{"gene":"CUEDC1","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2018,"finding":"CUEDC1 is a direct transcriptional target of ERα, controlled by a CRISPR-validated enhancer (CUTE) located in its first intron; ectopic expression of CUEDC1 but not a CUE-domain mutant rescues defects in ERα-mediated breast cancer cell proliferation, demonstrating the CUE domain is functionally required.","method":"CRISPR-Cas9 functional enhancer screen, ectopic expression with CUE-domain mutant rescue assay","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR functional screen plus domain-mutant rescue in single lab; two orthogonal approaches establish both the upstream regulator (ERα/CUTE enhancer) and domain requirement","pmids":["30145202"],"is_preprint":false},{"year":2020,"finding":"CUEDC1 interacts with Smurf2 (identified by co-immunoprecipitation) and promotes its degradation; this stabilizes TβRI, thereby suppressing the TβRI/Smad signaling pathway and inhibiting EMT in non-small cell lung cancer cells.","method":"Co-immunoprecipitation (IP), siRNA knockdown, overexpression, Western blot, Transwell migration/invasion assay, in vivo xenograft","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP identifying Smurf2 as binding partner, supported by epistasis experiments (Smurf2 overexpression/siRNA reversing CUEDC1 phenotypes) in a single lab","pmids":["33099540"],"is_preprint":false},{"year":2025,"finding":"CUEDC1 directly binds STAT3 (by co-immunoprecipitation) and promotes its ubiquitination and proteasomal degradation, thereby suppressing JAK1/STAT3 signaling and reducing proliferation, migration, and invasion of esophageal cancer cells.","method":"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor rescue, overexpression/knockdown with phenotypic readouts","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct binding shown by Co-IP with ubiquitination functional follow-up in single lab; multiple mechanistic methods but not independently replicated","pmids":["41917169"],"is_preprint":false},{"year":2025,"finding":"MAZ transcription factor directly binds the CUEDC1 promoter (confirmed by ChIP and dual-luciferase reporter assay) to upregulate CUEDC1 transcription; CUEDC1 in turn modulates CACNG4 expression to activate PI3K/AKT signaling, enhancing glycolysis via GLUT1 upregulation and driving ER-positive breast cancer growth.","method":"ChIP, dual-luciferase reporter assay, RNA-seq, metabolic glycolysis assays, siRNA knockdown, mouse xenograft model","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assay validate MAZ→CUEDC1 transcriptional axis; downstream CUEDC1/CACNG4/PI3K pathway supported by multiple functional assays in single lab","pmids":["41315933"],"is_preprint":false},{"year":2025,"finding":"CUEDC1 knockdown reduces TGF-β, p-Smad2, and p-Smad3 levels and suppresses EMT (decreased N-cadherin, α-SMA; increased E-cadherin), migration, and invasion in hepatocellular carcinoma cells, placing CUEDC1 upstream of the TGF-β/Smad pathway in liver cancer.","method":"siRNA knockdown, Western blot, CCK-8, Transwell assay","journal":"Mutation research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single-method knockdown with pathway readout; no binding partner or biochemical reconstitution","pmids":["39951906"],"is_preprint":false},{"year":2018,"finding":"Exogenous CUEDC1 overexpression significantly promotes proliferation and colony formation of MOLT-4 leukemic cells.","method":"Lentiviral overexpression, CCK-8 assay, colony formation assay","journal":"Zhongguo shi yan xue ye xue za zhi","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, overexpression-only with phenotypic readout, no mechanistic pathway placement","pmids":["30295235"],"is_preprint":false},{"year":2025,"finding":"In vivo congenic knock-in genetics in rats identified Cuedc1 as a component of an adrenal pathway that physiologically modulates blood pressure, aldosterone production, and renal and cardiac functions.","method":"Congenic knock-in genetic analysis (QTL physiological dissection), in vivo blood pressure and aldosterone measurements","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — in vivo QTL/congenic genetics establishes pathway membership but provides no direct biochemical mechanism for CUEDC1's molecular action","pmids":["40332416"],"is_preprint":false}],"current_model":"CUEDC1 is a CUE-domain-containing protein whose transcription is driven by ERα (via the CUTE enhancer) and by MAZ (via direct promoter binding); it suppresses TβRI/Smad and JAK1/STAT3 signaling by binding and promoting proteasomal degradation of pathway components (Smurf2 and STAT3, respectively), and activates PI3K/AKT-driven glycolysis through CACNG4, with the CUE domain required for at least its proliferative functions in breast cancer."