{"gene":"DKK4","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2018,"finding":"Dkk4 consists of two independent folded domains (CRD1 and CRD2) joined by a highly flexible, nonstructured linker. CRD1 has significant structural homology to CRD2, pointing to multiple gene duplication events during Dkk family evolution. Dkk4 CRD2 mediates high-affinity binding to both the E1E2 region of LRP6 and the Kremen1 (Krm1) extracellular domain, while the N-terminal region binds LRP6 E1E2 with only moderate affinity via the conserved NXI(R/K) motif but does not interact with Krm proteins. Dkk and Krm family proteins function synergistically to inhibit Wnt signaling.","method":"NMR structural determination, SPR binding assays, mutagenesis, functional Wnt signaling reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution structure, binding assays with domain-specific constructs, and functional validation in a single rigorous study","pmids":["29925589"],"is_preprint":false},{"year":2016,"finding":"Dkk4 selectively inhibits a subset of Wnts and is further inactivated by proteolytic cleavage. Intact Dkk4 inhibits meibomian gland extension, but the cleaved form progressively increases during meibomian gland development with a concomitant upswing in Wnt activity. Elevation of Lrp6 (a direct Eda target and Wnt co-receptor) eliminates Dkk4 inhibition in cell and organotypic cultures, and Lrp6 upregulation restores meibomian gland formation in Tabby mice.","method":"Transgenic mouse overexpression, cell culture, organotypic culture, in vivo genetic rescue (Lrp6 overexpression in Tabby mice), protein cleavage assays","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vivo and in vitro methods including genetic rescue and biochemical cleavage analysis","pmids":["27864382"],"is_preprint":false},{"year":2008,"finding":"Dkk4 is a direct transcriptional target of the Eda-A1/Edar signaling pathway (the most highly induced gene in the microarray screen), and its expression in ectodermal placodes also depends on prior Wnt activity. Dkk4 functions as a Wnt antagonist in ectodermal placodes, acting downstream of Edar to provide lateral inhibition for correct patterning of hair follicles.","method":"Microarray profiling of Eda-A1-stimulated eda-/- skin explants, in situ hybridization/co-localization with Edar, genetic analysis in NF-kappaB-deficient and eda-/- mice","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — microarray confirmed with genetic models and localization, single lab","pmids":["18508042"],"is_preprint":false},{"year":2010,"finding":"Dkk4 acts through an Eda-independent pathway to regulate secondary hair follicle development. A Dkk4 transgene blocked secondary follicle induction in Tabby (Eda-/y) mice without affecting primary hair, and Dkk4-regulated secondary hair development, like the Eda-dependent primary hair pathway, is further mediated by selective activation of Shh.","method":"Transgenic mouse overexpression, genetic epistasis with Tabby (Eda-/y) mice, Shh pathway analysis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic epistasis in multiple mouse models with specific pathway readout","pmids":["20386733"],"is_preprint":false},{"year":2012,"finding":"TFAP2E-dependent chemoresistance to fluorouracil in colorectal cancer is mediated through DKK4. Colorectal cancer cell lines overexpressing DKK4 showed increased chemoresistance to fluorouracil but not irinotecan or oxaliplatin.","method":"Cell line overexpression, cell viability assays, TFAP2E methylation-function correlation in patient cohorts","journal":"The New England journal of medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional overexpression assay with drug specificity, corroborated by patient cohort data but mechanistic detail limited to cell viability","pmids":["22216841"],"is_preprint":false},{"year":2012,"finding":"DKK4 attenuates Wnt/β-catenin signaling in hepatocellular carcinoma cells, reducing β-catenin-responsive luciferase activity, decreasing β-catenin and cyclin D1 protein levels, and its tumor-suppressive effect on β-catenin is masked by proteasome inhibition.","method":"Ectopic DKK4 expression in HCC cell lines, luciferase reporter assay, western blotting, proteasome inhibitor treatment, xenograft mouse model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay plus proteasome inhibitor rescue plus in vivo xenograft, single lab","pmids":["22249261"],"is_preprint":false},{"year":2012,"finding":"Restoration of wild-type APC in SW480 colon cancer cells induces secretion of DKK4 via exosomes, associated with reduced DKK4 promoter methylation and downregulation of DNMT-3a.","method":"Comparative proteomic analysis of exosomes by mass spectrometry, RT-PCR, immunoblotting, immunogold electron microscopy, methylation-specific PCR","journal":"Electrophoresis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (proteomics, immunoblot, electron microscopy, methylation PCR) in single lab","pmids":["22740476"],"is_preprint":false},{"year":2016,"finding":"Under hyperglycemic conditions, DKK4 expression is suppressed in HCC cells, leading to activation of canonical