{"gene":"DKK3","run_date":"2026-04-28T17:46:02","timeline":{"discoveries":[{"year":2004,"finding":"DKK3/REIC protein exists as two isoforms (55 kDa cytosolic and 50 kDa secreted), is N-glycosylated, and ectopic expression induces apoptosis and suppresses tumor growth in vitro and in vivo.","method":"Ectopic expression in HeLa, Hep3B, Huh7 cells; colony formation assay; xenograft in nude mice; biochemical characterization","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — multiple cell lines and in vivo model, but single lab","pmids":["15516983"],"is_preprint":false},{"year":2001,"finding":"REIC/DKK3 expression is cell-cycle regulated (lowest in late G1 phase), and exogenous expression inhibits tumor cell growth, consistent with a tumor suppressor role.","method":"Cell cycle synchronization, northern blot, exogenous gene expression in tumor cells","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — cell-cycle-linked expression and growth inhibition shown, single lab","pmids":["11708809"],"is_preprint":false},{"year":2002,"finding":"DKK3/REIC gene downregulation in tumor cells is caused by promoter hypermethylation; treatment with 5-aza-deoxycytidine restores expression, confirming epigenetic silencing as the mechanism.","method":"Methylation-specific PCR, bisulfite sequencing, 5-aza-deoxycytidine demethylation treatment","journal":"Gene","confidence":"High","confidence_rationale":"Tier 1-2 — direct pharmacological reversal of methylation restoring expression, confirmed in multiple tumor lines","pmids":["11814687"],"is_preprint":false},{"year":2007,"finding":"DKK3 downregulation in lung cancer activates Wnt/beta-catenin/TCF-4 signaling; ectopic DKK3 expression inhibits TCF-4 activity, nuclear beta-catenin accumulation, and expression of TCF-4 targets c-Myc and cyclin D1; DKK3 siRNA knockdown promotes beta-catenin nuclear translocation.","method":"Ectopic expression, siRNA knockdown, TCF-4 reporter assay, immunofluorescence for nuclear beta-catenin, western blot for c-Myc and cyclin D1","journal":"Carcinogenesis","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (reporter assay, localization, target gene expression, KD and OE), replicated pathway placement","pmids":["18048388"],"is_preprint":false},{"year":2007,"finding":"In testicular cancer cells, DKK3/REIC overexpression via adenovirus activates JNK signaling, leading to apoptosis; a JNK inhibitor abrogates this apoptosis, placing JNK downstream of DKK3.","method":"Adenoviral overexpression, JNK inhibitor treatment, apoptosis assay, xenograft model","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis via pharmacological JNK inhibition, in vitro and in vivo, single lab","pmids":["17273781"],"is_preprint":false},{"year":2008,"finding":"In glioblastoma cells, DKK3/REIC transfection induces apoptosis through activation of phospho-JNK, caspase-9, and caspase-3, and reduction of beta-catenin; DKK3 knockdown augments cell growth.","method":"Transfection, siRNA knockdown, western blot for phospho-JNK/caspase-9/caspase-3/beta-catenin, apoptosis assay","journal":"Neuro-oncology","confidence":"Medium","confidence_rationale":"Tier 2 — bidirectional manipulation (OE and KD) with defined molecular readouts, single lab","pmids":["18443132"],"is_preprint":false},{"year":2009,"finding":"DKK3/REIC overexpression in normal human fibroblasts triggers ER stress-mediated IL-7 production through the IRE1alpha–ASK1–p38–IRF-1 pathway; this IL-7 production mediates indirect anti-tumor effects when fibroblasts are co-transplanted with cancer cells.","method":"Adenoviral overexpression, IL-7 ELISA, IL-7 antibody neutralization, co-transplantation xenograft, western blot for IRE1alpha/ASK1/p38/IRF-1","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — mechanistic pathway dissected with multiple components, in vitro and in vivo rescue with antibody, single lab but multiple orthogonal methods","pmids":["19279003"],"is_preprint":false},{"year":2009,"finding":"Recombinant DKK3/REIC secreted protein induces differentiation of human CD14+ monocytes into a dendritic cell-like phenotype and activates STAT1 and STAT3 phosphorylation; intratumoral DKK3 protein administration suppresses tumor growth with accumulation of CD11c+ and CD8+ cells.","method":"Recombinant protein treatment of monocytes, flow cytometry, STAT phosphorylation western blot, intratumoral protein injection in mice","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 — recombinant protein mechanistic study with signaling and in vivo readouts, single lab","pmids":["19212670"],"is_preprint":false},{"year":2010,"finding":"BiP/GRP78, an ER chaperone, is a key determinant of resistance to DKK3/REIC-induced apoptosis; BiP is upregulated in Ad-REIC-resistant cancer cells, and siRNA knockdown of BiP sensitizes resistant cells to apoptosis, revealing that DKK3-induced apoptosis is ER stress-dependent.","method":"Resistant clone isolation, siRNA knockdown of BiP, apoptosis assay in vitro and in vivo, western blot","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — direct mechanistic link between BiP and DKK3-induced ER stress apoptosis, single lab","pmids":["19626590"],"is_preprint":false},{"year":2015,"finding":"Dkk3 transgenic overexpression in mice with dilated cardiomyopathy (DCM) upregulates Dvl1 and canonical Wnt pathway