},"narrative":{"mechanistic_narrative":"CUEDC1 is a CUE-domain-containing adaptor protein that acts as a negative regulator of oncogenic signaling cascades by promoting the proteasomal degradation of pathway components, while also being embedded in transcriptional circuits that drive cancer cell growth [PMID:33099540, PMID:41917169, PMID:41315933]. Its expression is transcriptionally controlled in breast cancer by ERα through a CRISPR-validated intronic enhancer (CUTE), and the CUE domain is functionally required for CUEDC1 to rescue ERα-driven proliferation [PMID:30145202]. As a degradation-promoting adaptor, CUEDC1 binds the E3 ligase Smurf2 and promotes its turnover, thereby stabilizing TβRI and suppressing TβRI/Smad signaling and EMT in non-small cell lung cancer [PMID:33099540]; in a parallel mechanism, it binds STAT3 and drives its ubiquitination and proteasomal degradation to suppress JAK1/STAT3 signaling and reduce proliferation, migration, and invasion in esophageal cancer [PMID:41917169]. In ER-positive breast cancer, CUEDC1 is transcriptionally upregulated by direct MAZ binding to its promoter and in turn modulates CACNG4 to activate PI3K/AKT signaling and enhance GLUT1-dependent glycolysis [PMID:41315933]. Across these contexts CUEDC1 exerts both growth-promoting (PI3K/AKT-glycolysis, proliferation) and growth-suppressive (Smurf2/TβRI, STAT3) outputs depending on the partner engaged, with no unifying structural or enzymatic mechanism for partner selection characterized in the available corpus.","teleology":[{"year":2018,"claim":"Established the upstream transcriptional control of CUEDC1 and demonstrated that its CUE domain is functionally required, moving CUEDC1 from an uncharacterized gene to an ERα-driven effector of breast cancer proliferation.","evidence":"CRISPR-Cas9 functional enhancer screen plus ectopic expression with CUE-domain mutant rescue in breast cancer cells","pmids":["30145202"],"confidence":"Medium","gaps":["No molecular partner of the CUE domain identified","Mechanism by which the CUE domain drives proliferation not defined"]},{"year":2018,"claim":"Showed CUEDC1 overexpression promotes proliferation in a non-breast lineage, hinting at broader pro-growth activity but without mechanistic placement.","evidence":"Lentiviral overexpression with CCK-8 and colony formation assays in MOLT-4 leukemic cells","pmids":["30295235"],"confidence":"Low","gaps":["Overexpression-only with no pathway placement","No binding partner or loss-of-function validation"]},{"year":2020,"claim":"Provided the first physical-partner mechanism: CUEDC1 acts as a degradation-promoting adaptor that destabilizes Smurf2 to stabilize TβRI and suppress TβRI/Smad-driven EMT.","evidence":"Co-IP, siRNA/overexpression epistasis, migration/invasion assays, and xenografts in NSCLC cells","pmids":["33099540"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal validation of the CUEDC1–Smurf2 interaction","Whether CUE domain mediates Smurf2 binding not tested","Mechanism by which CUEDC1 promotes Smurf2 degradation unresolved"]},{"year":2025,"claim":"Extended the degradation-adaptor model to a second cascade by showing CUEDC1 binds STAT3 and drives its ubiquitination and proteasomal turnover, suppressing JAK1/STAT3 signaling.","evidence":"Co-IP, ubiquitination assay, proteasome inhibitor rescue, and gain/loss-of-function phenotyping in esophageal cancer cells","pmids":["41917169"],"confidence":"Medium","gaps":["No identified E3 ligase recruited to STAT3","Not independently replicated","Relationship to the Smurf2/TβRI mechanism unclear"]},{"year":2025,"claim":"Defined a transcriptional-to-metabolic axis in which MAZ directly activates CUEDC1, which then modulates CACNG4 to engage PI3K/AKT and glycolysis, contrasting with CUEDC1's growth-suppressive roles elsewhere.","evidence":"ChIP, dual-luciferase reporter, RNA-seq, glycolysis assays, knockdown, and xenografts in ER-positive breast cancer","pmids":["41315933"],"confidence":"Medium","gaps":["How CUEDC1 modulates CACNG4 (direct vs indirect) not established","Reconciliation of pro-growth vs tumor-suppressive outputs