Wnt signaling and enhanced proliferation via β-catenin. Knockdown of DKK4 by shRNA promotes proliferation under normoglycemic conditions, which is suppressed by exogenous recombinant DKK4 protein.","method":"shRNA knockdown, recombinant protein rescue, β-catenin level measurement, cell cycle analysis, NOD/SCID mouse xenograft model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rescue with recombinant protein plus in vivo model, single lab","pmids":["27272409"],"is_preprint":false},{"year":2017,"finding":"DKK4 knockdown in docetaxel-resistant A549/DTX cells reduces colony formation and invasion and promotes pro-apoptotic effects of docetaxel via caspase 3 activation and BCL-2 inhibition, possibly mediated by activation of the c-Jun N-terminal kinase (JNK) signaling pathway.","method":"shRNA knockdown, cell viability assay, flow cytometry for apoptosis, caspase 3 and BCL-2 western blotting, invasion assay","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple phenotypic readouts with pathway marker analysis, single lab","pmids":["28981599"],"is_preprint":false},{"year":2019,"finding":"DLX3 regulates DKK4 expression through histone H3 lysine 27 trimethylation (H3K27me3) at the DKK4 promoter; DLX3 knockdown decreases H3K27me3 enrichment at the DKK4 promoter, increasing DKK4 expression and suppressing Wnt/β-catenin signaling during osteogenic differentiation of bone marrow mesenchymal stem cells.","method":"ChIP-qPCR, lentiviral overexpression/knockdown, RT-qPCR, western blotting, osteogenic differentiation assays (ALP, alizarin red staining)","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR directly demonstrates histone modification at DKK4 promoter, functional differentiation assays, single lab","pmids":["31202458"],"is_preprint":false},{"year":2022,"finding":"DKK4 inhibits colorectal cancer metastasis through a negative feedback mechanism: Wnt3a and LiCl induce DKK4 expression, and DKK4 in turn represses Wnt/β-catenin signaling by suppressing FZD6 and AKT2/s552 β-catenin phosphorylation. RNA-seq after DKK4 knockdown revealed upregulation of AKT2, FZD6, and JUN.","method":"RNA-seq, luciferase reporter assay, transwell assays, subcutaneous and metastatic mouse tumor models, cell counting kit-8 assays, bioinformatics","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq plus reporter assay plus in vivo models identifying specific signaling nodes, single lab","pmids":["36181792"],"is_preprint":false},{"year":2023,"finding":"LARP1 promotes DKK4 mRNA stabilization by competitively interacting with PABPC1 to prevent BTG2-dependent deadenylation and degradation of DKK4 mRNA, leading to elevated DKK4 protein, enhanced β-catenin expression and nuclear import in hepatoblastoma.","method":"Co-immunoprecipitation, RNA immunoprecipitation, RNA pull-down, mRNA stability assays, poly(A)-tail length assays, RNA-sequencing","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays (RIP, pull-down, mRNA stability) identifying specific mRNA regulatory mechanism, single lab","pmids":["37070251"],"is_preprint":false},{"year":2024,"finding":"DKK4 secreted from colorectal cancer cells inactivates β-catenin in stromal fibroblasts, inducing formation of stress fiber-containing fibroblasts and myofibroblasts, resulting in restricted expansion of primary tumor masses but enhanced CRC metastasis. Chemical inhibition of β-catenin by MSAB promoted CRC metastasis, supporting that reduced β-catenin activity in the tumor stroma facilitates progression.","method":"CRC cell-fibroblast co-culture, mouse CRC xenograft models, chemical β-catenin inhibitor (MSAB) treatment, immunofluorescence for stress fibers/myofibroblast markers","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo models with mechanistic rescue and inhibitor experiments, single lab","pmids":["38519641"],"is_preprint":false},{"year":2025,"finding":"METTL14 stimulates m6A methylation of DKK4 mRNA, stabilizing DKK4 expression and promoting docetaxel resistance and malignant progression in lung cancer. Downregulation of DKK4 reversed proliferation, cell cycle arrest, apoptosis resistance, migration, and M2 macrophage polarization in DTX-resistant cells.","method":"MeRIP assay (methylated RNA immunoprecipitation), RT-qPCR, western blot, EdU proliferation assay, flow cytometry, transwell assay, mouse xenograft model","journal":"Journal of biochemical and molecular toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP directly demonstrates m6A modification on DKK4 mRNA, functional assays in vitro and in vivo, single lab","pmids":["41208390"],"is_preprint":false}],"current_model":"DKK4 is a secreted Wnt antagonist with two cysteine-rich domains (CRD1 and CRD2); CRD2 mediates high-affinity binding to LRP6 and Kremen1 to synergistically inhibit Wnt signaling, while its activity is further modulated by proteolytic cleavage and by the ratio of LRP6 levels. DKK4 is transcriptionally induced by the Eda/Edar pathway and repressed by DLX3-mediated H3K27me3 or by hyperglycemia-driven epigenetic silencing; its mRNA is stabilized by LARP1-dependent protection from deadenylation and by METTL14-mediated m6A modification. In cancer contexts DKK4 can act as either a tumor suppressor (HCC) or a pro-metastatic factor (CRC, via paracrine inactivation of β-catenin in stromal fibroblasts), and DKK4 overexpression confers resistance to fluorouracil and docetaxel partly through JNK pathway modulation."