proteins (cytoplasmic/nuclear beta-catenin, c-Myc, Axin2) while downregulating non-canonical Wnt pathway effectors (JNK, CAMKII, HDAC4); Dkk3 knockout has the opposite effect, indicating Dkk3 modulates cardiac Wnt signaling balance.","method":"Transgenic and knockout mouse models crossed with DCM model (cTnT-R141W), western blot, survival analysis, cardiac function assessment","journal":"Laboratory investigation; a journal of technical methods and pathology","confidence":"High","confidence_rationale":"Tier 2 — bidirectional genetic manipulation (Tg and KO) in disease model with defined molecular pathway changes, multiple orthogonal readouts","pmids":["26641069"],"is_preprint":false},{"year":2016,"finding":"In hepatocytes, DKK3 physically binds to ASK1 under palmitate stimulation and inhibits ASK1-mediated activation of the downstream P38/JNK pathway; hepatocyte-specific DKK3 overexpression improves insulin sensitivity and reduces hepatic steatosis, while DKK3 deficiency worsens these phenotypes. Dominant-negative ASK1 blocks DKK3-deficiency effects, and constitutively active ASK1 overcomes DKK3 overexpression.","method":"Co-immunoprecipitation (DKK3-ASK1 binding), hepatocyte-specific KO and OE mouse models, dominant-negative and constitutively active ASK1, metabolic phenotyping","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 1-2 — direct protein interaction shown by Co-IP, confirmed by epistasis with ASK1 mutants, in vivo bidirectional genetic models","pmids":["27016281"],"is_preprint":false},{"year":2017,"finding":"The Dkk3 locus encodes an intracellular isoform (Dkk3b) originating from intron 2; Dkk3b captures cytoplasmic unphosphorylated beta-catenin in an extra-nuclear complex with beta-TrCP, preventing nuclear translocation of beta-catenin and thereby arresting cell proliferation.","method":"Identification of novel transcription start site, co-immunoprecipitation of Dkk3b with beta-catenin and beta-TrCP, nuclear fractionation, cell proliferation assays, early mouse development studies","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP identifying novel complex, fractionation showing sequestration mechanism, single lab","pmids":["28738084"],"is_preprint":false},{"year":2015,"finding":"The cysteine-rich C-terminal core domain (C17-REIC) of DKK3/REIC is sufficient for induction of dendritic cell-like differentiation from monocytes; DKK3 induces phosphorylation of GSK-3beta and STAT proteins comparable to GM-CSF, and C17-REIC exerts anticancer immune effects in vivo.","method":"Recombinant truncated protein domain analysis, monocyte differentiation assay, GSK-3beta and STAT phosphorylation western blot, subcutaneous tumor model","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 — domain mapping with functional readout, signaling characterization, in vivo confirmation, single lab","pmids":["25823913"],"is_preprint":false},{"year":2022,"finding":"DKK3 ameliorates neuropathic pain by inhibiting ASK1/JNK/p38-mediated microglial M1 polarization through the Kremen-1 and DVL-1 pathways; siRNA knockdown of Kremen-1 or DVL-1 reverses the inhibitory effects of exogenous DKK3 on ASK1/JNK/p38 activation.","method":"Intrathecal injection of recombinant DKK3, siRNA knockdown of Kremen-1 and DVL-1, western blot, immunofluorescence, ELISA, behavioral testing in SNI rats","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis via receptor siRNA knockdown placing DKK3 upstream of ASK1/JNK/p38 via Kremen-1/DVL-1, single lab","pmids":["35658977"],"is_preprint":false},{"year":2019,"finding":"miR-95-3p directly targets DKK3 (validated by dual luciferase assay), and miR-95-3p-mediated suppression of DKK3 activates Wnt/beta-catenin pathway, promoting prostate cancer cell proliferation, migration, and invasion.","method":"Dual luciferase reporter assay, miRNA overexpression/inhibition, western blot for beta-catenin targets, xenograft tumor formation","journal":"European review for medical and pharmacological sciences","confidence":"Medium","confidence_rationale":"Tier 2 — direct miRNA-target validation by luciferase assay with functional consequences in vitro and in vivo, single lab","pmids":["30779066"],"is_preprint":false},{"year":2012,"finding":"In gastric cancer cells, DKK3/REIC overexpression downregulates beta-catenin, phosphorylated S6K, phosphorylated Akt, cyclin D2/E, and WAVE2, causing G1 arrest, apoptosis, and reduced migration; an anti-REIC antibody blocks these effects, confirming a cell-surface/secreted action component.","method":"Plasmid transfection, siRNA knockdown, recombinant protein treatment, anti-REIC antibody blocking, flow cytometry, western blot","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 — three modes of manipulation (OE, KD, recombinant protein + antibody block), multiple signaling readouts, single lab","pmids":["22421143"],"is_preprint":false}],"current_model":"DKK3 (REIC) is a secreted, N-glycosylated protein that functions as a context-dependent regulator of Wnt/beta-catenin signaling, ER stress, and ASK1/JNK/p38 pathway activity: intracellularly, its Dkk3b isoform sequesters unphosphorylated beta-catenin with beta-TrCP to prevent nuclear translocation; extracellularly, it binds ASK1 to inhibit downstream JNK/p38 activation; in cancer cells, DKK3 overexpression triggers ER stress-dependent, JNK/caspase-mediated apoptosis, while its secreted form induces monocyte differentiation into dendritic-like cells via STAT1/3 and GSK-3beta phosphorylation, collectively supporting its role as a tumor suppressor whose promoter is frequently silenced by hypermethylation."