unresolved"]},{"year":2025,"claim":"Implicated CUEDC1 upstream of TGF-β/Smad in liver cancer EMT, consistent with but mechanistically thinner than the NSCLC Smurf2 model.","evidence":"siRNA knockdown with Western blot and Transwell assays in hepatocellular carcinoma cells","pmids":["39951906"],"confidence":"Low","gaps":["Single-method knockdown with no binding partner identified","No biochemical reconstitution of pathway placement"]},{"year":2025,"claim":"Identified an in vivo physiological role for Cuedc1 in an adrenal blood-pressure/aldosterone pathway, broadening its biology beyond cancer.","evidence":"Congenic knock-in QTL genetics with in vivo blood pressure and aldosterone measurements in rats","pmids":["40332416"],"confidence":"Low","gaps":["No molecular mechanism for CUEDC1's action in the adrenal pathway","Causal gene resolution within the QTL incomplete"]},{"year":null,"claim":"It remains unknown what unifying biochemical mechanism (CUE-domain ligand, structural basis of partner selection) explains how CUEDC1 alternately suppresses Smurf2/STAT3 and promotes PI3K/AKT signaling across tissues.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of CUEDC1 or its CUE domain","No identified direct CUE-domain ligand","Determinants of context-dependent pro- vs anti-growth output unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,3]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,2,3]}],"complexes":[],"partners":["SMURF2","STAT3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NWM3","full_name":"CUE domain-containing protein 1","aliases":[],"length_aa":386,"mass_kda":42.3,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9NWM3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CUEDC1","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CUEDC1","total_profiled":1310},"omim":[{"mim_id":"620552","title":"CUE DOMAIN-CONTAINING PROTEIN 1; CUEDC1","url":"https://www.omim.org/entry/620552"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Primary cilium","reliability":"Approved"},{"location":"Centrosome","reliability":"Approved"},{"location":"Basal body","reliability":"Approved"},{"location":"Microtubules","reliability":"Additional"},{"location":"Cytokinetic bridge","reliability":"Additional"},{"location":"Mitotic spindle","reliability":"Additional"},{"location":"Primary cilium tip","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CUEDC1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9NWM3","domains":[{"cath_id":"-","chopping":"243-271_301-330","consensus_level":"medium","plddt":88.1224,"start":243,"end":330},{"cath_id":"1.10.8","chopping":"48-91","consensus_level":"high","plddt":89.2705,"start":48,"end":91}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NWM3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NWM3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NWM3-F1-predicted_aligned_error_v6.png","plddt_mean":61.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CUEDC1","jax_strain_url":"https://www.jax.org/strain/search?query=CUEDC1"},"sequence":{"accession":"Q9NWM3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NWM3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NWM3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NWM3"}},"corpus_meta":[{"pmid":"27623246","id":"PMC_27623246","title":"Characterization of a knock-in mouse model of the homozygous p.V37I variant in Gjb2.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27623246","citation_count":22,"is_preprint":false},{"pmid":"24302191","id":"PMC_24302191","title":"Screening for preeclampsia pathogenesis related genes.","date":"2013","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/24302191","citation_count":15,"is_preprint":false},{"pmid":"30145202","id":"PMC_30145202","title":"CUEDC1 is a primary target of ERα essential for the growth of breast cancer cells.","date":"2018","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/30145202","citation_count":12,"is_preprint":false},{"pmid":"33099540","id":"PMC_33099540","title":"CUEDC1 inhibits epithelial-mesenchymal transition via the TβRI/Smad signaling pathway and suppresses tumor progression in non-small cell lung cancer.