},"narrative":{"mechanistic_narrative":"DKK4 is a secreted Wnt/β-catenin pathway antagonist that shapes tissue patterning and tumor progression by binding Wnt co-receptors at the cell surface [PMID:29925589, PMID:18508042]. Structurally it comprises two independently folded cysteine-rich domains joined by a flexible linker, with CRD2 mediating high-affinity engagement of both the LRP6 E1E2 region and the Kremen1 extracellular domain, while the N-terminal NXI(R/K) motif binds LRP6 E1E2 with moderate affinity; Dkk and Kremen proteins act synergistically to inhibit Wnt signaling [PMID:29925589]. DKK4 activity is tunable: it is inactivated by proteolytic cleavage and its inhibitory effect is overridden when LRP6 levels rise, a switch that controls Wnt-dependent appendage formation in vivo [PMID:27864382]. In development DKK4 is the most highly induced direct transcriptional target of Eda-A1/Edar signaling and provides lateral inhibition for hair follicle patterning, while also acting through an Eda-independent route to restrain secondary follicle induction via selective Shh activation [PMID:18508042, PMID:20386733]. In cancer DKK4 represses canonical Wnt signaling by lowering β-catenin and cyclin D1 and by suppressing FZD6 and AKT2-dependent β-catenin phosphorylation, behaving as a tumor suppressor in hepatocellular carcinoma yet, when secreted, inactivating β-catenin in stromal fibroblasts to drive myofibroblast conversion and CRC metastasis [PMID:22249261, PMID:36181792, PMID:38519641]. DKK4 expression is controlled at multiple layers — DLX3-directed H3K27me3 and promoter methylation repress it [PMID:31202458, PMID:22740476], hyperglycemia silences it to release Wnt-driven proliferation [PMID:27272409], and LARP1-mediated protection from BTG2/PABPC1 deadenylation and METTL14-catalyzed m6A methylation stabilize its mRNA [PMID:37070251, PMID:41208390] — and its overexpression confers resistance to fluorouracil and docetaxel partly through JNK pathway modulation [PMID:22216841, PMID:28981599, PMID:41208390].","teleology":[{"year":2008,"claim":"Established DKK4 as a transcriptional output of Eda/Edar signaling acting as a Wnt antagonist for ectodermal patterning, placing it within a defined developmental signaling circuit.","evidence":"Microarray of Eda-A1-stimulated eda-/- skin explants with in situ localization and genetic models","pmids":["18508042"],"confidence":"Medium","gaps":["Did not resolve the molecular receptor interactions of DKK4","Single lab, model-organism context only"]},{"year":2010,"claim":"Showed DKK4 also functions in an Eda-independent pathway via Shh, distinguishing primary from secondary hair follicle control and broadening its developmental role.","evidence":"Transgenic overexpression and genetic epistasis in Tabby mice with Shh pathway analysis","pmids":["20386733"],"confidence":"High","gaps":["Mechanism linking DKK4 to selective Shh activation not defined","No biochemical receptor data"]},{"year":2012,"claim":"Demonstrated context-dependent cancer roles — DKK4 suppresses Wnt/β-catenin and acts as a tumor suppressor in HCC, while mediating TFAP2E-dependent fluorouracil chemoresistance in colorectal cancer.","evidence":"Ectopic/overexpression in HCC and CRC cell lines, luciferase reporters, proteasome inhibitor rescue, xenografts, patient cohort correlation","pmids":["22249261","22216841","22740476"],"confidence":"Medium","gaps":["Opposing tumor-suppressive vs chemoresistance roles not mechanistically reconciled","Chemoresistance mechanism limited to viability readout"]},{"year":2016,"claim":"Defined two regulatory tuning mechanisms — proteolytic cleavage inactivation plus LRP6-level override in development, and hyperglycemia-driven suppression releasing Wnt-driven proliferation in cancer.","evidence":"Transgenic/organotypic culture with cleavage assays and Lrp6 rescue; shRNA knockdown with recombinant protein rescue and xenografts","pmids":["27864382","27272409"],"confidence":"High","gaps":["Identity of the cleavage protease not determined","Epigenetic basis of hyperglycemic suppression not fully resolved"]},{"year":2018,"claim":"Resolved the structural and binding logic of DKK4, showing CRD2 binds LRP6 and Kremen1 with high affinity for synergistic Wnt inhibition.","evidence":"NMR structure, SPR binding with domain constructs, mutagenesis, Wnt reporter assays","pmids":["29925589"],"confidence":"High","gaps":["Structure of full ternary LRP6–DKK4–Kremen complex not solved","In vivo relevance of individual binding interfaces not tested"]},{"year":2019,"claim":"Identified an epigenetic repression mechanism whereby DLX3 deposits H3K27me3 at the DKK4 promoter to permit Wnt signaling during osteogenic differentiation.","evidence":"ChIP-qPCR, lentiviral knockdown/overexpression, osteogenic differentiation assays","pmids":["31202458"],"confidence":"Medium","gaps":["Direct