{"gene":"CUEDC2","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2008,"finding":"CUEDC2 acts as an adaptor protein that recruits PP1 (via interaction with the PP1 regulatory subunit GADD34) to IKKα/IKKβ, forming an IKK–CUEDC2–PP1 complex that dephosphorylates and inactivates IKK, thereby suppressing NF-κB activation. IKK is released from this complex upon inflammatory stimuli (e.g., TNF).","method":"Co-immunoprecipitation, complex reconstitution, phosphorylation assays, identification of GADD34 interaction by yeast two-hybrid/Co-IP","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing ternary complex, functional dephosphorylation assay, multiple orthogonal methods in a focused study replicated across conditions","pmids":["18362886"],"is_preprint":false},{"year":2011,"finding":"CUEDC2 is phosphorylated by Cdk1 during mitosis; phosphorylated CUEDC2 binds Cdc20 (an APC/C activator) and promotes release of Mad2 from APC/C–Cdc20, leading to APC/C activation and spindle assembly checkpoint (SAC) inactivation. CUEDC2 depletion causes checkpoint-dependent delay in metaphase-anaphase transition; overexpression causes premature APC/C activation, chromosome missegregation, and aneuploidy.","method":"Kinase assay (Cdk1 phosphorylation), Co-immunoprecipitation (CUEDC2–Cdc20, Mad2 release), siRNA depletion with mitotic timing assays, overexpression with chromosomal instability readouts","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (kinase assay, reciprocal Co-IP, loss- and gain-of-function with defined mitotic phenotypes) in a single focused study","pmids":["21743465"],"is_preprint":false},{"year":2011,"finding":"CUEDC2 modulates ER-α protein stability through the ubiquitin-proteasome pathway, promoting ER-α degradation. Ectopic CUEDC2 expression impairs breast cancer cell responsiveness to tamoxifen.","method":"Ubiquitin-proteasome pathway assays, western blot for ER-α protein levels upon CUEDC2 manipulation, cell-based tamoxifen response assays, large cohort IHC for inverse correlation","journal":"Nature medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional ubiquitin-proteasome assay and loss/gain-of-function cellular phenotype in a single lab; mechanistic detail on the E3 ligase not specified in abstract","pmids":["21572428"],"is_preprint":false},{"year":2011,"finding":"CUEDC2 inhibits cytokine-induced phosphorylation of JAK1 and STAT3 by interacting with SOCS3 (via yeast two-hybrid confirmed by Co-IP) and increasing SOCS3 protein stability through enhancing SOCS3 association with Elongin C, thereby cooperatively suppressing JAK1/STAT3 signaling.","method":"Yeast two-hybrid, co-immunoprecipitation, STAT3 transcriptional activity assays, SOCS3 stability/ubiquitination assays, Elongin C interaction analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid plus Co-IP plus functional STAT3 activity assay plus protein stability mechanistic follow-up, multiple orthogonal methods in one study","pmids":["22084247"],"is_preprint":false},{"year":2013,"finding":"CUEDC2 binds and inhibits APC/C(Cdh1) in G1, stabilizing Cyclin A and promoting G1-S transition. In response to UV irradiation, CUEDC2 undergoes ERK1/2-dependent phosphorylation followed by ubiquitin-dependent degradation, releasing APC/C(Cdh1) to degrade Cyclin A, inactivate CDK2, and enforce G1 arrest. A non-phosphorylatable CUEDC2 mutant resists UV-induced degradation and overrides G1 arrest.","method":"Co-immunoprecipitation (CUEDC2–APC/C(Cdh1)), kinase assay (ERK1/2 phosphorylation), ubiquitination assay, phosphomutant rescue experiments, Cyclin A stability assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay, phosphomutant mutagenesis, Co-IP, ubiquitination assay, and functional cell-cycle readout with multiple orthogonal methods","pmids":["23776205"],"is_preprint":false},{"year":2016,"finding":"CUEDC2 promotes E3 ubiquitin ligase TRIM33-mediated ubiquitination and proteasome-dependent degradation of the antioxidant enzyme GPX1 in cardiomyocytes. Loss of CUEDC2 elevates GPX1 protein levels, enhancing ROS scavenging and protecting against oxidative stress-induced cardiac injury in vivo.","method":"CUEDC2 knockout mice, ubiquitination assay (TRIM33-GPX1), western blot for GPX1 levels, I/R injury model with infarct size measurement, ROS quantification","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse model, ubiquitination assay identifying E3 ligase (TRIM33), in vivo I/R phenotype, multiple orthogonal methods","pmids":["27286733"],"is_preprint":false},{"year":2014,"finding":"CUEDC2 interacts with HSP70 via its CUE domain (binding to the PBD and CT domains of HSP70) and negatively regulates HSP70 chaperone activity, as measured by an intracellular luciferase refolding assay.","method":"Affinity purification/mass spectrometry, co-immunoprecipitation, domain mapping, intracellular luciferase refolding assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping and functional chaperone assay, single lab, two orthogonal methods","pmids":["24685480"],"is_preprint":false},{"year":2018,"finding":"CUEDC2 interacts with SOCS1 and attenuates SOCS1 ubiquitination by enhancing SOCS1 association with Elongin C and Cullin-2 (CUL2), thereby stabilizing SOCS1 protein and suppressing JAK1-STAT3 pathway activation in acute myeloid leukemia cells.","method":"Co-immunoprecipitation (CUEDC2–SOCS1), ubiquitination assay, Elongin C/CUL2 interaction analysis, JAK1-STAT3 phosphorylation assays, overexpression/knockdown with proliferation and cell-cycle readouts","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, and functional pathway assay in a single lab","pmids":["29991678"],"is_preprint":false},{"year":2020,"finding":"CUEDC2 