK2 suppresses plantar hair follicle formation via canonical Wnt inhibition.

    Evidence Tumor immune evasion shown in APC-null CRC and PTEN-null melanoma models with antibody blockade and STAT5 nuclear localization assays; Xenopus morpholino knockdown with epistasis rescue for neural crest; Dkk2 conditional KO mice with Wnt reporter for plantar skin

    PMID:29431745 PMID:30035713 PMID:30509557

    Open questions at the time
    • How the same protein switches between Wnt antagonism and GSK3β-independent β-catenin activation remains mechanistically unresolved
    • The structural determinants distinguishing LRP5-STAT5 vs LRP6-β-catenin engagement are unknown
    • Whether the immune-suppressive LRP5-STAT5 axis operates in non-tumor contexts was not tested
  10. 2023 Medium

    Demonstrating that DKK2 blocks WNT7a-induced synaptogenesis and that microglial Dkk2 is upregulated in disease-associated microglia linked DKK2 to synapse loss in neurodegeneration.

    Evidence Recombinant DKK2 treatment of rat hippocampal neurons reduced spine/synapse density; in situ hybridization showed Dkk2 mRNA accumulation near amyloid plaques in AD mouse models

    PMID:36599670

    Open questions at the time
    • Whether microglial DKK2 causally drives synapse loss in vivo was not tested
    • The receptor mediating DKK2's anti-synaptic effect on neurons was not identified
  11. 2025 High

    Two studies in 2025 revealed new DKK2 mechanisms: suppression of Wnt/PCP-JNK signaling sustains adult hippocampal neurogenesis and context discrimination, while NAT10-mediated ac4C modification of DKK2 mRNA drives immune evasion through LRP6-AKT-mTOR-cholesterol signaling in CD8⁺ T cells.

    Evidence Dkk2 haploinsufficient mice with JNK inhibitor rescue for hippocampal neurogenesis; intestinal epithelial Nat10 conditional KO mice with ac4C assays, scRNA-seq, cholesterol measurements, and anti-PD-1 combination therapy in CRC syngeneic models

    PMID:41125965 PMID:41542770

    Open questions at the time
    • Whether the PCP-JNK suppression in hippocampus involves the same LRP receptor as canonical antagonism is unclear
    • How DKK2 engages both LRP5 (STAT5 axis) and LRP6 (AKT-mTOR axis) for immune suppression in different tumor contexts needs reconciliation
    • Whether ac4C modification of DKK2 mRNA occurs outside colorectal cancer is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The central unresolved question is how DKK2 switches between Wnt antagonism (canonical and PCP) and Wnt/β-catenin activation depending on cellular context, and what structural or co-receptor features determine this switch.
  • No structural model of DKK2 in complex with LRP5 or LRP6 exists
  • The molecular basis for context-dependent switching between agonist and antagonist modes is unknown
  • Whether DKK2's immune-suppressive functions are therapeutically targetable without disrupting developmental roles requires investigation

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 6 GO:0048018 receptor ligand activity 3
Localization
GO:0005576 extracellular region 6
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 2
Partners
KRM1LRP5LRP6NAT10PITX2STAT5