vs indirect role of DLX3 in H3K27me3 deposition not separated","Single lineage context"]},{"year":2022,"claim":"Placed DKK4 in a negative-feedback loop where Wnt induces DKK4, which then represses FZD6 and AKT2-dependent β-catenin phosphorylation to limit CRC metastasis.","evidence":"RNA-seq, luciferase reporter, transwell, subcutaneous and metastatic mouse models","pmids":["36181792"],"confidence":"Medium","gaps":["Apparent conflict with pro-metastatic stromal role unresolved","Direct DKK4 control of FZD6/AKT2 not biochemically shown"]},{"year":2023,"claim":"Uncovered post-transcriptional stabilization of DKK4 mRNA by LARP1 competing with PABPC1 to block BTG2-dependent deadenylation, elevating β-catenin in hepatoblastoma.","evidence":"Co-IP, RIP, RNA pull-down, mRNA stability and poly(A) assays, RNA-seq","pmids":["37070251"],"confidence":"Medium","gaps":["Why elevated DKK4 here increases rather than suppresses β-catenin not reconciled with antagonist role","Single lab"]},{"year":2024,"claim":"Demonstrated a paracrine mechanism: secreted DKK4 inactivates β-catenin in stromal fibroblasts, driving myofibroblast conversion that restricts primary tumor growth but promotes CRC metastasis.","evidence":"Cancer cell–fibroblast co-culture, xenografts, MSAB β-catenin inhibitor, immunofluorescence","pmids":["38519641"],"confidence":"Medium","gaps":["Tumor-cell-autonomous vs stromal effects of DKK4 not fully disentangled","Fibroblast receptor for secreted DKK4 not identified"]},{"year":2025,"claim":"Showed METTL14-catalyzed m6A methylation stabilizes DKK4 mRNA to promote docetaxel resistance, M2 macrophage polarization, and progression in lung cancer.","evidence":"MeRIP, RT-qPCR, EdU, flow cytometry, transwell, xenograft","pmids":["41208390"],"confidence":"Medium","gaps":["m6A reader mediating DKK4 stabilization not identified","Link between DKK4 and macrophage polarization mechanistically thin"]},{"year":null,"claim":"How DKK4's opposing tumor-suppressive and pro-metastatic activities are determined by cellular context, secretion, and cleavage state remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model reconciling cell-autonomous Wnt suppression with paracrine stromal effects","Protease and m6A reader identities unknown","No full receptor-complex structure in a physiological tissue"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,5,10]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,12]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5,10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,5,12,13]}],"complexes":[],"partners":["LRP6","KREMEN1","FZD6","PABPC1","LARP1","METTL14"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UBT3","full_name":"Dickkopf-related protein 4","aliases":[],"length_aa":224,"mass_kda":24.9,"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/Q9UBT3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DKK4","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DKK4","total_profiled":1310},"omim":[{"mim_id":"613303","title":"AlkB HOMOLOG 5, RNA DEMETHYLASE; ALKBH5","url":"https://www.omim.org/entry/613303"},{"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"},{"mim_id":"605189","title":"DICKKOPF WNT SIGNALING PATHWAY INHIBITOR 1; DKK1","url":"https://www.omim.org/entry/605189"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"esophagus","ntpm":4.6},{"tissue":"intestine","ntpm":2.3}],"url":"https://www.proteinatlas.org/search/DKK4"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9UBT3","domains":[{"cath_id":"2.10.80.10","chopping":"144-180_189-207_215-221","consensus_level":"high","plddt":90.6417,"start":144,"end":221}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBT3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBT3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBT3-F1-predicted_aligned_error_v6.png","plddt_mean":73.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DKK4","jax_strain_url":"https://www.jax.org/strain/search?query=DKK4"},"sequence":{"accession":"Q9UBT3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UBT3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UBT3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBT3"}},"corpus_meta":[{"pmid":"22216841","id":"PMC_22216841","title":"TFAP2E-DKK4 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full-length APC protein in SW480 colon cancer cells induces exosome-mediated secretion of DKK-4.","date":"2012","source":"Electrophoresis","url":"https://pubmed.ncbi.nlm.nih.gov/22740476","citation_count":35,"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":"29925589","id":"PMC_29925589","title":"Structural and functional analysis of Dickkopf 4 (Dkk4): New insights into Dkk evolution and regulation of Wnt signaling by Dkk and Kremen proteins.