promotes E3 ligase TRIM21-mediated ubiquitination and degradation of the transcription factor CREB. Downregulation of CUEDC2 in glioma reduces CREB ubiquitination, causing CREB accumulation in the nucleus and increased GDNF transcription.","method":"Co-immunoprecipitation (CUEDC2–TRIM21–CREB), ubiquitination assay, western blot for CREB levels, GDNF promoter binding assay, CUEDC2 knockdown/overexpression","journal":"Neurochemical research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying E3 ligase interaction, ubiquitination assay, functional GDNF readout, single lab","pmids":["33125618"],"is_preprint":false},{"year":2022,"finding":"The CUE domain of CUEDC2 directly binds to the ARM (7-9) domain of β-catenin, promotes β-catenin nuclear translocation, and enhances expression of β-catenin target genes, driving Wnt signaling hyperactivation and TNBC tumorigenesis. An 11-amino-acid competitive peptide targeting the CUE domain blocks CUEDC2–β-catenin interaction and abrogates TNBC malignant phenotype in vitro and in vivo.","method":"Co-immunoprecipitation, pull-down, LC-MS/MS, localized surface plasmon resonance (direct binding), nuclear translocation analysis, competitive peptide inhibition, xenograft model","journal":"Cells","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding confirmed by SPR (biophysical method), domain mapping by pull-down, nuclear translocation assay, and in vivo xenograft validation with multiple orthogonal methods","pmids":["36231027"],"is_preprint":false},{"year":2022,"finding":"CUEDC2 degrades ERα specifically during mitosis using the mitotic ubiquitination machinery, with mitosis-specific phosphorylation of CUEDC2 required for this process. Upregulated CUEDC2 also overrides mitotic arrest and increases aneuploidy.","method":"Western blot for ERα levels during mitotic progression, phosphorylation-dependent degradation assays, mitotic arrest override assays, aneuploidy quantification","journal":"Cancer gene therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional ubiquitination/degradation assay in mitotic context with phosphorylation requirement established, single lab","pmids":["35732909"],"is_preprint":false},{"year":2019,"finding":"CUEDC2 knockdown increases phosphorylation of p38 MAPK in ovarian serous carcinoma cells, contributing to cisplatin sensitization, suggesting CUEDC2 negatively regulates p38 MAPK signaling.","method":"siRNA knockdown of CUEDC2, western blot for p38 MAPK phosphorylation, cisplatin sensitivity assays","journal":"Journal of Cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method (western blot after knockdown) in a single lab without mechanistic detail on how CUEDC2 regulates p38","pmids":["31205536"],"is_preprint":false},{"year":2025,"finding":"CUEDC2 interacts directly with NLRP3 during inflammasome activation and inhibits NLRP3 inflammasome assembly, thereby suppressing caspase-1 activation and IL-1β maturation, and reducing pyroptosis in glomerular endothelial cells.","method":"Co-immunoprecipitation (CUEDC2–NLRP3), caspase-1 activity assay, IL-1β maturation assay, CUEDC2 overexpression/inhibition in GEC pyroptosis model","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional inflammasome assays (caspase-1 and IL-1β), single lab, two orthogonal methods","pmids":["41232582"],"is_preprint":false},{"year":2020,"finding":"CUEDC2 controls osteoblast differentiation by regulating SOCS3 protein stability, which in turn modulates STAT3 activation. CUEDC2 overexpression suppresses osteogenic differentiation and reduces bone parameters in vivo, while knockdown promotes differentiation; a STAT3 chemical inhibitor abolishes the pro-differentiation effect of CUEDC2 silencing.","method":"Overexpression/knockdown in osteoblast precursor cells, SOCS3 stability assay, STAT3 phosphorylation assay, ectopic bone formation model in vivo, calvarial defect repair model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro loss/gain-of-function with pathway inhibitor rescue, single lab","pmids":["32393737"],"is_preprint":false}],"current_model":"CUEDC2 is a multifunctional CUE-domain-containing adaptor/scaffold protein that (1) deactivates IKK by recruiting PP1 (via GADD34) to form a dephosphorylation complex, suppressing NF-κB; (2) inhibits JAK1/STAT3 signaling by binding SOCS3 or SOCS1 and stabilizing them through enhanced Elongin C/CUL2 association; (3) promotes spindle checkpoint inactivation by binding Cdk1-phosphorylated CUEDC2 to Cdc20, releasing Mad2 from APC/C-Cdc20; (4) inhibits APC/C(Cdh1) in G1, and is degraded via ERK1/2-dependent phosphorylation after UV damage to enforce G1 arrest; (5) promotes ubiquitin-proteasome degradation of ER-α and CREB through TRIM33 and TRIM21 E3 ligases respectively; (6) promotes GPX1 degradation via TRIM33, sensitizing cardiomyocytes to oxidative stress; (7) directly binds β-catenin via its CUE domain to drive nuclear translocation and Wnt target gene expression; and (8) interacts with NLRP3 to inhibit inflammasome assembly and suppress pyroptosis."