Evidence

Reading pass · 27 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; Dkk2-null mice show osteopenia with increased osteoids and poorly mineralized osteoblasts in culture; canonical Wnts upregulate Dkk2 expression in osteoblasts, and Dkk2 expression after peak Wnt7b induces a phenotype resembling terminal osteoblast differentiation leading to mineralization Dkk2 knockout mice, osteoblast differentiation cultures, exogenous Dkk2 overexpression, osteogenic marker expression assays Nature genetics High 16056226
2006 Dkk2-mediated repression of the Wnt/β-catenin pathway via interaction with LRP5/6 is essential to promote differentiation of corneal epithelial progenitor cells into a non-keratinizing stratified epithelium; loss of Dkk2 causes complete transformation of corneal epithelium into a keratinizing epithelium with epidermal identity Dkk2 knockout mice, immunohistochemistry, histological analysis of ocular surface epithelium Development (Cambridge, England) High 16672341
2008 Dkk2 is an essential downstream transcriptional target of the PITX2 homeodomain transcription factor in neural crest; PITX2 activates Dkk2 to locally suppress canonical Wnt signaling during eye development; loss of DKK2 results in ectopic canonical Wnt signaling activation in central ocular surface ectoderm and underlying mesenchyme, ectopic peripheral fates, and ectopic blood vessels in periocular mesenchyme Pitx2- and Dkk2-deficient mice, epistasis analysis, immunohistochemistry, analysis of Wnt signaling reporters Developmental biology High 18367164
2010 Retinoic acid (RA) signaling induces Pitx2 expression via a DR5 RA response element upstream of Pitx2 (binding all three RA receptors, shown by ChIP and gel mobility shift), which in turn induces Dkk2 in the perioptic mesenchyme to repress canonical Wnt/β-catenin signaling during eye development; loss of RA synthesis (Raldh1/Raldh3 double null) downregulates both Pitx2 and Dkk2 and upregulates Axin2 and Wnt5a Raldh1/Raldh3 double-null mice, chromatin immunoprecipitation (ChIP), gel mobility shift assay (EMSA), Axin2 reporter for Wnt readout Developmental biology High 20122913
2009 On microstructured titanium surfaces, DKK2 acts in an autocrine manner to promote late-stage osteoblast differentiation; silencing Dkk2 reduces the stimulatory effects of microstructured Ti surfaces on osteoblast differentiation, and exogenous Dkk2 (but not Dkk1) restores these effects, suggesting a role for Dkk2 and Wnt/Ca2+-dependent (non-canonical) signaling in late-stage osteoblast differentiation Stable Dkk2-silenced MG63 cell lines, exogenous rhDkk2 treatment, blocking antibodies to Dkk2, osteoblast differentiation assays on titanium surfaces Biomaterials Medium 20004015
2010 Dkk1 and Dkk2 redundantly inhibit Wnt signaling to regulate early myocardial proliferation during heart development; Dkk1/Dkk2 double-null mice show myocardial and epicardial hyperplasia and ventricular septal defects, with broadened proepicardial specification (Connexin 43 expression), while single knockouts show no cardiac phenotype Dkk1 and Dkk2 single and double-null mouse crosses, histological and immunohistochemical analysis of hearts at multiple developmental stages International journal of cardiology Medium 20439124
2018 DKK2, secreted by tumor cells (APC-loss CRC and PTEN-loss melanoma), acts on cytotoxic lymphocytes via its receptor 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 and enhances PD-1 blockade effects Genetic mouse models (APC-null, PTEN-null), antibody-mediated DKK2 blockade, STAT5 nuclear localization assays, co-immunoprecipitation for LRP5/LRP6, tumor immune infiltrate analysis Nature medicine High 29431745