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29925589","citation_count":26,"is_preprint":false},{"pmid":"29904276","id":"PMC_29904276","title":"Role of DKK4 in Tumorigenesis and Tumor Progression.","date":"2018","source":"International journal of biological 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metastasis.","date":"2024","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/38519641","citation_count":1,"is_preprint":false},{"pmid":"37435631","id":"PMC_37435631","title":"Generation and characterization of a Dkk4-Cre knock-in mouse line.","date":"2023","source":"Genesis (New York, N.Y. : 2000)","url":"https://pubmed.ncbi.nlm.nih.gov/37435631","citation_count":0,"is_preprint":false},{"pmid":"41208390","id":"PMC_41208390","title":"METTL14 Mediates Malignant Progression and Docetaxel Resistance of Lung Cancer by Regulating DKK4 Expression Through m6A Methylation Modification.","date":"2025","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/41208390","citation_count":0,"is_preprint":false},{"pmid":"23479175","id":"PMC_23479175","title":"Novel SNPs in the exon region of bovine DKK4 gene and their association with body measurement traits in Qinchuan cattle.","date":"2013","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/23479175","citation_count":0,"is_preprint":false},{"pmid":"39506574","id":"PMC_39506574","title":"Correlation and Prediction of IL-10Ra and DKK-4 Plasma Levels in Patients with Calcium Oxalate Urolithiasis.","date":"2024","source":"Clinical laboratory","url":"https://pubmed.ncbi.nlm.nih.gov/39506574","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16239,"output_tokens":3775,"usd":0.052671,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11421,"output_tokens":3639,"usd":0.07404,"stage2_stop_reason":"end_turn"},"total_usd":0.126711,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"Dkk4 consists of two independent folded domains (CRD1 and CRD2) joined by a highly flexible, nonstructured linker. CRD1 has significant structural homology to CRD2, pointing to multiple gene duplication events during Dkk family evolution. Dkk4 CRD2 mediates high-affinity binding to both the E1E2 region of LRP6 and the Kremen1 (Krm1) extracellular domain, while the N-terminal region binds LRP6 E1E2 with only moderate affinity via the conserved NXI(R/K) motif but does not interact with Krm proteins. Dkk and Krm family proteins function synergistically to inhibit Wnt signaling.\",\n      \"method\": \"NMR structural determination, SPR binding assays, mutagenesis, functional Wnt signaling reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution structure, binding assays with domain-specific constructs, and functional validation in a single rigorous study\",\n      \"pmids\": [\"29925589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Dkk4 selectively inhibits a subset of Wnts and is further inactivated by proteolytic cleavage. Intact Dkk4 inhibits meibomian gland extension, but the cleaved form progressively increases during meibomian gland development with a concomitant upswing in Wnt activity. Elevation of Lrp6 (a direct Eda target and Wnt co-receptor) eliminates Dkk4 inhibition in cell and organotypic cultures, and Lrp6 upregulation restores meibomian gland formation in Tabby mice.\",\n      \"method\": \"Transgenic mouse overexpression, cell culture, organotypic culture, in vivo genetic rescue (Lrp6 overexpression in Tabby mice), protein cleavage assays\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vivo and in vitro methods including genetic rescue and biochemical cleavage analysis\",\n      \"pmids\": [\"27864382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Dkk4 is a direct transcriptional target of the Eda-A1/Edar signaling pathway (the most highly induced gene in the microarray screen), and its expression in ectodermal placodes also depends on prior Wnt activity. Dkk4 functions as a Wnt antagonist in ectodermal placodes, acting downstream of Edar to provide lateral inhibition for correct patterning of hair follicles.\",\n      \"method\": \"Microarray profiling of Eda-A1-stimulated eda-/- skin explants, in situ hybridization/co-localization with Edar, genetic analysis in NF-kappaB-deficient and eda-/- mice\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — microarray confirmed with genetic models and localization, single lab\",\n      \"pmids\": [\"18508042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Dkk4 acts through an Eda-independent pathway to regulate secondary hair follicle development. A Dkk4 transgene blocked secondary follicle induction in Tabby (Eda-/y) mice without affecting primary hair, and Dkk4-regulated secondary hair development, like the Eda-dependent primary hair pathway, is further mediated by selective activation of Shh.\",\n      \"method\": \"Transgenic mouse overexpression, genetic epistasis with Tabby (Eda-/y) mice, Shh pathway analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic epistasis in multiple mouse models with specific pathway readout\",\n      \"pmids\": [\"20386733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TFAP2E-dependent chemoresistance to fluorouracil in colorectal cancer is mediated through DKK4. Colorectal cancer cell lines overexpressing DKK4 showed increased chemoresistance to fluorouracil but not irinotecan or oxaliplatin.