},"narrative":{"mechanistic_narrative":"CUEDC2 is a CUE-domain-containing adaptor/scaffold protein that negatively regulates multiple signaling pathways and cell-cycle transitions, largely by controlling the phosphorylation state, stability, or localization of partner proteins [PMID:18362886, PMID:21743465]. In inflammatory signaling, it acts as an adaptor that recruits the PP1 phosphatase (via the regulatory subunit GADD34) to the IKK complex, forming an IKK–CUEDC2–PP1 assembly that dephosphorylates and inactivates IKK to suppress NF-κB; this complex disassembles upon inflammatory stimuli such as TNF [PMID:18362886]. It restrains JAK1/STAT3 signaling by binding and stabilizing SOCS proteins—enhancing SOCS3 association with Elongin C and SOCS1 association with Elongin C/CUL2 to attenuate their ubiquitination [PMID:22084247, PMID:29991678]—a SOCS3-dependent axis that also governs osteoblast differentiation [PMID:32393737]. CUEDC2 is a Cdk1 substrate that, when phosphorylated in mitosis, binds Cdc20 and promotes Mad2 release from APC/C–Cdc20 to inactivate the spindle assembly checkpoint, with overexpression driving premature APC/C activation, chromosome missegregation, and aneuploidy [PMID:21743465]; in G1 it instead binds and inhibits APC/C(Cdh1) to stabilize Cyclin A, and is removed by ERK1/2-dependent phosphorylation and ubiquitin-dependent degradation after UV damage to enforce G1 arrest [PMID:23776205]. CUEDC2 further serves as a substrate-targeting cofactor that promotes ubiquitin-proteasome degradation of client proteins, directing TRIM33-mediated degradation of the antioxidant enzyme GPX1 in cardiomyocytes (sensitizing the heart to oxidative I/R injury) [PMID:27286733] and TRIM21-mediated degradation of the transcription factor CREB to limit GDNF transcription [PMID:33125618], and promoting mitosis-coupled ER-α degradation that impairs tamoxifen responsiveness [PMID:21572428, PMID:35732909]. Through its CUE domain it also directly binds the ARM(7-9) region of β-catenin to drive nuclear translocation and Wnt target gene expression, a CUE-domain interaction that can be blocked by a competitive peptide to abrogate triple-negative breast cancer malignancy [PMID:36231027].","teleology":[{"year":2008,"claim":"Established CUEDC2 as a negative regulator of NF-κB by defining a molecular mechanism: it scaffolds a phosphatase onto the kinase that normally activates the pathway.","evidence":"Reciprocal Co-IP, complex reconstitution and dephosphorylation assays defining an IKK–CUEDC2–PP1(GADD34) complex","pmids":["18362886"],"confidence":"High","gaps":["Does not establish what triggers complex disassembly at the molecular level beyond stimulus dependence","Stoichiometry and direct vs. indirect IKK contact not resolved"]},{"year":2011,"claim":"Showed CUEDC2 is a cell-cycle regulator, linking its Cdk1 phosphorylation to spindle checkpoint inactivation and genomic instability.","evidence":"Cdk1 kinase assay, CUEDC2–Cdc20 Co-IP with Mad2 release, siRNA timing assays and overexpression aneuploidy readouts","pmids":["21743465"],"confidence":"High","gaps":["Cdk1 phosphosites not fully mapped","Mechanism by which CUEDC2 binding displaces Mad2 from APC/C–Cdc20 not structurally defined"]},{"year":2011,"claim":"Extended CUEDC2 to hormone-receptor control by showing it lowers ER-α via the ubiquitin-proteasome pathway and blunts tamoxifen response.","evidence":"Ubiquitin-proteasome assays, ER-α western blots under CUEDC2 manipulation, tamoxifen-response cell assays, cohort IHC correlation","pmids":["21572428"],"confidence":"Medium","gaps":["E3 ligase not identified in this study","Direct vs. indirect role in ER-α ubiquitination unresolved"]},{"year":2011,"claim":"Defined a stabilization mechanism for SOCS3, showing CUEDC2 suppresses JAK1/STAT3 by protecting a negative-feedback inhibitor.","evidence":"Yeast two-hybrid, Co-IP, STAT3 activity assays, SOCS3 stability/ubiquitination and Elongin C interaction analysis","pmids":["22084247"],"confidence":"High","gaps":["How CUEDC2 enhances SOCS3–Elongin C association mechanistically not defined","Direct binding interface not mapped"]},{"year":2013,"claim":"Resolved an opposing cell-cycle role, showing CUEDC2 inhibits APC/C(Cdh1) in G1 and that its DNA-damage-triggered degradation enforces G1 arrest.","evidence":"CUEDC2–APC/C(Cdh1) Co-IP, ERK1/2 kinase assay, ubiquitination assay, phosphomutant rescue, Cyclin A stability readouts","pmids":["23776205"],"confidence":"High","gaps":["E3 ligase degrading CUEDC2 after UV not identified","Relationship between the mitotic Cdc20-binding and G1 Cdh1-inhibiting roles not unified"]},{"year":2014,"claim":"Identified a chaperone-regulatory function, showing the CUE domain binds HSP70 and dampens its refolding activity.","evidence":"AP-MS, Co-IP, domain mapping, intracellular luciferase refolding assay","pmids":["24685480"],"confidence":"Medium","gaps":["Single lab, two orthogonal methods","Physiological consequences of HSP70 inhibition not established"]},{"year":2016,"claim":"Connected CUEDC2 to redox protection in vivo by showing it directs TRIM33-mediated degradation of GPX1 and that its loss protects the heart from oxidative injury.","evidence":"CUEDC2 knockout mice, TRIM33–GPX1 ubiquitination assay, GPX1 westerns, I/R infarct and ROS measurements","pmids":["27286733"],"confidence":"High","gaps":["Whether CUEDC2 directly bridges TRIM33 and GPX1 not structurally shown","Tissue specificity of this axis not defined"]},{"year":2018,"claim":"Generalized the SOCS-stabilization mechanism to SOCS1/CUL2 in leukemia, reinforcing CUEDC2 as a brake on JAK1-STAT3.","evidence":"CUEDC2–SOCS1 Co-IP, ubiquitination assay, Elongin C/CUL2 interaction, JAK1-STAT3 phosphorylation and proliferation readouts","pmids":["29991678"],"confidence":"Medium","gaps":["Single lab","Binding interface between CUEDC2 and SOCS1 not mapped"]},{"year":2019,"claim":"Linked CUEDC2 to p38 MAPK and chemosensitivity, indicating it negatively regulates p38 in ovarian carcinoma.","evidence":"siRNA knockdown, p38 phosphorylation westerns, cisplatin sensitivity assays","pmids":["31205536"],"confidence":"Low","gaps":["Single method (western after knockdown) without mechanistic detail","Direct vs. indirect regulation of p38 unknown"]},{"year":2020,"claim":"Showed CUEDC2 directs TRIM21-mediated CREB degradation, controlling