2018 Dkk2 promotes neural crest specification as a positive regulator of Wnt/β-catenin signaling through Lrp6 and β-catenin, but in a GSK3β-independent manner distinct from Wnt8 transduction; Dkk2 depletion in Xenopus embryos causes loss of neural crest progenitors rescued by Lrp6 or β-catenin expression Xenopus morpholino knockdown, mRNA overexpression, epistasis rescue experiments, dominant-negative and constitutively active constructs eLife High 30035713
2012 DKK2 mediates invasion and metastatic spread in Ewing sarcoma; DKK2 knockdown reduces malignant cell outgrowth and invasion in vitro and in vivo; DKK2 regulates MMP1 (a potential DKK effector for invasion), CXCR4, PTHrP, RUNX2, TGFβ1, HIF1α, JAG1, IL6, and VEGF expression; DKK2 suppression simultaneously increases neuronal differentiation potential while decreasing chondrogenic and osteogenic differentiation RNA interference knockdown in Ewing sarcoma cells, orthotopic xenograft mouse model, Matrigel invasion assay, gene expression analysis Cancer research Medium 23204234
2013 DKK1 inhibits while DKK2 enhances angiogenesis in tumor contexts; adenoviral DKK2 expression increased tumor growth, vascular density, perfusion, and pericyte coverage in B16F10 melanoma models; endothelial-specific DKK2 transgenic mice showed increased tumor vascular density and pericyte coverage compared to DKK1 transgenic mice Adenovirus-mediated DKK1/DKK2 expression in melanoma-bearing mice, endothelial-specific transgenic mice, in vivo oxygen-induced retinopathy model, vascular density and pericyte coverage analysis Angiogenesis Medium 24091497
2011 Dkk2 suppresses myofibroblastic transformation of hepatic stellate cells (HSCs) by inhibiting canonical Wnt signaling; Sept4 loss reduces Dkk2 expression in HSCs; exogenous Dkk2 supplementation suppresses pro-fibrotic genes (α-SMA, collagen genes) and induces anti-fibrotic Smad7 in Sept4−/− HSCs; Dkk2 inhibits canonical Wnt pathway as measured by LEF/TCF-luciferase reporter DNA microarray comparison of Sept4+/+ vs Sept4−/− HSCs, LEF/TCF-luciferase reporter assay, exogenous Dkk2 protein supplementation, qRT-PCR Biochimica et biophysica acta Medium 21763422
2009 DKK2 is epigenetically silenced by promoter methylation in renal cell carcinoma; restoration of DKK2 expression decreases viable cell number, increases apoptosis, and reduces S/G2-M phase cells; DKK2 overexpression decreases Bcl2 and cyclin D1 expression; silencing is reversed by 5-Aza-2'-deoxycytidine treatment with accompanying changes in histone modifications (decreased acetyl H3/H4 and dimethylated H3K4; increased dimethylated H3K9) at the DKK2 locus Methylation assay, chromatin immunoprecipitation (ChIP) for histone modifications, stable DKK2-transfected cells, apoptosis assay, cell cycle analysis, colony formation assay Clinical cancer research Medium 19755393
2018 DKK2 suppresses plantar hair follicle development to permit formation of hairless skin; genetic deletion of Dkk2 in plantar skin permits formation of fully functional hair follicles with sebaceous glands and stem cell compartment; in the absence of Dkk2, Wnt/β-catenin signaling activity is initially broadly elevated in embryonic plantar skin and gradually becomes patterned Dkk2 conditional knockout mice, in situ hybridization, immunofluorescence, Wnt/β-catenin reporter analysis, follicle functional assessment Cell reports High 30509557
2016 In cardiac fibroblasts, miR-154 directly binds the DKK2 3'UTR (confirmed by dual-luciferase assay) to suppress DKK2 expression, leading to upregulation of β-catenin and activation of the canonical Wnt signaling pathway, resulting in increased proliferation, migration, and collagen production; DKK2 overexpression reverses these effects Dual-luciferase reporter assay, miR-154 mimic/inhibitor transfection, DKK2 siRNA, DKK2 overexpression vector, Western blot for β-catenin/α-SMA/collagens Cell biology international Medium 27542661