\",\n      \"method\": \"Cell line overexpression, cell viability assays, TFAP2E methylation-function correlation in patient cohorts\",\n      \"journal\": \"The New England journal of medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional overexpression assay with drug specificity, corroborated by patient cohort data but mechanistic detail limited to cell viability\",\n      \"pmids\": [\"22216841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DKK4 attenuates Wnt/β-catenin signaling in hepatocellular carcinoma cells, reducing β-catenin-responsive luciferase activity, decreasing β-catenin and cyclin D1 protein levels, and its tumor-suppressive effect on β-catenin is masked by proteasome inhibition.\",\n      \"method\": \"Ectopic DKK4 expression in HCC cell lines, luciferase reporter assay, western blotting, proteasome inhibitor treatment, xenograft mouse model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay plus proteasome inhibitor rescue plus in vivo xenograft, single lab\",\n      \"pmids\": [\"22249261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Restoration of wild-type APC in SW480 colon cancer cells induces secretion of DKK4 via exosomes, associated with reduced DKK4 promoter methylation and downregulation of DNMT-3a.\",\n      \"method\": \"Comparative proteomic analysis of exosomes by mass spectrometry, RT-PCR, immunoblotting, immunogold electron microscopy, methylation-specific PCR\",\n      \"journal\": \"Electrophoresis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (proteomics, immunoblot, electron microscopy, methylation PCR) in single lab\",\n      \"pmids\": [\"22740476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Under hyperglycemic conditions, DKK4 expression is suppressed in HCC cells, leading to activation of canonical Wnt signaling and enhanced proliferation via β-catenin. Knockdown of DKK4 by shRNA promotes proliferation under normoglycemic conditions, which is suppressed by exogenous recombinant DKK4 protein.\",\n      \"method\": \"shRNA knockdown, recombinant protein rescue, β-catenin level measurement, cell cycle analysis, NOD/SCID mouse xenograft model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rescue with recombinant protein plus in vivo model, single lab\",\n      \"pmids\": [\"27272409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DKK4 knockdown in docetaxel-resistant A549/DTX cells reduces colony formation and invasion and promotes pro-apoptotic effects of docetaxel via caspase 3 activation and BCL-2 inhibition, possibly mediated by activation of the c-Jun N-terminal kinase (JNK) signaling pathway.\",\n      \"method\": \"shRNA knockdown, cell viability assay, flow cytometry for apoptosis, caspase 3 and BCL-2 western blotting, invasion assay\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple phenotypic readouts with pathway marker analysis, single lab\",\n      \"pmids\": [\"28981599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DLX3 regulates DKK4 expression through histone H3 lysine 27 trimethylation (H3K27me3) at the DKK4 promoter; DLX3 knockdown decreases H3K27me3 enrichment at the DKK4 promoter, increasing DKK4 expression and suppressing Wnt/β-catenin signaling during osteogenic differentiation of bone marrow mesenchymal stem cells.\",\n      \"method\": \"ChIP-qPCR, lentiviral overexpression/knockdown, RT-qPCR, western blotting, osteogenic differentiation assays (ALP, alizarin red staining)\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR directly demonstrates histone modification at DKK4 promoter, functional differentiation assays, single lab\",\n      \"pmids\": [\"31202458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DKK4 inhibits colorectal cancer metastasis through a negative feedback mechanism: Wnt3a and LiCl induce DKK4 expression, and DKK4 in turn represses Wnt/β-catenin signaling by suppressing FZD6 and AKT2/s552 β-catenin phosphorylation. RNA-seq after DKK4 knockdown revealed upregulation of AKT2, FZD6, and JUN.\",\n      \"method\": \"RNA-seq, luciferase reporter assay, transwell assays, subcutaneous and metastatic mouse tumor models, cell counting kit-8 assays, bioinformatics\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq plus reporter assay plus in vivo models identifying specific signaling nodes, single lab\",\n      \"pmids\": [\"36181792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LARP1 promotes DKK4 mRNA stabilization by competitively interacting with PABPC1 to prevent BTG2-dependent deadenylation and degradation of DKK4 mRNA, leading to elevated DKK4 protein, enhanced β-catenin expression and nuclear import in hepatoblastoma.\",\n      \"method\": \"Co-immunoprecipitation, RNA immunoprecipitation, RNA pull-down, mRNA stability assays, poly(A)-tail length assays, RNA-sequencing\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays (RIP, pull-down, mRNA stability) identifying specific mRNA regulatory mechanism, single lab\",\n      \"pmids\": [\"37070251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DKK4 secreted from colorectal cancer cells inactivates β-catenin in stromal fibroblasts, inducing formation of stress fiber-containing fibroblasts and myofibroblasts, resulting in restricted expansion of primary tumor masses but enhanced CRC metastasis. Chemical inhibition of β-catenin by MSAB promoted CRC metastasis, supporting that reduced β-catenin activity in the tumor stroma facilitates progression.