GDNF transcription in glioma.","evidence":"CUEDC2–TRIM21–CREB Co-IP, ubiquitination assay, CREB westerns, GDNF promoter binding assays","pmids":["33125618"],"confidence":"Medium","gaps":["Single lab","Whether CUEDC2 is an obligate cofactor or modulator of TRIM21 not resolved"]},{"year":2020,"claim":"Demonstrated the SOCS3/STAT3 axis governs a developmental output, with CUEDC2 restraining osteoblast differentiation.","evidence":"Gain/loss-of-function in osteoblast precursors, SOCS3 stability and STAT3 phosphorylation assays, in vivo bone formation and calvarial repair with STAT3-inhibitor rescue","pmids":["32393737"],"confidence":"Medium","gaps":["Single lab","Whether bone phenotype is wholly STAT3-dependent vs. multifactorial unresolved"]},{"year":2022,"claim":"Provided direct biophysical evidence for a CUE-domain interaction with β-catenin driving Wnt activation, and a druggable peptide interface.","evidence":"Co-IP, pull-down, LC-MS/MS, SPR direct-binding, nuclear translocation assay, competitive peptide and xenograft in TNBC","pmids":["36231027"],"confidence":"High","gaps":["Mechanism of how CUE–β-catenin binding promotes nuclear import not defined","Relationship to the degradation/scaffold roles of the same CUE domain unclear"]},{"year":2022,"claim":"Refined the ER-α degradation mechanism by showing it is mitosis-restricted and dependent on mitotic phosphorylation of CUEDC2.","evidence":"ERα westerns across mitotic progression, phosphorylation-dependent degradation and mitotic-arrest override assays, aneuploidy quantification","pmids":["35732909"],"confidence":"Medium","gaps":["E3 ligase for ER-α still not named","Phosphosites and the responsible kinase not fully defined"]},{"year":2025,"claim":"Added an inflammasome-suppressive role, showing CUEDC2 binds NLRP3 to block assembly and limit pyroptosis.","evidence":"CUEDC2–NLRP3 Co-IP, caspase-1 activity and IL-1β maturation assays in glomerular endothelial cell pyroptosis model","pmids":["41232582"],"confidence":"Medium","gaps":["Single lab, two orthogonal methods","How CUEDC2 binding physically prevents NLRP3 oligomerization not defined"]},{"year":null,"claim":"How a single CUE-domain adaptor selects among its many partners (PP1/IKK, Cdc20, Cdh1, SOCS1/3, multiple TRIM ligases, β-catenin, NLRP3) and switches between stabilizing, degrading, and scaffolding modes remains unresolved.","evidence":"No structural or competitive-binding study in the timeline addresses how partner selection and functional mode are coordinated","pmids":[],"confidence":"Low","gaps":["No structure of CUEDC2 or its complexes","No systematic mapping of which interactions are mutually exclusive","Upstream signals controlling mode-switching incompletely defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3,7,6]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[5,8]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[9,8]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,9]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,12]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5,8,2]}],"complexes":["IKK–CUEDC2–PP1(GADD34) complex"],"partners":["IKBKB","GADD34","CDC20","FZR1","SOCS3","SOCS1","TRIM33","CTNNB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H467","full_name":"CUE domain-containing protein 2","aliases":[],"length_aa":287,"mass_kda":32.0,"function":"Down-regulates ESR1 protein levels through the ubiquitination-proteasome pathway, regardless of the presence of 17 beta-estradiol. Also involved in 17 beta-estradiol-induced ESR1 degradation. Controls PGR protein levels through a similar mechanism","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9H467/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CUEDC2","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CUEDC2","total_profiled":1310},"omim":[{"mim_id":"614142","title":"CUE DOMAIN-CONTAINING PROTEIN 2; CUEDC2","url":"https://www.omim.org/entry/614142"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Nuclear membrane","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Primary cilium tip","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CUEDC2"},"hgnc":{"alias_symbol":["MGC2491"],"prev_symbol":["C10orf66"]},"alphafold":{"accession":"Q9H467","domains":[{"cath_id":"-","chopping":"148-183","consensus_level":"high","plddt":88.8431,"start":148,"end":183},{"cath_id":"1.10.274","chopping":"1-93","consensus_level":"medium","plddt":89.5561,"start":1,"end":93}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H467","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H467-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H467-F1-predicted_aligned_error_v6.png","plddt_mean":72.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CUEDC2","jax_strain_url":"https://www.jax.org/strain/search?query=CUEDC2"},"sequence":{"accession":"Q9H467","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H467.