{"gene":"DKK2","run_date":"2026-04-28T17:46:02","timeline":{"discoveries":[{"year":2005,"finding":"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","method":"Dkk2 knockout mice, osteoblast differentiation cultures, exogenous Dkk2 overexpression, osteogenic marker expression assays","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KO mice, in vitro cultures, rescue experiments), replicated across several assays","pmids":["16056226"],"is_preprint":false},{"year":2006,"finding":"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","method":"Dkk2 knockout mice, immunohistochemistry, histological analysis of ocular surface epithelium","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — clean KO with specific phenotypic readout, pathway placement via LRP5/6 interaction","pmids":["16672341"],"is_preprint":false},{"year":2008,"finding":"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","method":"Pitx2- and Dkk2-deficient mice, epistasis analysis, immunohistochemistry, analysis of Wnt signaling reporters","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with two KO models, multiple phenotypic readouts, pathway placement","pmids":["18367164"],"is_preprint":false},{"year":2010,"finding":"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","method":"Raldh1/Raldh3 double-null mice, chromatin immunoprecipitation (ChIP), gel mobility shift assay (EMSA), Axin2 reporter for Wnt readout","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP and EMSA establish direct RA receptor binding to Pitx2 promoter, combined with KO mouse epistasis","pmids":["20122913"],"is_preprint":false},{"year":2009,"finding":"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","method":"Stable Dkk2-silenced MG63 cell lines, exogenous rhDkk2 treatment, blocking antibodies to Dkk2, osteoblast differentiation assays on titanium surfaces","journal":"Biomaterials","confidence":"Medium","confidence_rationale":"Tier 2 — multiple cell types and methods, single lab","pmids":["20004015"],"is_preprint":false},{"year":2010,"finding":"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","method":"Dkk1 and Dkk2 single and double-null mouse crosses, histological and immunohistochemical analysis of hearts at multiple developmental stages","journal":"International journal of cardiology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with double KO, but single lab","pmids":["20439124"],"is_preprint":false},{"year":2018,"finding":"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","method":"Genetic mouse models (APC-null, PTEN-null), antibody-mediated DKK2 blockade, STAT5 nuclear localization assays, co-immunoprecipitation for LRP5/LRP6, tumor immune infiltrate analysis","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (genetic models, antibody blockade, mechanistic STAT5 assays, receptor specificity), strong evidence from a high-impact journal","pmids":["29431745"],"is_preprint":false},{"year":2018,"finding":"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","method":"Xenopus morpholino knockdown, mRNA overexpression, epistasis rescue experiments, dominant-negative and constitutively active constructs","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in Xenopus with multiple rescue experiments demonstrating pathway position, ortholog with consistent mammalian function","pmids":["30035713"],"is_preprint":false},{"year":2012,"finding":"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","method":"RNA interference knockdown in Ewing sarcoma cells, orthotopic xenograft mouse model, Matrigel invasion assay, gene expression analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo KD with specific phenotypic readout, single lab","pmids":["23204234"],"is_preprint":false},{"year":2013,"finding":"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","method":"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","journal":"Angiogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo mouse models with specific vascular phenotypic readouts, single lab","pmids":["24091497"],"is_preprint":false},{"year":2011,"finding":"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","method":"DNA microarray comparison of Sept4+/+ vs Sept4−/− HSCs, LEF/TCF-luciferase reporter assay, exogenous Dkk2 protein supplementation, qRT-PCR","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 — reporter assay for pathway placement, rescue with exogenous protein, single lab","pmids":["21763422"],"is_preprint":false},{"year":2009,"finding":"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","method":"Methylation assay, chromatin immunoprecipitation (ChIP) for histone modifications, stable DKK2-transfected cells, apoptosis assay, cell cycle analysis, colony formation assay","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP for epigenetic mechanism plus functional overexpression studies, single lab","pmids":["19755393"],"is_preprint":false},{"year":2018,"finding":"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","method":"Dkk2 conditional knockout mice, in situ hybridization, immunofluorescence, Wnt/β-catenin reporter analysis, follicle functional assessment","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — clean conditional KO with specific spatial phenotype, Wnt reporter, strong evidence for mechanistic role","pmids":["30509557"],"is_preprint":false},{"year":2016,"finding":"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","method":"Dual-luciferase reporter assay, miR-154 mimic/inhibitor transfection, DKK2 siRNA, DKK2 overexpression vector, Western blot for β-catenin/α-SMA/collagens","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 3 — luciferase assay for direct targeting, functional rescue, single lab","pmids":["27542661"],"is_preprint":false},{"year":2019,"finding":"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","method":"Protein fusion expression in bacterial host, Wnt signaling reporter assay, HUVEC tube formation assay, in vivo Matrigel plug assay, solubility assessment","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1-2 — in vitro reconstitution plus in vivo assay, demonstrates intrinsic disorder and functional activity, single lab","pmids":["31212691"],"is_preprint":false},{"year":2017,"finding":"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","method":"LRP6 binding assay, LRP6 phosphorylation assay, pharmacokinetic studies in rodents, biophysical characterization (monomer, thermal stability), mutagenesis of heparan sulfate binding residues","journal":"Protein engineering, design & selection : PEDS","confidence":"Medium","confidence_rationale":"Tier 1-2 — direct binding assay for LRP6 with mutagenesis, in vivo PK studies, single lab","pmids":["28180900"],"is_preprint":false},{"year":2020,"finding":"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","method":"Rational