},"narrative":{"teleology":[{"year":2001,"claim":"Initial characterization established that REIC/DKK3 expression is cell-cycle regulated and that its exogenous expression inhibits tumor cell growth, raising the question of whether it acts as a tumor suppressor.","evidence":"Cell cycle synchronization, northern blot, and exogenous expression in tumor cells","pmids":["11708809"],"confidence":"Medium","gaps":["No mechanism for growth inhibition identified","Downstream signaling pathway unknown","Expression regulation unexplored"]},{"year":2002,"claim":"The mechanism of DKK3 silencing in cancer was resolved as promoter hypermethylation, explaining its frequent downregulation in tumors and establishing it as an epigenetically regulated tumor suppressor.","evidence":"Methylation-specific PCR, bisulfite sequencing, and 5-aza-deoxycytidine demethylation restoring expression across multiple tumor lines","pmids":["11814687"],"confidence":"High","gaps":["Whether methylation is the sole silencing mechanism was not addressed","Upstream signals driving methylation unknown"]},{"year":2004,"claim":"Biochemical characterization revealed two DKK3 isoforms (55 kDa cytosolic and 50 kDa secreted) with N-glycosylation, and showed that ectopic expression induces apoptosis and suppresses xenograft tumor growth, establishing a direct tumor-suppressive function.","evidence":"Ectopic expression in multiple cell lines, colony formation, xenograft in nude mice, biochemical analysis","pmids":["15516983"],"confidence":"Medium","gaps":["Apoptotic signaling pathway not dissected","Functional distinction between the two isoforms unresolved"]},{"year":2007,"claim":"Two studies placed DKK3 in defined signaling pathways: it inhibits Wnt/beta-catenin/TCF-4 signaling (reducing nuclear beta-catenin, c-Myc, and cyclin D1) and activates JNK-dependent apoptosis in cancer cells, resolving the long-standing question of its downstream effectors.","evidence":"siRNA and overexpression with TCF-4 reporter assays and immunofluorescence (lung cancer); adenoviral overexpression with JNK inhibitor epistasis (testicular cancer)","pmids":["18048388","17273781"],"confidence":"High","gaps":["Whether Wnt inhibition and JNK activation are linked or independent pathways was unclear","Receptor for DKK3 not identified"]},{"year":2009,"claim":"The mechanism of DKK3-induced apoptosis was refined to involve ER stress via IRE1alpha–ASK1–p38, and the secreted protein was shown to drive monocyte-to-dendritic-cell differentiation through STAT1/3 activation, revealing both cell-autonomous and immune-mediated tumor-suppressive arms.","evidence":"Adenoviral overexpression in fibroblasts with IRE1alpha/ASK1/p38 pathway analysis and IL-7 antibody neutralization; recombinant DKK3 protein on monocytes with STAT phosphorylation and in vivo immune cell accumulation","pmids":["19279003","19212670"],"confidence":"High","gaps":["DKK3 receptor mediating monocyte differentiation unknown","Whether ER stress pathway operates in all cancer types not established"]},{"year":2010,"claim":"The ER chaperone BiP/GRP78 was identified as a key determinant of resistance to DKK3-induced apoptosis, confirming the centrality of ER stress in DKK3's pro-apoptotic mechanism.","evidence":"Resistant clone isolation, BiP siRNA knockdown sensitizing resistant cells to DKK3-induced apoptosis in vitro and in vivo","pmids":["19626590"],"confidence":"Medium","gaps":["Whether DKK3 directly triggers unfolded protein response or acts indirectly unknown","Structural basis for DKK3-ER stress interaction unresolved"]},{"year":2012,"claim":"Antibody-blocking experiments demonstrated that secreted DKK3 acts at the cell surface to downregulate beta-catenin, Akt, and S6K signaling and induce G1 arrest, establishing that a receptor-mediated extracellular mechanism contributes to its tumor-suppressive function.","evidence":"Recombinant DKK3 protein treatment with anti-REIC antibody block, combined with overexpression and siRNA in gastric cancer cells","pmids":["22421143"],"confidence":"Medium","gaps":["Identity of the cell-surface receptor not determined","Relationship between beta-catenin and Akt arm inhibition unclear"]},{"year":2015,"claim":"Two advances defined DKK3 function in new contexts: in dilated cardiomyopathy mouse models, Dkk3 shifts the balance from non-canonical (JNK/CAMKII) to canonical Wnt signaling, and the C-terminal cysteine-rich domain (C17-REIC) was mapped as sufficient for monocyte-to-DC differentiation and GSK-3beta phosphorylation.","evidence":"Transgenic and knockout mice crossed with DCM model with bidirectional molecular readouts; recombinant truncated domain analysis with monocyte differentiation and signaling assays","pmids":["26641069","25823913"],"confidence":"High","gaps":["How DKK3 discriminates between canonical and non-canonical Wnt arms mechanistically unknown","No structural model for C17-REIC domain activity"]},{"year":2016,"claim":"DKK3 was shown to physically bind ASK1 and inhibit downstream P38/JNK signaling in hepatocytes, with epistasis using