2019 DKK2 protein is an intrinsically disordered protein (IDP) that can be stabilized by fusion to the RNA-binding protein lysyl-tRNA synthetase (LysRS); the fused DKK2 protein retains functional competence as measured by in vitro Wnt signaling reporter assay, HUVEC tube formation, and in vivo Matrigel plug assay; removal of LysRS causes insoluble aggregation, confirming RBP chaperone activity Protein fusion expression in bacterial host, Wnt signaling reporter assay, HUVEC tube formation assay, in vivo Matrigel plug assay, solubility assessment International journal of molecular sciences Medium 31212691
2017 DKK2 binds to and prevents phosphorylation of the Wnt co-receptor LRP6; human serum albumin (HSA) fusion significantly improves expression, biochemical properties, and pharmacokinetics of DKK2; substitution of residues that decrease heparan sulfate binding further improves PK; HSA-DKK2 variants remain monomeric and thermally stable LRP6 binding assay, LRP6 phosphorylation assay, pharmacokinetic studies in rodents, biophysical characterization (monomer, thermal stability), mutagenesis of heparan sulfate binding residues Protein engineering, design & selection : PEDS Medium 28180900
2020 Antibody-mediated neutralization of DKK2 abolishes DKK2's suppression of Wnt signaling in vitro and inhibits tumor growth in vivo; two linear epitopes (residues 34-42: KLNSIKSSL and residues 240-248: KVWKDATYS) of DKK2 were identified as immunogenic and capable of generating neutralizing monoclonal antibodies Rational peptide design, mouse immunization, Wnt signaling reporter assay in vitro, in vivo tumor growth inhibition assay with monoclonal antibodies Antibody therapeutics Medium 32391516
2016 DKK2 is silenced by promoter hypermethylation in cylindroma tumors; RNA interference-mediated silencing of DKK2 in cylindroma primary cell cultures increases colony formation, cell viability, and anchorage-independent growth; reduced DKK2 is associated with loss of tumour patterning and Wnt/β-catenin pathway overexpression Genome-wide transcriptomic analysis, promoter methylation assay, RNAi knockdown in primary cylindroma cells, colony formation and anchorage-independent growth assays The Journal of pathology Medium 21598248
2016 DKK2 acts as an antagonist of Wnt3a in a dose-dependent manner in HuH-7 hepatocellular carcinoma cells; selective retention of a transcriptionally inactive DKK2 allele (TAGC haplotype with lowest promoter activity) in tumors reduces DKK2 expression, allowing unchecked Wnt/β-catenin signaling to promote HCC oncogenesis Reporter assay for haplotype promoter activity, haplotype analysis of 47 HCC cases vs 88 controls, LOH analysis, DKK2 functional assay (Wnt3a antagonism and cell proliferation inhibition) PLoS genetics Medium 27203079
2020 Mechanical unloading (hindlimb unloading) increases Dkk2 mRNA and serum levels in mouse soleus muscle, while hypergravity decreases them; shear stress suppresses Dkk2 mRNA in C2C12 muscle cells via a cyclooxygenase-dependent mechanism; elevated Dkk2 suppresses osteogenic gene expression, alkaline phosphatase activity, mineralization, and increases RANKL in mouse osteoblasts, suggesting Dkk2 is a muscle-secreted factor (myokine) linking mechanical unloading to bone loss Hindlimb unloading mouse model, hypergravity mouse model, DNA microarray, serum Dkk2 ELISA, in vitro shear stress with cyclooxygenase inhibitors, Dkk2 treatment of primary osteoblasts International journal of molecular sciences Medium 32268570
2021 DKK2 is a beige fat-enriched adipokine that inhibits adipogenesis; Dkk2 treatment inhibits adipogenesis in 3T3-L1 pre-adipocytes, C3H10T1/2 mesenchymal stem cells, and primary bone marrow mesenchymal stromal cells; activation of PPARγ with rosiglitazone largely rescues Dkk2-mediated inhibition of adipogenesis; adenoviral Dkk2 overexpression in liver shows minimal effect on whole-body metabolism, suggesting paracrine rather than endocrine action Dkk2 protein treatment of pre-adipocyte cell lines and primary cells, adenoviral overexpression, rosiglitazone rescue, adipogenesis assays Biochemical and biophysical research communications Medium 33647798