peptide design, mouse immunization, Wnt signaling reporter assay in vitro, in vivo tumor growth inhibition assay with monoclonal antibodies","journal":"Antibody therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 — functional neutralization confirmed by Wnt reporter and in vivo assay, single lab","pmids":["32391516"],"is_preprint":false},{"year":2016,"finding":"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","method":"Genome-wide transcriptomic analysis, promoter methylation assay, RNAi knockdown in primary cylindroma cells, colony formation and anchorage-independent growth assays","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional KD in primary cells with multiple readouts, methylation mechanism established, single lab","pmids":["21598248"],"is_preprint":false},{"year":2016,"finding":"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","method":"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)","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 — reporter assay establishing functional difference, in vitro Wnt antagonism assay, supported by clinical genotyping","pmids":["27203079"],"is_preprint":false},{"year":2020,"finding":"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","method":"Hindlimb unloading mouse model, hypergravity mouse model, DNA microarray, serum Dkk2 ELISA, in vitro shear stress with cyclooxygenase inhibitors, Dkk2 treatment of primary osteoblasts","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — multiple in vivo and in vitro methods, single lab, mechanistic pathway placement","pmids":["32268570"],"is_preprint":false},{"year":2021,"finding":"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","method":"Dkk2 protein treatment of pre-adipocyte cell lines and primary cells, adenoviral overexpression, rosiglitazone rescue, adipogenesis assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — multiple cell types tested, paracrine vs endocrine distinction established, single lab","pmids":["33647798"],"is_preprint":false},{"year":2023,"finding":"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","method":"Recombinant DKK2 treatment of primary rat hippocampal neurons, dendritic spine/synapse counting, in situ hybridization for Dkk2 mRNA in mouse AD models, immunohistochemistry","journal":"eNeuro","confidence":"Medium","confidence_rationale":"Tier 2 — direct recombinant protein treatment with quantified synaptic readout, in vivo disease model localization","pmids":["36599670"],"is_preprint":false},{"year":2025,"finding":"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","method":"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","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (KO mice, scRNA-seq, biochemical ac4C modification, receptor signaling, metabolic readout), strong mechanistic chain","pmids":["41542770"],"is_preprint":false},{"year":2025,"finding":"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","method":"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","journal":"Neuropsychopharmacology","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic models, pathway-specific readouts, pharmacological rescue, single lab with multiple orthogonal methods","pmids":["41125965"],"is_preprint":false},{"year":2024,"finding":"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","method":"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","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 — in vivo and in vitro models, m6A modification mechanistic assays, single lab","pmids":["38945954"],"is_preprint":false},{"year":2015,"finding":"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","method":"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","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1-2 — ChIP and EMSA for direct TF binding, multiple orthogonal promoter analysis methods, single lab (porcine ortholog)","pmids":["26656471"],"is_preprint":false},{"year":2025,"finding":"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","method":"5'Hoxd conditional KO mice combined with Dkk2 genetic removal, βcatCA expression in interdigit mesenchyme, pSmad1/5 immunostaining, limb bud culture with Gsk3β antagonists","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis in mouse with multiple models, preprint not yet peer reviewed","pmids":["bio_10.1101_2025.07.17.665381"],"is_preprint":true}],"current_model":"DKK2 is a secreted Wnt-pathway modulator that primarily antagonizes canonical Wnt/β-catenin signaling by binding to LRP5/6 co-receptors, but can also activate β-catenin in a GSK3β-independent manner (e.g., during neural crest specification); it plays context-dependent roles in terminal osteoblast differentiation/mineralization, corneal fate specification, plantar skin hairlessness, adult hippocampal neurogenesis (by suppressing Wnt/PCP-JNK signaling), and tumor immune evasion through a distinct LRP5-STAT5 axis independent of β-catenin, and its mRNA is stabilized by NAT10-mediated ac4C modification in colorectal cancer, linking it to CD8+ T cell dysfunction via LRP6-AKT-mTOR-cholesterol signaling."},"narrative":{"teleology":[{"year":2005,"claim":"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","pmids":["16056226"],"confidence":"High","gaps":["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"]},{"year":2006,"claim":"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","pmids":["16672341"],"confidence":"High","gaps":["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"]},{"year":2008,"claim":"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","pmids":["18367164","20122913"],"confidence":"High","gaps":["Whether DKK2 has PITX2-independent roles in other periocular tissues was not tested","Direct ChIP for PITX2 on the Dkk2 promoter was not shown"]},{"year":2009,"claim":"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","pmids":["19755393"],"confidence":"Medium","gaps":["Epigenetic silencing was shown in one tumor type; generalizability across cancers was not established","No in vivo tumor suppression experiment was performed"]},{"year":2010,"claim":"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","pmids":["20439124"],"confidence":"Medium","gaps":["The individual contributions of Dkk1 vs Dkk2 could not be separated","Downstream effectors in cardiac progenitors were not identified"]},{"year":2013,"claim":"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","pmids":["24091497"],"confidence":"Medium","gaps":["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"]},{"year":2015,"claim":"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","pmids":["26656471"],"confidence":"Medium","gaps":["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"]},{"year":2017,"claim":"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","pmids":["28180900"],"confidence":"Medium","gaps":["Whether