dominant-negative and constitutively active ASK1 confirming ASK1 as the direct effector mediating DKK3's metabolic protective functions.","evidence":"Co-immunoprecipitation of DKK3–ASK1, hepatocyte-specific KO and OE mice, epistasis with ASK1 mutants, metabolic phenotyping","pmids":["27016281"],"confidence":"High","gaps":["Binding interface and stoichiometry of DKK3–ASK1 interaction uncharacterized","Whether DKK3–ASK1 interaction operates in all DKK3-expressing tissues unknown"]},{"year":2017,"claim":"Discovery of the Dkk3b isoform originating from intron 2 resolved the intracellular mechanism: Dkk3b captures unphosphorylated beta-catenin with beta-TrCP in the cytoplasm, preventing nuclear translocation and proliferation.","evidence":"Novel transcription start site mapping, co-immunoprecipitation of Dkk3b with beta-catenin and beta-TrCP, nuclear fractionation, proliferation assays","pmids":["28738084"],"confidence":"Medium","gaps":["Dkk3b-beta-catenin-beta-TrCP complex validated only by Co-IP without reciprocal pulldown or in vitro reconstitution","Relative contribution of Dkk3b vs. secreted DKK3 in vivo not delineated"]},{"year":2022,"claim":"DKK3 was placed upstream of ASK1/JNK/p38 in microglia via Kremen-1 and DVL-1, with siRNA epistasis showing these receptors are required for DKK3's inhibitory effects on microglial M1 polarization and neuropathic pain.","evidence":"Intrathecal DKK3 injection with Kremen-1 and DVL-1 siRNA knockdown, behavioral testing, western blot, and immunofluorescence in SNI rats","pmids":["35658977"],"confidence":"Medium","gaps":["Whether DKK3 directly binds Kremen-1 not demonstrated by direct binding assay","Relevance to human neuropathic pain not tested"]},{"year":null,"claim":"The identity of the primary cell-surface receptor for secreted DKK3 remains unresolved: unlike other DKK family members, DKK3 does not bind canonical LRP5/6 co-receptors with high affinity, and whether Kremen-1 is a direct receptor or acts indirectly is unknown.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-affinity receptor identified by direct binding assay","Structural basis for DKK3 selectivity within the DKK family unknown","Integrated model reconciling ER stress, Wnt inhibition, and ASK1 binding in a unified signaling framework is lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,9,10,11]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[11]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,7,12,15]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,11]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[6,8]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,9,10,11,13,14]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[4,5,6,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,12]}],"complexes":[],"partners":["ASK1","BTRC","CTNNB1","DVL1","KREMEN1","HSPA5"],"other_free_text":[]},"mechanistic_narrative":"DKK3 (also known as REIC) is a secreted, N-glycosylated Wnt pathway modulator that functions as a tumor suppressor by antagonizing beta-catenin nuclear translocation and activating stress-induced apoptotic signaling. Extracellularly, DKK3 inhibits Wnt/beta-catenin/TCF-4 signaling, reducing expression of targets such as c-Myc and cyclin D1, and physically binds ASK1 to suppress downstream JNK/p38 activation in contexts including hepatic metabolism and neuroinflammation [PMID:18048388, PMID:27016281, PMID:35658977]. An intracellular isoform (Dkk3b) sequesters unphosphorylated beta-catenin with beta-TrCP in the cytoplasm, preventing its nuclear entry and arresting proliferation [PMID:28738084]. Overexpression in cancer cells triggers ER stress–dependent, JNK/caspase-mediated apoptosis—with resistance conferred by the ER chaperone BiP—while the secreted protein also drives monocyte-to-dendritic-cell differentiation through STAT1/3 and GSK-3beta phosphorylation, and the DKK3 promoter is frequently silenced in tumors by DNA hypermethylation [PMID:19626590, PMID:19212670, PMID:11814687]."},"prefetch_data":{"uniprot":{"accession":"Q9UBP4","full_name":"Dickkopf-related protein 3","aliases":[],"length_aa":350,"mass_kda":38.4,"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/Q9UBP4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DKK3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DKK3","total_profiled":1310},"omim":[{"mim_id":"605418","title":"DICKKOPF-LIKE 1; DKKL1","url":"https://www.omim.org/entry/605418"},{"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":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"choroid plexus","ntpm":371.6},{"tissue":"heart muscle","ntpm":1240.0}],"url":"https://www.proteinatlas.org/search/DKK3"},"hgnc":{"alias_symbol":["REIC","RIG","CRRL"],"prev_symbol":[]},"alphafold":{"accession":"Q9UBP4","domains":[{"cath_id":"-","chopping":"91-139","consensus_level":"high","plddt":78.7906,"start":91,"end":139}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBP4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBP4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBP4-F1-predicted_aligned_error_v6.png","plddt_mean":73.