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H467/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H467"}},"corpus_meta":[{"pmid":"18362886","id":"PMC_18362886","title":"Deactivation of the kinase IKK by CUEDC2 through recruitment of the phosphatase PP1.","date":"2008","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18362886","citation_count":118,"is_preprint":false},{"pmid":"21572428","id":"PMC_21572428","title":"Elevated expression of CUEDC2 protein confers endocrine resistance in breast cancer.","date":"2011","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21572428","citation_count":114,"is_preprint":false},{"pmid":"32978519","id":"PMC_32978519","title":"LncRNA BCYRN1 inhibits glioma tumorigenesis by competitively binding with miR-619-5p to regulate CUEDC2 expression and the PTEN/AKT/p21 pathway.","date":"2020","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/32978519","citation_count":87,"is_preprint":false},{"pmid":"26166821","id":"PMC_26166821","title":"Sinomenine inhibits breast cancer cell invasion and migration by suppressing NF-κB activation mediated by IL-4/miR-324-5p/CUEDC2 axis.","date":"2015","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/26166821","citation_count":75,"is_preprint":false},{"pmid":"21743465","id":"PMC_21743465","title":"Cdk1-phosphorylated CUEDC2 promotes spindle checkpoint inactivation and chromosomal instability.","date":"2011","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21743465","citation_count":70,"is_preprint":false},{"pmid":"24882011","id":"PMC_24882011","title":"Dysregulation of the miR-324-5p-CUEDC2 axis leads to macrophage dysfunction and is associated with colon cancer.","date":"2014","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/24882011","citation_count":54,"is_preprint":false},{"pmid":"30045983","id":"PMC_30045983","title":"MicroRNA hsa-miR-324-5p Suppresses H5N1 Virus Replication by Targeting the Viral PB1 and Host CUEDC2.","date":"2018","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/30045983","citation_count":43,"is_preprint":false},{"pmid":"21976060","id":"PMC_21976060","title":"CUEDC2: an emerging key player in inflammation and tumorigenesis.","date":"2011","source":"Protein & cell","url":"https://pubmed.ncbi.nlm.nih.gov/21976060","citation_count":26,"is_preprint":false},{"pmid":"22084247","id":"PMC_22084247","title":"CUEDC2 (CUE domain-containing 2) and SOCS3 (suppressors of cytokine signaling 3) cooperate to negatively regulate Janus kinase 1/signal transducers and activators of transcription 3 signaling.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22084247","citation_count":23,"is_preprint":false},{"pmid":"28534933","id":"PMC_28534933","title":"CUEDC2 suppresses glioma tumorigenicity by inhibiting the activation of STAT3 and NF-κB signaling pathway.","date":"2017","source":"International journal of 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controls osteoblast differentiation and bone formation via SOCS3-STAT3 pathway.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/32393737","citation_count":14,"is_preprint":false},{"pmid":"23776205","id":"PMC_23776205","title":"Phosphorylation-triggered CUEDC2 degradation promotes UV-induced G1 arrest through APC/C(Cdh1) regulation.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/23776205","citation_count":13,"is_preprint":false},{"pmid":"33494071","id":"PMC_33494071","title":"CUEDC2 ablation enhances the efficacy of mesenchymal stem cells in ameliorating cerebral ischemia/reperfusion insult.","date":"2021","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/33494071","citation_count":13,"is_preprint":false},{"pmid":"34257080","id":"PMC_34257080","title":"MicroRNA-324-5p-CUEDC2 Axis Mediates Gain-of-Function Mutant p53-Driven Cancer Stemness.","date":"2021","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/34257080","citation_count":12,"is_preprint":false},{"pmid":"31205536","id":"PMC_31205536","title":"CUEDC2 Contributes to Cisplatin-Based Chemotherapy Resistance in Ovarian Serious Carcinoma by Regulating p38 MAPK Signaling.","date":"2019","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31205536","citation_count":11,"is_preprint":false},{"pmid":"33125618","id":"PMC_33125618","title":"Down-Regulated CUEDC2 Increases GDNF Expression by Stabilizing CREB Through Reducing Its Ubiquitination in Glioma.","date":"2020","source":"Neurochemical research","url":"https://pubmed.ncbi.nlm.nih.gov/33125618","citation_count":10,"is_preprint":false},{"pmid":"32688371","id":"PMC_32688371","title":"Kawasaki disease: SOCS2-AS1/miR-324-5p/CUEDC2 axis regulates the progression of human umbilical vein endothelial cells.","date":"2020","source":"Pediatric research","url":"https://pubmed.ncbi.nlm.nih.gov/32688371","citation_count":10,"is_preprint":false},{"pmid":"24125838","id":"PMC_24125838","title":"CUEDC2 sensitizes chronic myeloid leukemic cells to imatinib treatment.","date":"2013","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/24125838","citation_count":10,"is_preprint":false},{"pmid":"36231027","id":"PMC_36231027","title":"CUEDC2 Drives β-Catenin Nuclear Translocation and Promotes Triple-Negative Breast Cancer Tumorigenesis.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36231027","citation_count":6,"is_preprint":false},{"pmid":"30651016","id":"PMC_30651016","title":"Expression of CUEDC2 in colorectal cancer with different invasion and migration abilities.","date":"2019","source":"The Journal of international medical research","url":"https://pubmed.ncbi.nlm.nih.gov/30651016","citation_count":5,"is_preprint":false},{"pmid":"37036350","id":"PMC_37036350","title":"Long Noncoding RNA AROD Inhibits Host Antiviral Innate Immunity via the miR-324-5p-CUEDC2 Axis.","date":"2023","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/37036350","citation_count":5,"is_preprint":false},{"pmid":"29845245","id":"PMC_29845245","title":"Downregulation of CUEDC2 prevents doxorubicin‑induced cardiotoxicity in H9c2 cells.","date":"2018","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/29845245","citation_count":5,"is_preprint":false},{"pmid":"39864604","id":"PMC_39864604","title":"Dandelion extract suppresses the stem-like properties of triple-negative breast cancer cells by regulating CUEDC2/β-catenin/OCT4 signaling axis.","date":"2025","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39864604","citation_count":5,"is_preprint":false},{"pmid":"26182901","id":"PMC_26182901","title":"CUEDC2 