LRP5 and LRP6 are engaged with different affinities was not resolved","Structural basis of the DKK2-LRP6 interaction was not determined"]},{"year":2018,"claim":"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","pmids":["29431745","30035713","30509557"],"confidence":"High","gaps":["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"]},{"year":2023,"claim":"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","pmids":["36599670"],"confidence":"Medium","gaps":["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"]},{"year":2025,"claim":"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","pmids":["41125965","41542770"],"confidence":"High","gaps":["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"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"High","gaps":["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":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,6,7,12,23]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[6,15,22]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,6,14,19,20,22]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,6,7,12,15,22,23]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,2,5,12]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,22]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,8,11,22]}],"complexes":[],"partners":["LRP5","LRP6","PITX2","KRM1","STAT5","NAT10"],"other_free_text":[]},"mechanistic_narrative":"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]."},"prefetch_data":{"uniprot":{"accession":"Q9UBU2","full_name":"Dickkopf-related protein 2","aliases":[],"length_aa":259,"mass_kda":28.4,"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 (By similarity)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q9UBU2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DKK2","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DKK2","total_profiled":1310},"omim":[{"mim_id":"619857","title":"SPERMATOGENESIS-ASSOCIATED PROTEIN 3; SPATA3","url":"https://www.omim.org/entry/619857"},{"mim_id":"615372","title":"MICRO RNA 1260B; MIR1260B","url":"https://www.omim.org/entry/615372"},{"mim_id":"605417","title":"DICKKOPF WNT SIGNALING PATHWAY INHIBITOR 4; DKK4","url":"https://www.omim.org/entry/605417"},{"mim_id":"605416","title":"DICKKOPF WNT SIGNALING PATHWAY INHIBITOR 3; DKK3","url":"https://www.omim.org/entry/605416"},{"mim_id":"605415","title":"DICKKOPF WNT SIGNALING PATHWAY INHIBITOR 2; DKK2","url":"https://www.omim.org/entry/605415"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Golgi apparatus","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"cervix","ntpm":14.2}],"url":"https://www.proteinatlas.org/search/DKK2"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9UBU2","domains":[{"cath_id":"-","chopping":"82-134","consensus_level":"high","plddt":89.3621,"start":82,"end":134},{"cath_id":"2.10.80.10","chopping":"182-259","consensus_level":"high","plddt":85.8635,"start":182,"end":259}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBU2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBU2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBU2-F1-predicted_aligned_error_v6.png","plddt_mean":70.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DKK2","jax_strain_url":"https://www.jax.org/strain/search?query=DKK2"},"sequence":{"accession":"Q9UBU2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UBU2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UBU2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBU2"}},"corpus_meta":[{"pmid":"16056226","id":"PMC_16056226","title":"Dkk2 has a role in terminal osteoblast differentiation and mineralized matrix formation.","date":"2005","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16056226","citation_count":265,"is_preprint":false},{"pmid":"16672341","id":"PMC_16672341","title":"Dkk2 plays an essential role in the corneal fate of the ocular surface epithelium.","date":"2006","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/16672341","citation_count":124,"is_preprint":false},{"pmid":"32160712","id":"PMC_32160712","title":"The lncRNA-GAS5/miR-221-3p/DKK2 Axis Modulates ABCB1-Mediated Adriamycin Resistance of Breast Cancer via the Wnt/β-Catenin Signaling Pathway.","date":"2020","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/32160712","citation_count":120,"is_preprint":false},{"pmid":"29431745","id":"PMC_29431745","title":"DKK2 imparts tumor immunity evasion through β-catenin-independent suppression of cytotoxic immune-cell activation.","date":"2018","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29431745","citation_count":108,"is_preprint":false},{"pmid":"18367164","id":"PMC_18367164","title":"The canonical Wnt signaling antagonist DKK2 is an essential effector of PITX2 function during normal eye development.","date":"2008","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/18367164","citation_count":107,"is_preprint":false},{"pmid":"23999978","id":"PMC_23999978","title":"MicroRNA-21 promotes oral cancer invasion via the Wnt/β-catenin pathway by targeting DKK2.","date":"2013","source":"Pathology oncology research : POR","url":"https://pubmed.ncbi.nlm.nih.gov/23999978","citation_count":103,"is_preprint":false},{"pmid":"20122913","id":"PMC_20122913","title":"Retinoic acid signaling in perioptic mesenchyme represses Wnt signaling via induction of Pitx2 and Dkk2.","date":"2010","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/20122913","citation_count":85,"is_preprint":false},{"pmid":"19755393","id":"PMC_19755393","title":"Wnt antagonist gene DKK2 is epigenetically silenced and inhibits renal cancer progression through apoptotic and cell cycle pathways.","date":"2009","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/19755393","citation_count":78,"is_preprint":false},{"pmid":"27501171","id":"PMC_27501171","title":"miR-221 Mediates Chemoresistance of Esophageal Adenocarcinoma by Direct Targeting of DKK2 Expression.","date":"2016","source":"Annals of surgery","url":"https://pubmed.ncbi.nlm.nih.gov/27501171","citation_count":69,"is_preprint":false},{"pmid":"20004015","id":"PMC_20004015","title":"The roles of Wnt signaling modulators Dickkopf-1 (Dkk1) and Dickkopf-2 (Dkk2) and cell maturation state in osteogenesis on microstructured titanium surfaces.","date":"2009","source":"Biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/20004015","citation_count":57,"is_preprint":false},{"pmid":"23204234","id":"PMC_23204234","title":"DKK2 mediates osteolysis, invasiveness, and metastatic spread in Ewing sarcoma.","date":"2012","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/23204234","citation_count":54,"is_preprint":false},{"pmid":"22964660","id":"PMC_22964660","title":"Epigenetic