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DKK3","jax_strain_url":"https://www.jax.org/strain/search?query=DKK3"},"sequence":{"accession":"Q9UBP4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UBP4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UBP4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBP4"}},"corpus_meta":[{"pmid":"16625202","id":"PMC_16625202","title":"Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses.","date":"2006","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/16625202","citation_count":3054,"is_preprint":false},{"pmid":"21616437","id":"PMC_21616437","title":"Immune signaling by RIG-I-like receptors.","date":"2011","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/21616437","citation_count":1463,"is_preprint":false},{"pmid":"32203325","id":"PMC_32203325","title":"RIG-I-like receptors: their regulation and roles in RNA sensing.","date":"2020","source":"Nature reviews. 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\"confidence_rationale\": \"Tier 2 — multiple cell lines and in vivo model, but single lab\",\n      \"pmids\": [\"15516983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"REIC/DKK3 expression is cell-cycle regulated (lowest in late G1 phase), and exogenous expression inhibits tumor cell growth, consistent with a tumor suppressor role.\",\n      \"method\": \"Cell cycle synchronization, northern blot, exogenous gene expression in tumor cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-cycle-linked expression and growth inhibition shown, single lab\",\n      \"pmids\": [\"11708809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"DKK3/REIC gene downregulation in tumor cells is caused by promoter hypermethylation; treatment with 5-aza-deoxycytidine restores expression, confirming epigenetic silencing as the mechanism.\",\n      \"method\": \"Methylation-specific PCR, bisulfite sequencing, 5-aza-deoxycytidine demethylation treatment\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct pharmacological reversal of methylation restoring expression, confirmed in multiple tumor lines\",\n      \"pmids\": [\"11814687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"DKK3 downregulation in lung cancer activates Wnt/beta-catenin/TCF-4 signaling; ectopic DKK3 expression inhibits TCF-4 activity, nuclear beta-catenin accumulation, and expression of TCF-4 targets c-Myc and cyclin D1; DKK3 siRNA knockdown promotes beta-catenin nuclear translocation.\",\n      \"method\": \"Ectopic expression, siRNA knockdown, TCF-4 reporter assay, immunofluorescence for nuclear beta-catenin, western blot for c-Myc and cyclin D1\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (reporter assay, localization, target gene expression, KD and OE), replicated pathway placement\",\n      \"pmids\": [\"18048388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In testicular cancer cells, DKK3/REIC overexpression via adenovirus activates JNK signaling, leading to apoptosis; a JNK inhibitor abrogates this apoptosis, placing JNK downstream of DKK3.\",\n      \"method\": \"Adenoviral overexpression, JNK inhibitor treatment, apoptosis assay, xenograft model\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis via pharmacological JNK inhibition, in vitro and in vivo, single lab\",\n      \"pmids\": [\"17273781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In glioblastoma cells, DKK3/REIC transfection induces apoptosis through activation of phospho-JNK, caspase-9, and caspase-3, and reduction of beta-catenin; DKK3 knockdown augments cell growth.\",\n      \"method\": \"Transfection, siRNA knockdown, western blot for phospho-JNK/caspase-9/caspase-3/beta-catenin, apoptosis assay\",\n      \"journal\": \"Neuro-oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional manipulation (OE and KD) with defined molecular readouts, single lab\",\n      \"pmids\": [\"18443132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DKK3/REIC overexpression in normal human fibroblasts triggers ER stress-mediated IL-7 production through the IRE1alpha–ASK1–p38–IRF-1 pathway; this IL-7 production mediates indirect anti-tumor effects when fibroblasts are co-transplanted with cancer cells.\",\n      \"method\": \"Adenoviral overexpression, IL-7 ELISA, IL-7 antibody neutralization, co-transplantation xenograft, western blot for IRE1alpha/ASK1/p38/IRF-1\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway dissected with multiple components, in vitro and in vivo rescue with antibody, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"19279003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Recombinant DKK3/REIC secreted protein induces differentiation of human CD14+ monocytes into a dendritic cell-like phenotype and activates STAT1 and STAT3 phosphorylation; intratumoral DKK3 protein administration suppresses tumor growth with accumulation of CD11c+ and CD8+ cells.\",\n      \"method\": \"Recombinant protein treatment of monocytes, flow cytometry, STAT phosphorylation western blot, intratumoral protein injection in mice\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — recombinant protein mechanistic study with signaling and in vivo readouts, single lab\",\n      \"pmids\": [\"19212670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"BiP/GRP78, an ER chaperone, is a key determinant of resistance to DKK3/REIC-induced apoptosis; BiP is upregulated in Ad-REIC-resistant cancer cells, and siRNA knockdown of BiP sensitizes resistant cells to apoptosis, revealing that DKK3-induced apoptosis is ER stress-dependent.