\",\n      \"method\": \"CRC cell-fibroblast co-culture, mouse CRC xenograft models, chemical β-catenin inhibitor (MSAB) treatment, immunofluorescence for stress fibers/myofibroblast markers\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo models with mechanistic rescue and inhibitor experiments, single lab\",\n      \"pmids\": [\"38519641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL14 stimulates m6A methylation of DKK4 mRNA, stabilizing DKK4 expression and promoting docetaxel resistance and malignant progression in lung cancer. Downregulation of DKK4 reversed proliferation, cell cycle arrest, apoptosis resistance, migration, and M2 macrophage polarization in DTX-resistant cells.\",\n      \"method\": \"MeRIP assay (methylated RNA immunoprecipitation), RT-qPCR, western blot, EdU proliferation assay, flow cytometry, transwell assay, mouse xenograft model\",\n      \"journal\": \"Journal of biochemical and molecular toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP directly demonstrates m6A modification on DKK4 mRNA, functional assays in vitro and in vivo, single lab\",\n      \"pmids\": [\"41208390\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DKK4 is a secreted Wnt antagonist with two cysteine-rich domains (CRD1 and CRD2); CRD2 mediates high-affinity binding to LRP6 and Kremen1 to synergistically inhibit Wnt signaling, while its activity is further modulated by proteolytic cleavage and by the ratio of LRP6 levels. DKK4 is transcriptionally induced by the Eda/Edar pathway and repressed by DLX3-mediated H3K27me3 or by hyperglycemia-driven epigenetic silencing; its mRNA is stabilized by LARP1-dependent protection from deadenylation and by METTL14-mediated m6A modification. In cancer contexts DKK4 can act as either a tumor suppressor (HCC) or a pro-metastatic factor (CRC, via paracrine inactivation of β-catenin in stromal fibroblasts), and DKK4 overexpression confers resistance to fluorouracil and docetaxel partly through JNK pathway modulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DKK4 is a secreted Wnt/β-catenin pathway antagonist that shapes tissue patterning and tumor progression by binding Wnt co-receptors at the cell surface [#0, #2]. Structurally it comprises two independently folded cysteine-rich domains joined by a flexible linker, with CRD2 mediating high-affinity engagement of both the LRP6 E1E2 region and the Kremen1 extracellular domain, while the N-terminal NXI(R/K) motif binds LRP6 E1E2 with moderate affinity; Dkk and Kremen proteins act synergistically to inhibit Wnt signaling [#0]. DKK4 activity is tunable: it is inactivated by proteolytic cleavage and its inhibitory effect is overridden when LRP6 levels rise, a switch that controls Wnt-dependent appendage formation in vivo [#1]. In development DKK4 is the most highly induced direct transcriptional target of Eda-A1/Edar signaling and provides lateral inhibition for hair follicle patterning, while also acting through an Eda-independent route to restrain secondary follicle induction via selective Shh activation [#2, #3]. In cancer DKK4 represses canonical Wnt signaling by lowering β-catenin and cyclin D1 and by suppressing FZD6 and AKT2-dependent β-catenin phosphorylation, behaving as a tumor suppressor in hepatocellular carcinoma yet, when secreted, inactivating β-catenin in stromal fibroblasts to drive myofibroblast conversion and CRC metastasis [#5, #10, #12]. DKK4 expression is controlled at multiple layers — DLX3-directed H3K27me3 and promoter methylation repress it [#9, #6], hyperglycemia silences it to release Wnt-driven proliferation [#7], and LARP1-mediated protection from BTG2/PABPC1 deadenylation and METTL14-catalyzed m6A methylation stabilize its mRNA [#11, #13] — and its overexpression confers resistance to fluorouracil and docetaxel partly through JNK pathway modulation [#4, #8, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established DKK4 as a transcriptional output of Eda/Edar signaling acting as a Wnt antagonist for ectodermal patterning, placing it within a defined developmental signaling circuit.\",\n      \"evidence\": \"Microarray of Eda-A1-stimulated eda-/- skin explants with in situ localization and genetic models\",\n      \"pmids\": [\"18508042\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Did not resolve the molecular receptor interactions of DKK4\", \"Single lab, model-organism context only\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed DKK4 also functions in an Eda-independent pathway via Shh, distinguishing primary from secondary hair follicle control and broadening its developmental role.\",\n      \"evidence\": \"Transgenic overexpression and genetic epistasis in Tabby mice with Shh pathway analysis\",\n      \"pmids\": [\"20386733\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism linking DKK4 to selective Shh activation not defined\", \"No biochemical receptor data\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated context-dependent cancer roles — DKK4 suppresses Wnt/β-catenin and acts as a tumor suppressor in HCC, while mediating TFAP2E-dependent fluorouracil chemoresistance in colorectal cancer.