silencing of DKK2 and Wnt signal pathway components in human ovarian carcinoma.","date":"2012","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/22964660","citation_count":52,"is_preprint":false},{"pmid":"24091497","id":"PMC_24091497","title":"Distinct roles of DKK1 and DKK2 in tumor angiogenesis.","date":"2013","source":"Angiogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/24091497","citation_count":41,"is_preprint":false},{"pmid":"30151888","id":"PMC_30151888","title":"MiR-27a targets DKK2 and SFRP1 to promote reosseointegration in the regenerative treatment of peri-implantitis.","date":"2018","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/30151888","citation_count":41,"is_preprint":false},{"pmid":"24463139","id":"PMC_24463139","title":"Dkk2/Frzb in the dermal papillae regulates feather regeneration.","date":"2014","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/24463139","citation_count":38,"is_preprint":false},{"pmid":"19815336","id":"PMC_19815336","title":"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.","date":"2009","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/19815336","citation_count":37,"is_preprint":false},{"pmid":"20439124","id":"PMC_20439124","title":"Dkk1 and Dkk2 regulate epicardial specification during mouse heart development.","date":"2010","source":"International journal of cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/20439124","citation_count":36,"is_preprint":false},{"pmid":"35132536","id":"PMC_35132536","title":"circCELF1 Inhibits Myocardial Fibrosis by Regulating the Expression of DKK2 Through FTO/m6A and miR-636.","date":"2022","source":"Journal of cardiovascular translational research","url":"https://pubmed.ncbi.nlm.nih.gov/35132536","citation_count":35,"is_preprint":false},{"pmid":"27542661","id":"PMC_27542661","title":"MiR-154 directly suppresses DKK2 to activate Wnt signaling pathway and enhance activation of cardiac fibroblasts.","date":"2016","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/27542661","citation_count":33,"is_preprint":false},{"pmid":"30035713","id":"PMC_30035713","title":"Dkk2 promotes neural crest specification by activating Wnt/β-catenin signaling in a GSK3β independent manner.","date":"2018","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/30035713","citation_count":33,"is_preprint":false},{"pmid":"23587485","id":"PMC_23587485","title":"MicroRNA-222 promotes tumorigenesis via targeting DKK2 and activating the Wnt/β-catenin signaling pathway.","date":"2013","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/23587485","citation_count":32,"is_preprint":false},{"pmid":"16077958","id":"PMC_16077958","title":"Comparative genomics on DKK2 and DKK4 orthologs.","date":"2005","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16077958","citation_count":31,"is_preprint":false},{"pmid":"32945363","id":"PMC_32945363","title":"miR‑483‑3p promotes the osteogenesis of human osteoblasts by targeting Dikkopf 2 (DKK2) and the Wnt signaling pathway.","date":"2020","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32945363","citation_count":30,"is_preprint":false},{"pmid":"34676493","id":"PMC_34676493","title":"Mesenchymal Stem Cell-Derived Extracellular Vesicles Inhibit Osteoporosis via MicroRNA-27a-Induced Inhibition of DKK2-Mediated Wnt/β-Catenin Pathway.","date":"2021","source":"Inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/34676493","citation_count":29,"is_preprint":false},{"pmid":"17143565","id":"PMC_17143565","title":"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.","date":"2007","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/17143565","citation_count":29,"is_preprint":false},{"pmid":"32268570","id":"PMC_32268570","title":"Roles of Dkk2 in the Linkage from Muscle to Bone during Mechanical Unloading in Mice.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32268570","citation_count":26,"is_preprint":false},{"pmid":"30509557","id":"PMC_30509557","title":"Regional Control of Hairless versus Hair-Bearing Skin by Dkk2.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/30509557","citation_count":26,"is_preprint":false},{"pmid":"27296949","id":"PMC_27296949","title":"miR-187-5p Regulates Cell Growth and Apoptosis in Acute Lymphoblastic Leukemia via DKK2.","date":"2016","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/27296949","citation_count":23,"is_preprint":false},{"pmid":"21763422","id":"PMC_21763422","title":"Downregulation of the Wnt antagonist Dkk2 links the loss of Sept4 and myofibroblastic transformation of hepatic stellate cells.","date":"2011","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/21763422","citation_count":20,"is_preprint":false},{"pmid":"31985779","id":"PMC_31985779","title":"MiR-128 promotes osteogenic differentiation of bone marrow mesenchymal stem cells in rat by targeting DKK2.","date":"2020","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/31985779","citation_count":19,"is_preprint":false},{"pmid":"21598248","id":"PMC_21598248","title":"Transition from cylindroma to spiradenoma in CYLD-defective tumours is associated with reduced DKK2 expression.","date":"2011","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/21598248","citation_count":17,"is_preprint":false},{"pmid":"20332099","id":"PMC_20332099","title":"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.","date":"2010","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20332099","citation_count":14,"is_preprint":false},{"pmid":"31489578","id":"PMC_31489578","title":"Up-regulation of long non-coding RNA AWPPH inhibits proliferation and invasion of gastric cancer cells via miR-203a/DKK2 axis.","date":"2019","source":"Human cell","url":"https://pubmed.ncbi.nlm.nih.gov/31489578","citation_count":13,"is_preprint":false},{"pmid":"33488078","id":"PMC_33488078","title":"Echogenic, Ultrasound-Sensitive Chitosan Nanodroplets for Spatiotemporally Controlled DKK-2 Gene Delivery to Prostate Cancer Cells.","date":"2021","source":"International journal of nanomedicine","url":"https://pubmed.ncbi.nlm.nih.gov/33488078","citation_count":11,"is_preprint":false},{"pmid":"38945954","id":"PMC_38945954","title":"Noncoding RNA regulates the expression of Krm1 and Dkk2 to synergistically affect aortic valve lesions.","date":"2024","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38945954","citation_count":10,"is_preprint":false},{"pmid":"37454937","id":"PMC_37454937","title":"ARHGAP9 knockdown promotes lung adenocarcinoma metastasis by activating Wnt/β-catenin signaling pathway via suppressing DKK2.","date":"2023","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/37454937","citation_count":10,"is_preprint":false},{"pmid":"32559853","id":"PMC_32559853","title":"DKK2 blockage-mediated immunotherapy enhances anti-angiogenic therapy of Kras mutated colorectal cancer.","date":"2020","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/32559853","citation_count":10,"is_preprint":false},{"pmid":"38910391","id":"PMC_38910391","title":"Spatial Multi-omics Reveals the Role of the Wnt Modulator, Dkk2, in Palatogenesis'.","date":"2024","source":"Journal of dental research","url":"https://pubmed.ncbi.nlm.nih.gov/38910391","citation_count":9,"is_preprint":false},{"pmid":"32075129","id":"PMC_32075129","title":"Dickkopf-2 (DKK2) as Context Dependent Factor in Patients with Esophageal Adenocarcinoma.