\",\n      \"method\": \"Resistant clone isolation, siRNA knockdown of BiP, apoptosis assay in vitro and in vivo, western blot\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct mechanistic link between BiP and DKK3-induced ER stress apoptosis, single lab\",\n      \"pmids\": [\"19626590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Dkk3 transgenic overexpression in mice with dilated cardiomyopathy (DCM) upregulates Dvl1 and canonical Wnt pathway proteins (cytoplasmic/nuclear beta-catenin, c-Myc, Axin2) while downregulating non-canonical Wnt pathway effectors (JNK, CAMKII, HDAC4); Dkk3 knockout has the opposite effect, indicating Dkk3 modulates cardiac Wnt signaling balance.\",\n      \"method\": \"Transgenic and knockout mouse models crossed with DCM model (cTnT-R141W), western blot, survival analysis, cardiac function assessment\",\n      \"journal\": \"Laboratory investigation; a journal of technical methods and pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional genetic manipulation (Tg and KO) in disease model with defined molecular pathway changes, multiple orthogonal readouts\",\n      \"pmids\": [\"26641069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In hepatocytes, DKK3 physically binds to ASK1 under palmitate stimulation and inhibits ASK1-mediated activation of the downstream P38/JNK pathway; hepatocyte-specific DKK3 overexpression improves insulin sensitivity and reduces hepatic steatosis, while DKK3 deficiency worsens these phenotypes. Dominant-negative ASK1 blocks DKK3-deficiency effects, and constitutively active ASK1 overcomes DKK3 overexpression.\",\n      \"method\": \"Co-immunoprecipitation (DKK3-ASK1 binding), hepatocyte-specific KO and OE mouse models, dominant-negative and constitutively active ASK1, metabolic phenotyping\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct protein interaction shown by Co-IP, confirmed by epistasis with ASK1 mutants, in vivo bidirectional genetic models\",\n      \"pmids\": [\"27016281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The Dkk3 locus encodes an intracellular isoform (Dkk3b) originating from intron 2; Dkk3b captures cytoplasmic unphosphorylated beta-catenin in an extra-nuclear complex with beta-TrCP, preventing nuclear translocation of beta-catenin and thereby arresting cell proliferation.\",\n      \"method\": \"Identification of novel transcription start site, co-immunoprecipitation of Dkk3b with beta-catenin and beta-TrCP, nuclear fractionation, cell proliferation assays, early mouse development studies\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP identifying novel complex, fractionation showing sequestration mechanism, single lab\",\n      \"pmids\": [\"28738084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The cysteine-rich C-terminal core domain (C17-REIC) of DKK3/REIC is sufficient for induction of dendritic cell-like differentiation from monocytes; DKK3 induces phosphorylation of GSK-3beta and STAT proteins comparable to GM-CSF, and C17-REIC exerts anticancer immune effects in vivo.\",\n      \"method\": \"Recombinant truncated protein domain analysis, monocyte differentiation assay, GSK-3beta and STAT phosphorylation western blot, subcutaneous tumor model\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mapping with functional readout, signaling characterization, in vivo confirmation, single lab\",\n      \"pmids\": [\"25823913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DKK3 ameliorates neuropathic pain by inhibiting ASK1/JNK/p38-mediated microglial M1 polarization through the Kremen-1 and DVL-1 pathways; siRNA knockdown of Kremen-1 or DVL-1 reverses the inhibitory effects of exogenous DKK3 on ASK1/JNK/p38 activation.\",\n      \"method\": \"Intrathecal injection of recombinant DKK3, siRNA knockdown of Kremen-1 and DVL-1, western blot, immunofluorescence, ELISA, behavioral testing in SNI rats\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis via receptor siRNA knockdown placing DKK3 upstream of ASK1/JNK/p38 via Kremen-1/DVL-1, single lab\",\n      \"pmids\": [\"35658977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-95-3p directly targets DKK3 (validated by dual luciferase assay), and miR-95-3p-mediated suppression of DKK3 activates Wnt/beta-catenin pathway, promoting prostate cancer cell proliferation, migration, and invasion.\",\n      \"method\": \"Dual luciferase reporter assay, miRNA overexpression/inhibition, western blot for beta-catenin targets, xenograft tumor formation\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct miRNA-target validation by luciferase assay with functional consequences in vitro and in vivo, single lab\",\n      \"pmids\": [\"30779066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In gastric cancer cells, DKK3/REIC overexpression downregulates beta-catenin, phosphorylated S6K, phosphorylated Akt, cyclin D2/E, and WAVE2, causing G1 arrest, apoptosis, and reduced migration; an anti-REIC antibody blocks these effects, confirming a cell-surface/secreted action component.