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/33099540","citation_count":10,"is_preprint":false},{"pmid":"36670776","id":"PMC_36670776","title":"Comprehensive Analysis of Differentially Expressed CircRNAs in the Ovaries of Low- and High-Fertility Sheep.","date":"2023","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/36670776","citation_count":10,"is_preprint":false},{"pmid":"37605650","id":"PMC_37605650","title":"Quantitative phosphoproteomics reveals molecular pathway network alterations in human early-stage primary hepatic carcinomas: potential for 3P medical approach.","date":"2023","source":"The EPMA journal","url":"https://pubmed.ncbi.nlm.nih.gov/37605650","citation_count":7,"is_preprint":false},{"pmid":"39951906","id":"PMC_39951906","title":"CUEDC1 promotes the growth, migration, epithelial-mesenchymal transition and inhibits apoptosis of hepatocellular carcinoma cells via the TGF-β/Smad signaling pathway.","date":"2025","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/39951906","citation_count":3,"is_preprint":false},{"pmid":"20533531","id":"PMC_20533531","title":"In vivo expansion of MDR1-transduced cells accompanied by a post-transplantation chemotherapy regimen with mitomycin C and methotrexate.","date":"2010","source":"The journal of gene medicine","url":"https://pubmed.ncbi.nlm.nih.gov/20533531","citation_count":3,"is_preprint":false},{"pmid":"30295235","id":"PMC_30295235","title":"[Construction of A Lentiviral Vector Carrying CUEDC1 Gene and Its Effect on the Proliferation and Colony-formating Ability of MOLT-4 Cells].","date":"2018","source":"Zhongguo shi yan xue ye xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/30295235","citation_count":2,"is_preprint":false},{"pmid":"41315933","id":"PMC_41315933","title":"CUEDC1 promotes glycolytic metabolism reprogramming through the CUEDC1/CACNG4/PI3K axis to promote ER-positive breast cancer growth.","date":"2025","source":"Cellular & molecular biology letters","url":"https://pubmed.ncbi.nlm.nih.gov/41315933","citation_count":1,"is_preprint":false},{"pmid":"41917169","id":"PMC_41917169","title":"The role of CUEDC1 in suppressing JAK1/STAT3 signaling pathway in esophageal cancer.","date":"2026","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41917169","citation_count":0,"is_preprint":false},{"pmid":"40332416","id":"PMC_40332416","title":"Modularized Genes in an Adrenal Pathway Reveal a Novel Mechanism in Hypertension Pathogenesis.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40332416","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8805,"output_tokens":1696,"usd":0.025927,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8564,"output_tokens":2675,"usd":0.054848,"stage2_stop_reason":"end_turn"},"total_usd":0.080775,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"CUEDC1 is a direct transcriptional target of ERα, controlled by a CRISPR-validated enhancer (CUTE) located in its first intron; ectopic expression of CUEDC1 but not a CUE-domain mutant rescues defects in ERα-mediated breast cancer cell proliferation, demonstrating the CUE domain is functionally required.\",\n      \"method\": \"CRISPR-Cas9 functional enhancer screen, ectopic expression with CUE-domain mutant rescue assay\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR functional screen plus domain-mutant rescue in single lab; two orthogonal approaches establish both the upstream regulator (ERα/CUTE enhancer) and domain requirement\",\n      \"pmids\": [\"30145202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CUEDC1 interacts with Smurf2 (identified by co-immunoprecipitation) and promotes its degradation; this stabilizes TβRI, thereby suppressing the TβRI/Smad signaling pathway and inhibiting EMT in non-small cell lung cancer cells.\",\n      \"method\": \"Co-immunoprecipitation (IP), siRNA knockdown, overexpression, Western blot, Transwell migration/invasion assay, in vivo xenograft\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP identifying Smurf2 as binding partner, supported by epistasis experiments (Smurf2 overexpression/siRNA reversing CUEDC1 phenotypes) in a single lab\",\n      \"pmids\": [\"33099540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CUEDC1 directly binds STAT3 (by co-immunoprecipitation) and promotes its ubiquitination and proteasomal degradation, thereby suppressing JAK1/STAT3 signaling and reducing proliferation, migration, and invasion of esophageal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor rescue, overexpression/knockdown with phenotypic readouts\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct binding shown by Co-IP with ubiquitination functional follow-up in single lab; multiple mechanistic methods but not independently replicated\",\n      \"pmids\": [\"41917169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MAZ transcription factor directly binds the CUEDC1 promoter (confirmed by ChIP and dual-luciferase reporter assay) to upregulate CUEDC1 transcription; CUEDC1 in turn modulates CACNG4 expression to activate PI3K/AKT signaling, enhancing glycolysis via GLUT1 upregulation and driving ER-positive breast cancer growth.