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/32075129","citation_count":9,"is_preprint":false},{"pmid":"38178019","id":"PMC_38178019","title":"Integrated analysis strategy of genome-wide functional gene mining reveals DKK2 gene underlying meat quality in Shaziling synthesized pigs.","date":"2024","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/38178019","citation_count":9,"is_preprint":false},{"pmid":"36599670","id":"PMC_36599670","title":"Microglial Expression of the Wnt Signaling Modulator DKK2 Differs between Human Alzheimer's Disease Brains and Mouse Neurodegeneration Models.","date":"2023","source":"eNeuro","url":"https://pubmed.ncbi.nlm.nih.gov/36599670","citation_count":8,"is_preprint":false},{"pmid":"27053129","id":"PMC_27053129","title":"Identification of host proteins, Spata3 and Dkk2, interacting with Toxoplasma gondii micronemal protein MIC3.","date":"2016","source":"Parasitology research","url":"https://pubmed.ncbi.nlm.nih.gov/27053129","citation_count":8,"is_preprint":false},{"pmid":"26656471","id":"PMC_26656471","title":"The transcription factor ccaat/enhancer binding protein β (C/EBPβ) and miR-27a regulate the expression of porcine Dickkopf2 (DKK2).","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26656471","citation_count":8,"is_preprint":false},{"pmid":"25826080","id":"PMC_25826080","title":"Increased liver carcinogenesis and enrichment of stem cell properties in livers of Dickkopf 2 (Dkk2) deleted mice.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/25826080","citation_count":7,"is_preprint":false},{"pmid":"27203079","id":"PMC_27203079","title":"Selective Retention of an Inactive Allele of the DKK2 Tumor Suppressor Gene in Hepatocellular Carcinoma.","date":"2016","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27203079","citation_count":7,"is_preprint":false},{"pmid":"34364402","id":"PMC_34364402","title":"CircCNIH4 inhibits gastric cancer progression via regulating DKK2 and FRZB expression and Wnt/β-catenin pathway.","date":"2021","source":"Journal of biological research (Thessalonike, Greece)","url":"https://pubmed.ncbi.nlm.nih.gov/34364402","citation_count":7,"is_preprint":false},{"pmid":"40340623","id":"PMC_40340623","title":"Fusobacterium mortiferum and its metabolite 5-aminovaleric acid promote the development of colorectal cancer in obese individuals through Wnt/β-catenin pathway by DKK2.","date":"2025","source":"Gut microbes","url":"https://pubmed.ncbi.nlm.nih.gov/40340623","citation_count":6,"is_preprint":false},{"pmid":"33647798","id":"PMC_33647798","title":"Dickkopf (Dkk)-2 is a beige fat-enriched adipokine to regulate adipogenesis.","date":"2021","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/33647798","citation_count":6,"is_preprint":false},{"pmid":"32391516","id":"PMC_32391516","title":"Rational design of peptides for identification of linear epitopes and generation of neutralizing monoclonal antibodies against DKK2 for cancer therapy.","date":"2020","source":"Antibody therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/32391516","citation_count":5,"is_preprint":false},{"pmid":"31212691","id":"PMC_31212691","title":"Stabilization of Intrinsically Disordered DKK2 Protein by Fusion to RNA-Binding Domain.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31212691","citation_count":4,"is_preprint":false},{"pmid":"33346226","id":"PMC_33346226","title":"Methylation Assessment of Two DKK2 and DKK4 Genes in Oral Squamous Cell Carcinoma Patients.","date":"2020","source":"Iranian journal of public health","url":"https://pubmed.ncbi.nlm.nih.gov/33346226","citation_count":4,"is_preprint":false},{"pmid":"33352594","id":"PMC_33352594","title":"Role of Dkk2 in the Muscle/bone Interaction of Androgen-Deficient Mice.","date":"2020","source":"Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association","url":"https://pubmed.ncbi.nlm.nih.gov/33352594","citation_count":4,"is_preprint":false},{"pmid":"28180900","id":"PMC_28180900","title":"Engineering potent long-acting variants of the Wnt inhibitor DKK2.","date":"2017","source":"Protein engineering, design & selection : PEDS","url":"https://pubmed.ncbi.nlm.nih.gov/28180900","citation_count":3,"is_preprint":false},{"pmid":"38795388","id":"PMC_38795388","title":"DKK2 promotes the progression of oral squamous cell carcinoma through the PI3K/AKT signaling pathway.","date":"2024","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/38795388","citation_count":2,"is_preprint":false},{"pmid":"24057189","id":"PMC_24057189","title":"Polymorphisms of the bovine DKK2 and their associations with body measurement traits and meat quality traits in Qinchuan cattle.","date":"2013","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/24057189","citation_count":2,"is_preprint":false},{"pmid":"40615098","id":"PMC_40615098","title":"From traditional medicine to targeted therapy: Structure-activity relationship-guided optimization of scorpion toxin DKK2 for pain-associated sodium channel blockade.","date":"2025","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40615098","citation_count":2,"is_preprint":false},{"pmid":"37551167","id":"PMC_37551167","title":"Promoter methylation analysis of DKK2 may be a potential biomarker for early detection of cervical cancer.","date":"2022","source":"Asian biomedicine : research, reviews and news","url":"https://pubmed.ncbi.nlm.nih.gov/37551167","citation_count":1,"is_preprint":false},{"pmid":"37149202","id":"PMC_37149202","title":"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.","date":"2023","source":"The Journal of steroid biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/37149202","citation_count":1,"is_preprint":false},{"pmid":"37292772","id":"PMC_37292772","title":"Spatial Multiomics Reveal the Role of Wnt Modulator, Dkk2, in Palatogenesis.