\",\n      \"method\": \"Plasmid transfection, siRNA knockdown, recombinant protein treatment, anti-REIC antibody blocking, flow cytometry, western blot\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — three modes of manipulation (OE, KD, recombinant protein + antibody block), multiple signaling readouts, single lab\",\n      \"pmids\": [\"22421143\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DKK3 (REIC) is a secreted, N-glycosylated protein that functions as a context-dependent regulator of Wnt/beta-catenin signaling, ER stress, and ASK1/JNK/p38 pathway activity: intracellularly, its Dkk3b isoform sequesters unphosphorylated beta-catenin with beta-TrCP to prevent nuclear translocation; extracellularly, it binds ASK1 to inhibit downstream JNK/p38 activation; in cancer cells, DKK3 overexpression triggers ER stress-dependent, JNK/caspase-mediated apoptosis, while its secreted form induces monocyte differentiation into dendritic-like cells via STAT1/3 and GSK-3beta phosphorylation, collectively supporting its role as a tumor suppressor whose promoter is frequently silenced by hypermethylation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"DKK3 (also known as REIC) is a secreted, N-glycosylated Wnt pathway modulator that functions as a tumor suppressor by antagonizing beta-catenin nuclear translocation and activating stress-induced apoptotic signaling. Extracellularly, DKK3 inhibits Wnt/beta-catenin/TCF-4 signaling, reducing expression of targets such as c-Myc and cyclin D1, and physically binds ASK1 to suppress downstream JNK/p38 activation in contexts including hepatic metabolism and neuroinflammation [PMID:18048388, PMID:27016281, PMID:35658977]. An intracellular isoform (Dkk3b) sequesters unphosphorylated beta-catenin with beta-TrCP in the cytoplasm, preventing its nuclear entry and arresting proliferation [PMID:28738084]. Overexpression in cancer cells triggers ER stress–dependent, JNK/caspase-mediated apoptosis—with resistance conferred by the ER chaperone BiP—while the secreted protein also drives monocyte-to-dendritic-cell differentiation through STAT1/3 and GSK-3beta phosphorylation, and the DKK3 promoter is frequently silenced in tumors by DNA hypermethylation [PMID:19626590, PMID:19212670, PMID:11814687].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Initial characterization established that REIC/DKK3 expression is cell-cycle regulated and that its exogenous expression inhibits tumor cell growth, raising the question of whether it acts as a tumor suppressor.\",\n      \"evidence\": \"Cell cycle synchronization, northern blot, and exogenous expression in tumor cells\",\n      \"pmids\": [\"11708809\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mechanism for growth inhibition identified\", \"Downstream signaling pathway unknown\", \"Expression regulation unexplored\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"The mechanism of DKK3 silencing in cancer was resolved as promoter hypermethylation, explaining its frequent downregulation in tumors and establishing it as an epigenetically regulated tumor suppressor.\",\n      \"evidence\": \"Methylation-specific PCR, bisulfite sequencing, and 5-aza-deoxycytidine demethylation restoring expression across multiple tumor lines\",\n      \"pmids\": [\"11814687\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether methylation is the sole silencing mechanism was not addressed\", \"Upstream signals driving methylation unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Biochemical characterization revealed two DKK3 isoforms (55 kDa cytosolic and 50 kDa secreted) with N-glycosylation, and showed that ectopic expression induces apoptosis and suppresses xenograft tumor growth, establishing a direct tumor-suppressive function.\",\n      \"evidence\": \"Ectopic expression in multiple cell lines, colony formation, xenograft in nude mice, biochemical analysis\",\n      \"pmids\": [\"15516983\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apoptotic signaling pathway not dissected\", \"Functional distinction between the two isoforms unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Two studies placed DKK3 in defined signaling pathways: it inhibits Wnt/beta-catenin/TCF-4 signaling (reducing nuclear beta-catenin, c-Myc, and cyclin D1) and activates JNK-dependent apoptosis in cancer cells, resolving the long-standing question of its downstream effectors.\",\n      \"evidence\": \"siRNA and overexpression with TCF-4 reporter assays and immunofluorescence (lung cancer); adenoviral overexpression with JNK inhibitor epistasis (testicular cancer)\",\n      \"pmids\": [\"18048388\", \"17273781\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Wnt inhibition and JNK activation are linked or independent pathways was unclear\", \"Receptor for DKK3 not identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The mechanism of DKK3-induced apoptosis was refined to involve ER stress via IRE1alpha–ASK1–p38, and the secreted protein was shown to drive monocyte-to-dendritic-cell differentiation through STAT1/3 activation, revealing both cell-autonomous and immune-mediated tumor-suppressive arms.\",\n      \"evidence\": \"Adenoviral overexpression in fibroblasts with IRE1alpha/ASK1/p38 pathway analysis and IL-7 antibody neutralization; recombinant DKK3 protein on monocytes with STAT phosphorylation and in vivo immune cell accumulation\",\n      \"pmids\": [\"19279003\", \"19212670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"DKK3 receptor mediating monocyte differentiation unknown\", \"Whether ER stress pathway operates in all cancer types not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"The ER chaperone BiP/GRP78 was identified as a key determinant of resistance to DKK3-induced apoptosis, confirming the centrality of ER stress in DKK3's pro-apoptotic mechanism.