\",\n      \"evidence\": \"Ectopic/overexpression in HCC and CRC cell lines, luciferase reporters, proteasome inhibitor rescue, xenografts, patient cohort correlation\",\n      \"pmids\": [\"22249261\", \"22216841\", \"22740476\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Opposing tumor-suppressive vs chemoresistance roles not mechanistically reconciled\", \"Chemoresistance mechanism limited to viability readout\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined two regulatory tuning mechanisms — proteolytic cleavage inactivation plus LRP6-level override in development, and hyperglycemia-driven suppression releasing Wnt-driven proliferation in cancer.\",\n      \"evidence\": \"Transgenic/organotypic culture with cleavage assays and Lrp6 rescue; shRNA knockdown with recombinant protein rescue and xenografts\",\n      \"pmids\": [\"27864382\", \"27272409\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Identity of the cleavage protease not determined\", \"Epigenetic basis of hyperglycemic suppression not fully resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved the structural and binding logic of DKK4, showing CRD2 binds LRP6 and Kremen1 with high affinity for synergistic Wnt inhibition.\",\n      \"evidence\": \"NMR structure, SPR binding with domain constructs, mutagenesis, Wnt reporter assays\",\n      \"pmids\": [\"29925589\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structure of full ternary LRP6–DKK4–Kremen complex not solved\", \"In vivo relevance of individual binding interfaces not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified an epigenetic repression mechanism whereby DLX3 deposits H3K27me3 at the DKK4 promoter to permit Wnt signaling during osteogenic differentiation.\",\n      \"evidence\": \"ChIP-qPCR, lentiviral knockdown/overexpression, osteogenic differentiation assays\",\n      \"pmids\": [\"31202458\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct vs indirect role of DLX3 in H3K27me3 deposition not separated\", \"Single lineage context\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed DKK4 in a negative-feedback loop where Wnt induces DKK4, which then represses FZD6 and AKT2-dependent β-catenin phosphorylation to limit CRC metastasis.\",\n      \"evidence\": \"RNA-seq, luciferase reporter, transwell, subcutaneous and metastatic mouse models\",\n      \"pmids\": [\"36181792\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Apparent conflict with pro-metastatic stromal role unresolved\", \"Direct DKK4 control of FZD6/AKT2 not biochemically shown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Uncovered post-transcriptional stabilization of DKK4 mRNA by LARP1 competing with PABPC1 to block BTG2-dependent deadenylation, elevating β-catenin in hepatoblastoma.\",\n      \"evidence\": \"Co-IP, RIP, RNA pull-down, mRNA stability and poly(A) assays, RNA-seq\",\n      \"pmids\": [\"37070251\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Why elevated DKK4 here increases rather than suppresses β-catenin not reconciled with antagonist role\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated a paracrine mechanism: secreted DKK4 inactivates β-catenin in stromal fibroblasts, driving myofibroblast conversion that restricts primary tumor growth but promotes CRC metastasis.\",\n      \"evidence\": \"Cancer cell–fibroblast co-culture, xenografts, MSAB β-catenin inhibitor, immunofluorescence\",\n      \"pmids\": [\"38519641\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Tumor-cell-autonomous vs stromal effects of DKK4 not fully disentangled\", \"Fibroblast receptor for secreted DKK4 not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed METTL14-catalyzed m6A methylation stabilizes DKK4 mRNA to promote docetaxel resistance, M2 macrophage polarization, and progression in lung cancer.\",\n      \"evidence\": \"MeRIP, RT-qPCR, EdU, flow cytometry, transwell, xenograft\",\n      \"pmids\": [\"41208390\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"m6A reader mediating DKK4 stabilization not identified\", \"Link between DKK4 and macrophage polarization mechanistically thin\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DKK4's opposing tumor-suppressive and pro-metastatic activities are determined by cellular context, secretion, and cleavage state remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No unifying model reconciling cell-autonomous Wnt suppression with paracrine stromal effects\", \"Protease and m6A reader identities unknown\", \"No full receptor-complex structure in a physiological tissue\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 5, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5, 10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 5, 12, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LRP6\", \"KREMEN1\", \"FZD6\", \"PABPC1\", \"LARP1\", \"METTL14\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}