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37292772","citation_count":1,"is_preprint":false},{"pmid":"31372588","id":"PMC_31372588","title":"Low Serum Levels of DKK2 Predict Incident Low-Impact Fracture in Older Women.","date":"2019","source":"JBMR plus","url":"https://pubmed.ncbi.nlm.nih.gov/31372588","citation_count":1,"is_preprint":false},{"pmid":"24117450","id":"PMC_24117450","title":"Association study of DKK2 polymorphisms with alcohol dependence and alcohol-related harm.","date":"2013","source":"Alcoholism, clinical and experimental research","url":"https://pubmed.ncbi.nlm.nih.gov/24117450","citation_count":1,"is_preprint":false},{"pmid":"33909798","id":"PMC_33909798","title":"RNAM EXPRESSION AND DNA METHYLATION OF DKK2 GENE IN COLORECTAL CÂNCER.","date":"2021","source":"Arquivos de gastroenterologia","url":"https://pubmed.ncbi.nlm.nih.gov/33909798","citation_count":1,"is_preprint":false},{"pmid":"41542770","id":"PMC_41542770","title":"Targeting the N-acetyltransferase 10/DKK2 axis enhances CD8+ T cell antitumor activity in colorectal cancer models.","date":"2026","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/41542770","citation_count":0,"is_preprint":false},{"pmid":"37404627","id":"PMC_37404627","title":"Accumulated X-ray irradiation induces miR-187-5p upregulation mediating fibrotic buccal mucosal fibroblasts activities via DKK2.","date":"2022","source":"Journal of dental sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37404627","citation_count":0,"is_preprint":false},{"pmid":"41125965","id":"PMC_41125965","title":"DKK2 contributes to context discrimination and adult hippocampal neurogenesis by suppressing Wnt/PCP signaling.","date":"2025","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41125965","citation_count":0,"is_preprint":false},{"pmid":"34856466","id":"PMC_34856466","title":"Generation of a DKK2 homozygous knockout human embryonic stem cell line using the CRISPR/Cas9 system.","date":"2021","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/34856466","citation_count":0,"is_preprint":false},{"pmid":"39667489","id":"PMC_39667489","title":"Downregulated DKK2 may serve as a molecular mechanism of high-fat diet-induced myocardial injury via Wnt/β-catenin pathway.","date":"2024","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39667489","citation_count":0,"is_preprint":false},{"pmid":"34048597","id":"PMC_34048597","title":"Retraction statement: MicroRNA-222 promotes tumorigenesis via targeting DKK2 and activating the Wnt/β-catenin signaling pathway.","date":"2021","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/34048597","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.07.17.665381","title":"A pivotal role for Wnt antagonists in constraining Wnt activity to promote digit joint specification","date":"2025-07-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.17.665381","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.05.24318588","title":"Assessment of MYC Gene and WNT Pathway Alterations in Early-Onset Colorectal Cancer Among Hispanic/Latino Patients Using Integrated Multi-Omics Approaches","date":"2024-12-08","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.05.24318588","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.06.24.600143","title":"Synovial fluid transcriptome dynamics in osteoarthritis progression: Implications in pathogenesis","date":"2024-06-28","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.24.600143","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":38325,"output_tokens":7554,"usd":0.114142},"stage2":{"model":"claude-opus-4-6","input_tokens":11334,"output_tokens":3326,"usd":0.20973},"total_usd":0.323872,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"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\",\n      \"method\": \"Dkk2 knockout mice, osteoblast differentiation cultures, exogenous Dkk2 overexpression, osteogenic marker expression assays\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KO mice, in vitro cultures, rescue experiments), replicated across several assays\",\n      \"pmids\": [\"16056226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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\",\n      \"method\": \"Dkk2 knockout mice, immunohistochemistry, histological analysis of ocular surface epithelium\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with specific phenotypic readout, pathway placement via LRP5/6 interaction\",\n      \"pmids\": [\"16672341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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\",\n      \"method\": \"Pitx2- and Dkk2-deficient mice, epistasis analysis, immunohistochemistry, analysis of Wnt signaling reporters\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with two KO models, multiple phenotypic readouts, pathway placement\",\n      \"pmids\": [\"18367164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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\",\n      \"method\": \"Raldh1/Raldh3 double-null mice, chromatin immunoprecipitation (ChIP), gel mobility shift assay (EMSA), Axin2 reporter for Wnt readout\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP and EMSA establish direct RA receptor binding to Pitx2 promoter, combined with KO mouse epistasis\",\n      \"pmids\": [\"20122913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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\",\n      \"method\": \"Stable Dkk2-silenced MG63 cell lines, exogenous rhDkk2 treatment, blocking antibodies to Dkk2, osteoblast differentiation assays on titanium surfaces\",\n      \"journal\": \"Biomaterials\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple cell types and methods, single lab\",\n      \"pmids\": [\"20004015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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\",\n      \"method\": \"Dkk1 and Dkk2 single and double-null mouse crosses, histological and immunohistochemical analysis of hearts at multiple developmental stages\",\n      \"journal\": \"International journal of cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with double KO, but single lab\",\n      \"pmids\": [\"20439124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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\",\n      \"method\": \"Genetic mouse models (APC-null, PTEN-null), antibody-mediated DKK2 blockade, STAT5 nuclear localization assays, co-immunoprecipitation for LRP5/LRP6, tumor immune infiltrate analysis\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (genetic models, antibody blockade, mechanistic STAT5 assays, receptor specificity), strong evidence from a high-impact journal\",\n      \"pmids\": [\"29431745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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\",\n      \"method\": \"Xenopus morpholino knockdown, mRNA overexpression, epistasis rescue experiments, dominant-negative and constitutively active constructs\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in Xenopus with multiple rescue experiments demonstrating pathway position, ortholog with consistent mammalian