Protects Against Experimental Colitis and Suppresses Excessive Proliferation of Intestinal Mucosa.","date":"2015","source":"Digestive diseases and sciences","url":"https://pubmed.ncbi.nlm.nih.gov/26182901","citation_count":4,"is_preprint":false},{"pmid":"38697957","id":"PMC_38697957","title":"miRNA-7145-cuedc2 axis controls hematopoiesis through JAK1/STAT3 signaling pathway.","date":"2024","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/38697957","citation_count":3,"is_preprint":false},{"pmid":"35732909","id":"PMC_35732909","title":"Molecular crosstalk between CUEDC2 and ERα influences the clinical outcome by regulating mitosis in breast cancer.","date":"2022","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/35732909","citation_count":2,"is_preprint":false},{"pmid":"24685480","id":"PMC_24685480","title":"CUEDC2 interacts with heat shock protein 70 and negatively regulates its chaperone activity.","date":"2014","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/24685480","citation_count":1,"is_preprint":false},{"pmid":"32960074","id":"PMC_32960074","title":"Comparison of ADAM19 and CUEDC2 expression in EHCC and their clinicopathological significance.","date":"2020","source":"Biomarkers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32960074","citation_count":0,"is_preprint":false},{"pmid":"41232582","id":"PMC_41232582","title":"CUEDC2 improves pyroptosis and kidney damage in diabetic kidney disease by inhibiting NLRP3 inflammasome activation.","date":"2025","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/41232582","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18052,"output_tokens":3962,"usd":0.056793,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11763,"output_tokens":4813,"usd":0.08957,"stage2_stop_reason":"end_turn"},"total_usd":0.146363,"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\": 2008,\n      \"finding\": \"CUEDC2 acts as an adaptor protein that recruits PP1 (via interaction with the PP1 regulatory subunit GADD34) to IKKα/IKKβ, forming an IKK–CUEDC2–PP1 complex that dephosphorylates and inactivates IKK, thereby suppressing NF-κB activation. IKK is released from this complex upon inflammatory stimuli (e.g., TNF).\",\n      \"method\": \"Co-immunoprecipitation, complex reconstitution, phosphorylation assays, identification of GADD34 interaction by yeast two-hybrid/Co-IP\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing ternary complex, functional dephosphorylation assay, multiple orthogonal methods in a focused study replicated across conditions\",\n      \"pmids\": [\"18362886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CUEDC2 is phosphorylated by Cdk1 during mitosis; phosphorylated CUEDC2 binds Cdc20 (an APC/C activator) and promotes release of Mad2 from APC/C–Cdc20, leading to APC/C activation and spindle assembly checkpoint (SAC) inactivation. CUEDC2 depletion causes checkpoint-dependent delay in metaphase-anaphase transition; overexpression causes premature APC/C activation, chromosome missegregation, and aneuploidy.\",\n      \"method\": \"Kinase assay (Cdk1 phosphorylation), Co-immunoprecipitation (CUEDC2–Cdc20, Mad2 release), siRNA depletion with mitotic timing assays, overexpression with chromosomal instability readouts\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (kinase assay, reciprocal Co-IP, loss- and gain-of-function with defined mitotic phenotypes) in a single focused study\",\n      \"pmids\": [\"21743465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CUEDC2 modulates ER-α protein stability through the ubiquitin-proteasome pathway, promoting ER-α degradation. Ectopic CUEDC2 expression impairs breast cancer cell responsiveness to tamoxifen.\",\n      \"method\": \"Ubiquitin-proteasome pathway assays, western blot for ER-α protein levels upon CUEDC2 manipulation, cell-based tamoxifen response assays, large cohort IHC for inverse correlation\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional ubiquitin-proteasome assay and loss/gain-of-function cellular phenotype in a single lab; mechanistic detail on the E3 ligase not specified in abstract\",\n      \"pmids\": [\"21572428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CUEDC2 inhibits cytokine-induced phosphorylation of JAK1 and STAT3 by interacting with SOCS3 (via yeast two-hybrid confirmed by Co-IP) and increasing SOCS3 protein stability through enhancing SOCS3 association with Elongin C, thereby cooperatively suppressing JAK1/STAT3 signaling.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, STAT3 transcriptional activity assays, SOCS3 stability/ubiquitination assays, Elongin C interaction analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid plus Co-IP plus functional STAT3 activity assay plus protein stability mechanistic follow-up, multiple orthogonal methods in one study\",\n      \"pmids\": [\"22084247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CUEDC2 binds and inhibits APC/C(Cdh1) in G1, stabilizing Cyclin A and promoting G1-S transition. In response to UV irradiation, CUEDC2 undergoes ERK1/2-dependent phosphorylation followed by ubiquitin-dependent degradation, releasing APC/C(Cdh1) to degrade Cyclin A, inactivate CDK2, and enforce G1 arrest. A non-phosphorylatable CUEDC2 mutant resists UV-induced degradation and overrides G1 arrest.\",\n      \"method\": \"Co-immunoprecipitation (CUEDC2–APC/C(Cdh1)), kinase assay (ERK1/2 phosphorylation), ubiquitination assay, phosphomutant rescue experiments, Cyclin A stability assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay, phosphomutant mutagenesis, Co-IP, ubiquitination assay, and functional cell-cycle readout with multiple orthogonal methods\",\n      \"pmids\": [\"23776205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CUEDC2 promotes E3 ubiquitin ligase TRIM33-mediated ubiquitination and proteasome-dependent degradation of the antioxidant enzyme GPX1 in cardiomyocytes. Loss of CUEDC2 elevates GPX1 protein levels, enhancing ROS scavenging and protecting against oxidative stress-induced cardiac injury in vivo.