2023 Recombinant DKK2 treatment of rat hippocampal primary neurons blocks WNT7a-induced dendritic spine and synapse formation, indicating an anti-synaptic effect; microglial Dkk2 mRNA is upregulated in disease-associated microglia (DAM/ARM) in APP/PS1 and APP Alzheimer's disease mouse models and SOD1 ALS mouse models in a disease-stage-dependent manner, accumulating near β-amyloid plaques Recombinant DKK2 treatment of primary rat hippocampal neurons, dendritic spine/synapse counting, in situ hybridization for Dkk2 mRNA in mouse AD models, immunohistochemistry eNeuro Medium 36599670
2025 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 inhibition (Remodelin) or DKK2 neutralization restores CD8+ T cell function and synergizes with anti-PD-1 therapy in CRC models Syngeneic mouse models (MC38/CT-26), intestinal epithelial-specific Nat10 conditional KO mice, patient-derived organoids, single-cell RNA-seq, multi-omics integration, ac4C modification assay, LRP6 receptor assay, AKT-mTOR signaling assay, cholesterol accumulation measurement, anti-PD-1 combination therapy The Journal of clinical investigation High 41542770
2025 DKK2 contributes to adult hippocampal neurogenesis (AHN) and context discrimination by suppressing Wnt/PCP (planar cell polarity) signaling via JNK; complete loss of Dkk2 enhances both Wnt/β-catenin and Wnt/PCP signaling, while haploinsufficiency primarily enhances Wnt/PCP signaling; in hippocampal slices, DKK2 suppresses both Wnt3a-induced Wnt/β-catenin and Wnt5a-induced Wnt/PCP signaling; chronic JNK inhibition rescues impaired AHN and context discrimination in Dkk2+/− mice Dkk2+/− and Dkk2−/− mice, chronic intracranial DKK2 administration, hippocampal slice assays, Wnt pathway signaling assays (β-catenin and PCP), JNK inhibitor rescue, behavioral context discrimination test, adult hippocampal neurogenesis quantification Neuropsychopharmacology High 41125965
2024 miR-182-5p suppresses DKK2 expression (the ligand for Kremen1/Krm1), and m6A-modified circHIPK3 (promoted by DDX5-recruited METTL3) stabilizes Krm1 mRNA; together, the Krm1-Dkk2 axis inhibits Wnt/β-catenin signaling in aortic valves and noncoding RNAs are upstream regulators of this axis during aortic valve calcification Sequencing of normal vs calcified aortic valves, CAVD mouse model, in vitro osteogenic assays of aortic valve interstitial cells, m6A modification assay, mRNA stability assay for Krm1, miR-182-5p target validation for DKK2 Experimental & molecular medicine Medium 38945954
2015 C/EBPβ transcription factor directly binds to four sites within the DKK2 core promoter to activate DKK2 transcription; a spontaneous T>C mutation at DKK2 c.-1130 alters C/EBPβ binding ability; miR-27a negatively regulates DKK2 by binding its 3'UTR; these regulations were confirmed in porcine DKK2 Deletion/mutation analysis of DKK2 promoter, chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), C/EBPβ overexpression and RNAi, miR-27a overexpression and inhibition with mutation analysis Scientific reports Medium 26656471
2025 Dkk2 is required for digit joint specification; genetic removal of Dkk2 in 5'Hoxd mutant mice prevented joint rescue by stabilized β-catenin (βcatCA), demonstrating that Dkk2 acts downstream of Wnt/β-catenin to reduce digit tip pSmad1/5 levels and maintain mesenchymal plasticity for joint progenitor fate commitment 5'Hoxd conditional KO mice combined with Dkk2 genetic removal, βcatCA expression in interdigit mesenchyme, pSmad1/5 immunostaining, limb bud culture with Gsk3β antagonists bioRxivpreprint Medium bio_10.1101_2025.07.17.665381