function\",\n      \"pmids\": [\"30035713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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\",\n      \"method\": \"RNA interference knockdown in Ewing sarcoma cells, orthotopic xenograft mouse model, Matrigel invasion assay, gene expression analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo KD with specific phenotypic readout, single lab\",\n      \"pmids\": [\"23204234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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\",\n      \"method\": \"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\",\n      \"journal\": \"Angiogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo mouse models with specific vascular phenotypic readouts, single lab\",\n      \"pmids\": [\"24091497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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\",\n      \"method\": \"DNA microarray comparison of Sept4+/+ vs Sept4−/− HSCs, LEF/TCF-luciferase reporter assay, exogenous Dkk2 protein supplementation, qRT-PCR\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter assay for pathway placement, rescue with exogenous protein, single lab\",\n      \"pmids\": [\"21763422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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\",\n      \"method\": \"Methylation assay, chromatin immunoprecipitation (ChIP) for histone modifications, stable DKK2-transfected cells, apoptosis assay, cell cycle analysis, colony formation assay\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP for epigenetic mechanism plus functional overexpression studies, single lab\",\n      \"pmids\": [\"19755393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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\",\n      \"method\": \"Dkk2 conditional knockout mice, in situ hybridization, immunofluorescence, Wnt/β-catenin reporter analysis, follicle functional assessment\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with specific spatial phenotype, Wnt reporter, strong evidence for mechanistic role\",\n      \"pmids\": [\"30509557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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\",\n      \"method\": \"Dual-luciferase reporter assay, miR-154 mimic/inhibitor transfection, DKK2 siRNA, DKK2 overexpression vector, Western blot for β-catenin/α-SMA/collagens\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — luciferase assay for direct targeting, functional rescue, single lab\",\n      \"pmids\": [\"27542661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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\",\n      \"method\": \"Protein fusion expression in bacterial host, Wnt signaling reporter assay, HUVEC tube formation assay, in vivo Matrigel plug assay, solubility assessment\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution plus in vivo assay, demonstrates intrinsic disorder and functional activity, single lab\",\n      \"pmids\": [\"31212691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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\",\n      \"method\": \"LRP6 binding assay, LRP6 phosphorylation assay, pharmacokinetic studies in rodents, biophysical characterization (monomer, thermal stability), mutagenesis of heparan sulfate binding residues\",\n      \"journal\": \"Protein engineering, design & selection : PEDS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding assay for LRP6 with mutagenesis, in vivo PK studies, single lab\",\n      \"pmids\": [\"28180900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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\",\n      \"method\": \"Rational peptide design, mouse immunization, Wnt signaling reporter assay in vitro, in vivo tumor growth inhibition assay with monoclonal antibodies\",\n      \"journal\": \"Antibody therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional neutralization confirmed by Wnt reporter and in vivo assay, single lab\",\n      \"pmids\": [\"32391516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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\",\n      \"method\": \"Genome-wide transcriptomic analysis, promoter methylation assay, RNAi knockdown in primary cylindroma cells, colony formation and anchorage-independent growth assays\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional KD in primary cells with multiple readouts, methylation mechanism established, single lab\",\n      \"pmids\": [\"21598248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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\",\n      \"method\": \"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)\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter assay establishing functional difference, in vitro Wnt antagonism assay, supported by clinical genotyping\",\n      \"pmids\": [\"27203079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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\",\n      \"method\": \"Hindlimb unloading mouse model, hypergravity mouse model, DNA microarray, serum Dkk2 ELISA, in vitro shear stress with cyclooxygenase inhibitors, Dkk2 treatment of primary osteoblasts\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vivo and in vitro methods, single lab, mechanistic pathway placement\",\n      \"pmids\": [\"32268570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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\",\n      \"method\": \"Dkk2 protein treatment of pre-adipocyte cell lines and primary cells, adenoviral overexpression, rosiglitazone rescue, adipogenesis assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple cell types tested, paracrine vs endocrine distinction established, single lab\",\n      \"pmids\": [\"33647798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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\",\n      \"method\": \"Recombinant DKK2 treatment of primary rat hippocampal neurons, dendritic spine/synapse counting, in situ hybridization for Dkk2 mRNA in mouse AD models, immunohistochemistry\",\n      \"journal\": \"eNeuro\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct recombinant protein treatment with quantified synaptic readout, in vivo disease model localization\",\n      \"pmids\": [\"36599670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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\",\n      \"method\": \"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\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (KO mice, scRNA-seq, biochemical ac4C modification, receptor signaling, metabolic readout), strong mechanistic chain\",\n      \"pmids\": [\"41542770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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\",\n      \"method\": \"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\",\n      \"journal\": \"Neuropsychopharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic models, pathway-specific readouts, pharmacological rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41125965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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\",\n      \"method\": \"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\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — in vivo and in vitro models, m6A modification mechanistic assays, single lab\",\n      \"pmids\": [\"38945954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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\",\n      \"method\": \"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\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP and EMSA for direct TF binding, multiple orthogonal promoter analysis methods, single lab (porcine ortholog)\",\n      \"pmids\": [\"26656471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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\",\n      \"method\": \"5'Hoxd conditional KO mice combined with Dkk2 genetic removal, βcatCA expression in interdigit mesenchyme, pSmad1/5 immunostaining, limb bud culture with Gsk3β antagonists\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in mouse with multiple models, preprint not yet peer reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.07.17.665381\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"DKK2 is a secreted Wnt-pathway modulator that primarily antagonizes canonical Wnt/β-catenin signaling by binding to LRP5/6 co-receptors, but can also activate β-catenin in a GSK3β-independent manner (e.g., during neural crest specification); it plays context-dependent roles in terminal osteoblast differentiation/mineralization, corneal fate specification, plantar skin hairlessness, adult hippocampal neurogenesis (by suppressing Wnt/PCP-JNK signaling), and tumor immune evasion through a distinct LRP5-STAT5 axis independent of β-catenin, and its mRNA is stabilized by NAT10-mediated ac4C modification in colorectal cancer, linking it to CD8+ T cell dysfunction via LRP6-AKT-mTOR-cholesterol signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"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].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"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.\",\n      \"evidence\": \"Dkk2-null mice exhibited osteopenia with unmineralized osteoids; exogenous Dkk2 drove osteoblast cultures toward terminal differentiation\",\n      \"pmids\": [\"16056226\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"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.\",\n      \"evidence\": \"Dkk2-knockout mice showed complete transformation of corneal epithelium into keratinizing skin-like epithelium\",\n      \"pmids\": [\"16672341\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"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.\",\n      \"evidence\": \"Pitx2- and Dkk2-deficient mice showed epistatic relationships; Raldh1/3 double-null mice lost both Pitx2 and Dkk2 expression with ectopic Wnt activation\",\n      \"pmids\": [\"18367164\", \"20122913\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DKK2 has PITX2-independent roles in other periocular tissues was not tested\", \"Direct ChIP for PITX2 on the Dkk2 promoter was not shown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"Methylation-specific analysis and ChIP for histone marks at the DKK2 locus in RCC; DKK2 re-expression increased apoptosis and reduced proliferation\",\n      \"pmids\": [\"19755393\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Epigenetic silencing was shown in one tumor type; generalizability across cancers was not established\", \"No in vivo tumor suppression experiment was performed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"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.\",\n      \"evidence\": \"Dkk1/Dkk2 double-null mice displayed myocardial and epicardial hyperplasia with ventricular septal defects\",\n      \"pmids\": [\"20439124\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The individual contributions of Dkk1 vs Dkk2 could not be separated\", \"Downstream effectors in cardiac progenitors were not identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showing that DKK2 enhances angiogenesis—opposite to DKK1—established a functional divergence between DKK family members in vascular biology.\",\n      \"evidence\": \"Adenoviral DKK2 expression and endothelial-specific DKK2 transgenic mice increased tumor vascular density and pericyte coverage in melanoma models\",\n      \"pmids\": [\"24091497\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"ChIP and EMSA confirmed C/EBPβ binding at four DKK2 promoter sites; miR-27a directly targeted the DKK2 3′UTR\",\n      \"pmids\": [\"26656471\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Biochemical demonstration that DKK2 directly binds LRP6 and prevents its phosphorylation established the molecular mechanism of Wnt co-receptor blockade.\",\n      \"evidence\": \"Direct LRP6 binding and phosphorylation inhibition assays with purified HSA-DKK2 fusion proteins and heparan sulfate binding mutants\",\n      \"pmids\": [\"28180900\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether LRP5 and LRP6 are engaged with different affinities was not resolved\", \"Structural basis of the DKK2-LRP6 interaction was not determined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"29431745\", \"30035713\", \"30509557\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating that DKK2 blocks WNT7a-induced synaptogenesis and that microglial Dkk2 is upregulated in disease-associated microglia linked DKK2 to synapse loss in neurodegeneration.\",\n      \"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\",\n      \"pmids\": [\"36599670\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"41125965\", \"41542770\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 6, 7, 12, 23]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [6, 15, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 6, 14, 19, 20, 22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 6, 7, 12, 15, 22, 23]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2, 5, 12]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 22]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 8, 11, 22]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"LRP5\",\n      \"LRP6\",\n      \"PITX2\",\n      \"KRM1\",\n      \"STAT5\",\n      \"NAT10\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}