\",\n      \"method\": \"CUEDC2 knockout mice, ubiquitination assay (TRIM33-GPX1), western blot for GPX1 levels, I/R injury model with infarct size measurement, ROS quantification\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse model, ubiquitination assay identifying E3 ligase (TRIM33), in vivo I/R phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"27286733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CUEDC2 interacts with HSP70 via its CUE domain (binding to the PBD and CT domains of HSP70) and negatively regulates HSP70 chaperone activity, as measured by an intracellular luciferase refolding assay.\",\n      \"method\": \"Affinity purification/mass spectrometry, co-immunoprecipitation, domain mapping, intracellular luciferase refolding assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping and functional chaperone assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"24685480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CUEDC2 interacts with SOCS1 and attenuates SOCS1 ubiquitination by enhancing SOCS1 association with Elongin C and Cullin-2 (CUL2), thereby stabilizing SOCS1 protein and suppressing JAK1-STAT3 pathway activation in acute myeloid leukemia cells.\",\n      \"method\": \"Co-immunoprecipitation (CUEDC2–SOCS1), ubiquitination assay, Elongin C/CUL2 interaction analysis, JAK1-STAT3 phosphorylation assays, overexpression/knockdown with proliferation and cell-cycle readouts\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, and functional pathway assay in a single lab\",\n      \"pmids\": [\"29991678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CUEDC2 promotes E3 ligase TRIM21-mediated ubiquitination and degradation of the transcription factor CREB. Downregulation of CUEDC2 in glioma reduces CREB ubiquitination, causing CREB accumulation in the nucleus and increased GDNF transcription.\",\n      \"method\": \"Co-immunoprecipitation (CUEDC2–TRIM21–CREB), ubiquitination assay, western blot for CREB levels, GDNF promoter binding assay, CUEDC2 knockdown/overexpression\",\n      \"journal\": \"Neurochemical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying E3 ligase interaction, ubiquitination assay, functional GDNF readout, single lab\",\n      \"pmids\": [\"33125618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The CUE domain of CUEDC2 directly binds to the ARM (7-9) domain of β-catenin, promotes β-catenin nuclear translocation, and enhances expression of β-catenin target genes, driving Wnt signaling hyperactivation and TNBC tumorigenesis. An 11-amino-acid competitive peptide targeting the CUE domain blocks CUEDC2–β-catenin interaction and abrogates TNBC malignant phenotype in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, pull-down, LC-MS/MS, localized surface plasmon resonance (direct binding), nuclear translocation analysis, competitive peptide inhibition, xenograft model\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding confirmed by SPR (biophysical method), domain mapping by pull-down, nuclear translocation assay, and in vivo xenograft validation with multiple orthogonal methods\",\n      \"pmids\": [\"36231027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CUEDC2 degrades ERα specifically during mitosis using the mitotic ubiquitination machinery, with mitosis-specific phosphorylation of CUEDC2 required for this process. Upregulated CUEDC2 also overrides mitotic arrest and increases aneuploidy.\",\n      \"method\": \"Western blot for ERα levels during mitotic progression, phosphorylation-dependent degradation assays, mitotic arrest override assays, aneuploidy quantification\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional ubiquitination/degradation assay in mitotic context with phosphorylation requirement established, single lab\",\n      \"pmids\": [\"35732909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CUEDC2 knockdown increases phosphorylation of p38 MAPK in ovarian serous carcinoma cells, contributing to cisplatin sensitization, suggesting CUEDC2 negatively regulates p38 MAPK signaling.\",\n      \"method\": \"siRNA knockdown of CUEDC2, western blot for p38 MAPK phosphorylation, cisplatin sensitivity assays\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (western blot after knockdown) in a single lab without mechanistic detail on how CUEDC2 regulates p38\",\n      \"pmids\": [\"31205536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CUEDC2 interacts directly with NLRP3 during inflammasome activation and inhibits NLRP3 inflammasome assembly, thereby suppressing caspase-1 activation and IL-1β maturation, and reducing pyroptosis in glomerular endothelial cells.\",\n      \"method\": \"Co-immunoprecipitation (CUEDC2–NLRP3), caspase-1 activity assay, IL-1β maturation assay, CUEDC2 overexpression/inhibition in GEC pyroptosis model\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional inflammasome assays (caspase-1 and IL-1β), single lab, two orthogonal methods\",\n      \"pmids\": [\"41232582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CUEDC2 controls osteoblast differentiation by regulating SOCS3 protein stability, which in turn modulates STAT3 activation. CUEDC2 overexpression suppresses osteogenic differentiation and reduces bone parameters in vivo, while knockdown promotes differentiation; a STAT3 chemical inhibitor abolishes the pro-differentiation effect of CUEDC2 silencing.