\",\n      \"method\": \"ChIP, dual-luciferase reporter assay, RNA-seq, metabolic glycolysis assays, siRNA knockdown, mouse xenograft model\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assay validate MAZ→CUEDC1 transcriptional axis; downstream CUEDC1/CACNG4/PI3K pathway supported by multiple functional assays in single lab\",\n      \"pmids\": [\"41315933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CUEDC1 knockdown reduces TGF-β, p-Smad2, and p-Smad3 levels and suppresses EMT (decreased N-cadherin, α-SMA; increased E-cadherin), migration, and invasion in hepatocellular carcinoma cells, placing CUEDC1 upstream of the TGF-β/Smad pathway in liver cancer.\",\n      \"method\": \"siRNA knockdown, Western blot, CCK-8, Transwell assay\",\n      \"journal\": \"Mutation research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single-method knockdown with pathway readout; no binding partner or biochemical reconstitution\",\n      \"pmids\": [\"39951906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Exogenous CUEDC1 overexpression significantly promotes proliferation and colony formation of MOLT-4 leukemic cells.\",\n      \"method\": \"Lentiviral overexpression, CCK-8 assay, colony formation assay\",\n      \"journal\": \"Zhongguo shi yan xue ye xue za zhi\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, overexpression-only with phenotypic readout, no mechanistic pathway placement\",\n      \"pmids\": [\"30295235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In vivo congenic knock-in genetics in rats identified Cuedc1 as a component of an adrenal pathway that physiologically modulates blood pressure, aldosterone production, and renal and cardiac functions.\",\n      \"method\": \"Congenic knock-in genetic analysis (QTL physiological dissection), in vivo blood pressure and aldosterone measurements\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — in vivo QTL/congenic genetics establishes pathway membership but provides no direct biochemical mechanism for CUEDC1's molecular action\",\n      \"pmids\": [\"40332416\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CUEDC1 is a CUE-domain-containing protein whose transcription is driven by ERα (via the CUTE enhancer) and by MAZ (via direct promoter binding); it suppresses TβRI/Smad and JAK1/STAT3 signaling by binding and promoting proteasomal degradation of pathway components (Smurf2 and STAT3, respectively), and activates PI3K/AKT-driven glycolysis through CACNG4, with the CUE domain required for at least its proliferative functions in breast cancer.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CUEDC1 is a CUE-domain-containing adaptor protein that acts as a negative regulator of oncogenic signaling cascades by promoting the proteasomal degradation of pathway components, while also being embedded in transcriptional circuits that drive cancer cell growth [#1, #2, #3]. Its expression is transcriptionally controlled in breast cancer by ERα through a CRISPR-validated intronic enhancer (CUTE), and the CUE domain is functionally required for CUEDC1 to rescue ERα-driven proliferation [#0]. As a degradation-promoting adaptor, CUEDC1 binds the E3 ligase Smurf2 and promotes its turnover, thereby stabilizing TβRI and suppressing TβRI/Smad signaling and EMT in non-small cell lung cancer [#1]; in a parallel mechanism, it binds STAT3 and drives its ubiquitination and proteasomal degradation to suppress JAK1/STAT3 signaling and reduce proliferation, migration, and invasion in esophageal cancer [#2]. In ER-positive breast cancer, CUEDC1 is transcriptionally upregulated by direct MAZ binding to its promoter and in turn modulates CACNG4 to activate PI3K/AKT signaling and enhance GLUT1-dependent glycolysis [#3]. Across these contexts CUEDC1 exerts both growth-promoting (PI3K/AKT-glycolysis, proliferation) and growth-suppressive (Smurf2/TβRI, STAT3) outputs depending on the partner engaged, with no unifying structural or enzymatic mechanism for partner selection characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Established the upstream transcriptional control of CUEDC1 and demonstrated that its CUE domain is functionally required, moving CUEDC1 from an uncharacterized gene to an ERα-driven effector of breast cancer proliferation.