Source papers

Stage 0 corpus · 68 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 120 32160712
2018 DKK2 imparts tumor immunity evasion through β-catenin-independent suppression of cytotoxic immune-cell activation. Nature medicine 108 29431745
2008 The canonical Wnt signaling antagonist DKK2 is an essential effector of PITX2 function during normal eye development. Developmental biology 107 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
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
2010 Dkk1 and Dkk2 regulate epicardial specification during mouse heart development. International journal of cardiology 36 20439124
2022 circCELF1 Inhibits Myocardial Fibrosis by Regulating the Expression of DKK2 Through FTO/m6A and miR-636. Journal of cardiovascular translational research 35 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
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
2021 Mesenchymal Stem Cell-Derived Extracellular Vesicles Inhibit Osteoporosis via MicroRNA-27a-Induced Inhibition of DKK2-Mediated Wnt/β-Catenin Pathway. Inflammation 29 34676493
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
2020 Roles of Dkk2 in the Linkage from Muscle to Bone during Mechanical Unloading in Mice. International journal of molecular sciences 26 32268570
2018 Regional Control of Hairless versus Hair-Bearing Skin by Dkk2. Cell reports 26 30509557
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 17 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
2021 Echogenic, Ultrasound-Sensitive Chitosan Nanodroplets for Spatiotemporally Controlled DKK-2 Gene Delivery to Prostate Cancer Cells. International journal of nanomedicine 11 33488078
2024 Noncoding RNA regulates the expression of Krm1 and Dkk2 to synergistically affect aortic valve lesions. Experimental & molecular medicine 10 38945954
2023 ARHGAP9 knockdown promotes lung adenocarcinoma metastasis by activating Wnt/β-catenin signaling pathway via suppressing DKK2. Genomics 10 37454937
2020 DKK2 blockage-mediated immunotherapy enhances anti-angiogenic therapy of Kras mutated colorectal cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 10 32559853
2024 Integrated analysis strategy of genome-wide functional gene mining reveals DKK2 gene underlying meat quality in Shaziling synthesized pigs. BMC genomics 9 38178019
2024 Spatial Multi-omics Reveals the Role of the Wnt Modulator, Dkk2, in Palatogenesis'. Journal of dental research 9 38910391
2020 Dickkopf-2 (DKK2) as Context Dependent Factor in Patients with Esophageal Adenocarcinoma. Cancers 9 32075129
2023 Microglial Expression of the Wnt Signaling Modulator DKK2 Differs between Human Alzheimer's Disease Brains and Mouse Neurodegeneration Models. eNeuro 8 36599670
2016 Identification of host proteins, Spata3 and Dkk2, interacting with Toxoplasma gondii micronemal protein MIC3. Parasitology research 8 27053129
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
2021 CircCNIH4 inhibits gastric cancer progression via regulating DKK2 and FRZB expression and Wnt/β-catenin pathway. Journal of biological research (Thessalonike, Greece) 7 34364402
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
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 6 40340623
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
2017 Engineering potent long-acting variants of the Wnt inhibitor DKK2. Protein engineering, design & selection : PEDS 3 28180900
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 2 40615098
2024 DKK2 promotes the progression of oral squamous cell carcinoma through the PI3K/AKT signaling pathway. Aging 2 38795388
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
2024 Spatial Multiomics Reveal the Role of Wnt Modulator, Dkk2, in Palatogenesis. bioRxiv : the preprint server for biology 1 37292772
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
2022 Promoter methylation analysis of DKK2 may be a potential biomarker for early detection of cervical cancer. Asian biomedicine : research, reviews and news 1 37551167
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 Targeting the N-acetyltransferase 10/DKK2 axis enhances CD8+ T cell antitumor activity in colorectal cancer models. The Journal of clinical investigation 0 41542770
2025 DKK2 contributes to context discrimination and adult hippocampal neurogenesis by suppressing Wnt/PCP signaling. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 0 41125965
2024 Downregulated DKK2 may serve as a molecular mechanism of high-fat diet-induced myocardial injury via Wnt/β-catenin pathway. Life sciences 0 39667489
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