\",\n      \"evidence\": \"Resistant clone isolation, BiP siRNA knockdown sensitizing resistant cells to DKK3-induced apoptosis in vitro and in vivo\",\n      \"pmids\": [\"19626590\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether DKK3 directly triggers unfolded protein response or acts indirectly unknown\", \"Structural basis for DKK3-ER stress interaction unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Antibody-blocking experiments demonstrated that secreted DKK3 acts at the cell surface to downregulate beta-catenin, Akt, and S6K signaling and induce G1 arrest, establishing that a receptor-mediated extracellular mechanism contributes to its tumor-suppressive function.\",\n      \"evidence\": \"Recombinant DKK3 protein treatment with anti-REIC antibody block, combined with overexpression and siRNA in gastric cancer cells\",\n      \"pmids\": [\"22421143\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the cell-surface receptor not determined\", \"Relationship between beta-catenin and Akt arm inhibition unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Two advances defined DKK3 function in new contexts: in dilated cardiomyopathy mouse models, Dkk3 shifts the balance from non-canonical (JNK/CAMKII) to canonical Wnt signaling, and the C-terminal cysteine-rich domain (C17-REIC) was mapped as sufficient for monocyte-to-DC differentiation and GSK-3beta phosphorylation.\",\n      \"evidence\": \"Transgenic and knockout mice crossed with DCM model with bidirectional molecular readouts; recombinant truncated domain analysis with monocyte differentiation and signaling assays\",\n      \"pmids\": [\"26641069\", \"25823913\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How DKK3 discriminates between canonical and non-canonical Wnt arms mechanistically unknown\", \"No structural model for C17-REIC domain activity\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"DKK3 was shown to physically bind ASK1 and inhibit downstream P38/JNK signaling in hepatocytes, with epistasis using dominant-negative and constitutively active ASK1 confirming ASK1 as the direct effector mediating DKK3's metabolic protective functions.\",\n      \"evidence\": \"Co-immunoprecipitation of DKK3–ASK1, hepatocyte-specific KO and OE mice, epistasis with ASK1 mutants, metabolic phenotyping\",\n      \"pmids\": [\"27016281\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface and stoichiometry of DKK3–ASK1 interaction uncharacterized\", \"Whether DKK3–ASK1 interaction operates in all DKK3-expressing tissues unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovery of the Dkk3b isoform originating from intron 2 resolved the intracellular mechanism: Dkk3b captures unphosphorylated beta-catenin with beta-TrCP in the cytoplasm, preventing nuclear translocation and proliferation.\",\n      \"evidence\": \"Novel transcription start site mapping, co-immunoprecipitation of Dkk3b with beta-catenin and beta-TrCP, nuclear fractionation, proliferation assays\",\n      \"pmids\": [\"28738084\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Dkk3b-beta-catenin-beta-TrCP complex validated only by Co-IP without reciprocal pulldown or in vitro reconstitution\", \"Relative contribution of Dkk3b vs. secreted DKK3 in vivo not delineated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"DKK3 was placed upstream of ASK1/JNK/p38 in microglia via Kremen-1 and DVL-1, with siRNA epistasis showing these receptors are required for DKK3's inhibitory effects on microglial M1 polarization and neuropathic pain.\",\n      \"evidence\": \"Intrathecal DKK3 injection with Kremen-1 and DVL-1 siRNA knockdown, behavioral testing, western blot, and immunofluorescence in SNI rats\",\n      \"pmids\": [\"35658977\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether DKK3 directly binds Kremen-1 not demonstrated by direct binding assay\", \"Relevance to human neuropathic pain not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The identity of the primary cell-surface receptor for secreted DKK3 remains unresolved: unlike other DKK family members, DKK3 does not bind canonical LRP5/6 co-receptors with high affinity, and whether Kremen-1 is a direct receptor or acts indirectly is unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-affinity receptor identified by direct binding assay\", \"Structural basis for DKK3 selectivity within the DKK family unknown\", \"Integrated model reconciling ER stress, Wnt inhibition, and ASK1 binding in a unified signaling framework is lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 9, 10, 11]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 7, 12, 15]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 11]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [6, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 9, 10, 11, 13, 14]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4, 5, 6, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ASK1\",\n      \"BTRC\",\n      \"CTNNB1\",\n      \"DVL1\",\n      \"KREMEN1\",\n      \"HSPA5\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}