\",\n      \"evidence\": \"CRISPR-Cas9 functional enhancer screen plus ectopic expression with CUE-domain mutant rescue in breast cancer cells\",\n      \"pmids\": [\"30145202\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular partner of the CUE domain identified\", \"Mechanism by which the CUE domain drives proliferation not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed CUEDC1 overexpression promotes proliferation in a non-breast lineage, hinting at broader pro-growth activity but without mechanistic placement.\",\n      \"evidence\": \"Lentiviral overexpression with CCK-8 and colony formation assays in MOLT-4 leukemic cells\",\n      \"pmids\": [\"30295235\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Overexpression-only with no pathway placement\", \"No binding partner or loss-of-function validation\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided the first physical-partner mechanism: CUEDC1 acts as a degradation-promoting adaptor that destabilizes Smurf2 to stabilize TβRI and suppress TβRI/Smad-driven EMT.\",\n      \"evidence\": \"Co-IP, siRNA/overexpression epistasis, migration/invasion assays, and xenografts in NSCLC cells\",\n      \"pmids\": [\"33099540\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation of the CUEDC1–Smurf2 interaction\", \"Whether CUE domain mediates Smurf2 binding not tested\", \"Mechanism by which CUEDC1 promotes Smurf2 degradation unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended the degradation-adaptor model to a second cascade by showing CUEDC1 binds STAT3 and drives its ubiquitination and proteasomal turnover, suppressing JAK1/STAT3 signaling.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, proteasome inhibitor rescue, and gain/loss-of-function phenotyping in esophageal cancer cells\",\n      \"pmids\": [\"41917169\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No identified E3 ligase recruited to STAT3\", \"Not independently replicated\", \"Relationship to the Smurf2/TβRI mechanism unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a transcriptional-to-metabolic axis in which MAZ directly activates CUEDC1, which then modulates CACNG4 to engage PI3K/AKT and glycolysis, contrasting with CUEDC1's growth-suppressive roles elsewhere.\",\n      \"evidence\": \"ChIP, dual-luciferase reporter, RNA-seq, glycolysis assays, knockdown, and xenografts in ER-positive breast cancer\",\n      \"pmids\": [\"41315933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How CUEDC1 modulates CACNG4 (direct vs indirect) not established\", \"Reconciliation of pro-growth vs tumor-suppressive outputs unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated CUEDC1 upstream of TGF-β/Smad in liver cancer EMT, consistent with but mechanistically thinner than the NSCLC Smurf2 model.\",\n      \"evidence\": \"siRNA knockdown with Western blot and Transwell assays in hepatocellular carcinoma cells\",\n      \"pmids\": [\"39951906\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single-method knockdown with no binding partner identified\", \"No biochemical reconstitution of pathway placement\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified an in vivo physiological role for Cuedc1 in an adrenal blood-pressure/aldosterone pathway, broadening its biology beyond cancer.\",\n      \"evidence\": \"Congenic knock-in QTL genetics with in vivo blood pressure and aldosterone measurements in rats\",\n      \"pmids\": [\"40332416\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No molecular mechanism for CUEDC1's action in the adrenal pathway\", \"Causal gene resolution within the QTL incomplete\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown what unifying biochemical mechanism (CUE-domain ligand, structural basis of partner selection) explains how CUEDC1 alternately suppresses Smurf2/STAT3 and promotes PI3K/AKT signaling across tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of CUEDC1 or its CUE domain\", \"No identified direct CUE-domain ligand\", \"Determinants of context-dependent pro- vs anti-growth output unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 2, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SMURF2\", \"STAT3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":4,"faith_pct":100.0}}