\",\n      \"method\": \"Overexpression/knockdown in osteoblast precursor cells, SOCS3 stability assay, STAT3 phosphorylation assay, ectopic bone formation model in vivo, calvarial defect repair model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro loss/gain-of-function with pathway inhibitor rescue, single lab\",\n      \"pmids\": [\"32393737\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CUEDC2 is a multifunctional CUE-domain-containing adaptor/scaffold protein that (1) deactivates IKK by recruiting PP1 (via GADD34) to form a dephosphorylation complex, suppressing NF-κB; (2) inhibits JAK1/STAT3 signaling by binding SOCS3 or SOCS1 and stabilizing them through enhanced Elongin C/CUL2 association; (3) promotes spindle checkpoint inactivation by binding Cdk1-phosphorylated CUEDC2 to Cdc20, releasing Mad2 from APC/C-Cdc20; (4) inhibits APC/C(Cdh1) in G1, and is degraded via ERK1/2-dependent phosphorylation after UV damage to enforce G1 arrest; (5) promotes ubiquitin-proteasome degradation of ER-α and CREB through TRIM33 and TRIM21 E3 ligases respectively; (6) promotes GPX1 degradation via TRIM33, sensitizing cardiomyocytes to oxidative stress; (7) directly binds β-catenin via its CUE domain to drive nuclear translocation and Wnt target gene expression; and (8) interacts with NLRP3 to inhibit inflammasome assembly and suppress pyroptosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CUEDC2 is a CUE-domain-containing adaptor/scaffold protein that negatively regulates multiple signaling pathways and cell-cycle transitions, largely by controlling the phosphorylation state, stability, or localization of partner proteins [#0, #1]. In inflammatory signaling, it acts as an adaptor that recruits the PP1 phosphatase (via the regulatory subunit GADD34) to the IKK complex, forming an IKK\\u2013CUEDC2\\u2013PP1 assembly that dephosphorylates and inactivates IKK to suppress NF-\\u03baB; this complex disassembles upon inflammatory stimuli such as TNF [#0]. It restrains JAK1/STAT3 signaling by binding and stabilizing SOCS proteins\\u2014enhancing SOCS3 association with Elongin C and SOCS1 association with Elongin C/CUL2 to attenuate their ubiquitination [#3, #7]\\u2014a SOCS3-dependent axis that also governs osteoblast differentiation [#13]. CUEDC2 is a Cdk1 substrate that, when phosphorylated in mitosis, binds Cdc20 and promotes Mad2 release from APC/C\\u2013Cdc20 to inactivate the spindle assembly checkpoint, with overexpression driving premature APC/C activation, chromosome missegregation, and aneuploidy [#1]; in G1 it instead binds and inhibits APC/C(Cdh1) to stabilize Cyclin A, and is removed by ERK1/2-dependent phosphorylation and ubiquitin-dependent degradation after UV damage to enforce G1 arrest [#4]. CUEDC2 further serves as a substrate-targeting cofactor that promotes ubiquitin-proteasome degradation of client proteins, directing TRIM33-mediated degradation of the antioxidant enzyme GPX1 in cardiomyocytes (sensitizing the heart to oxidative I/R injury) [#5] and TRIM21-mediated degradation of the transcription factor CREB to limit GDNF transcription [#8], and promoting mitosis-coupled ER-\\u03b1 degradation that impairs tamoxifen responsiveness [#2, #10]. Through its CUE domain it also directly binds the ARM(7-9) region of \\u03b2-catenin to drive nuclear translocation and Wnt target gene expression, a CUE-domain interaction that can be blocked by a competitive peptide to abrogate triple-negative breast cancer malignancy [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established CUEDC2 as a negative regulator of NF-\\u03baB by defining a molecular mechanism: it scaffolds a phosphatase onto the kinase that normally activates the pathway.\",\n      \"evidence\": \"Reciprocal Co-IP, complex reconstitution and dephosphorylation assays defining an IKK\\u2013CUEDC2\\u2013PP1(GADD34) complex\",\n      \"pmids\": [\"18362886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not establish what triggers complex disassembly at the molecular level beyond stimulus dependence\", \"Stoichiometry and direct vs. indirect IKK contact not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed CUEDC2 is a cell-cycle regulator, linking its Cdk1 phosphorylation to spindle checkpoint inactivation and genomic instability.\",\n      \"evidence\": \"Cdk1 kinase assay, CUEDC2\\u2013Cdc20 Co-IP with Mad2 release, siRNA timing assays and overexpression aneuploidy readouts\",\n      \"pmids\": [\"21743465\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cdk1 phosphosites not fully mapped\", \"Mechanism by which CUEDC2 binding displaces Mad2 from APC/C\\u2013Cdc20 not structurally defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended CUEDC2 to hormone-receptor control by showing it lowers ER-\\u03b1 via the ubiquitin-proteasome pathway and blunts tamoxifen response.\",\n      \"evidence\": \"Ubiquitin-proteasome assays, ER-\\u03b1 western blots under CUEDC2 manipulation, tamoxifen-response cell assays, cohort IHC correlation\",\n      \"pmids\": [\"21572428\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase not identified in this study\", \"Direct vs. indirect role in ER-\\u03b1 ubiquitination unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined a stabilization mechanism for SOCS3, showing CUEDC2 suppresses JAK1/STAT3 by protecting a negative-feedback inhibitor.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, STAT3 activity assays, SOCS3 stability/ubiquitination and Elongin C interaction analysis\",\n      \"pmids\": [\"22084247\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CUEDC2 enhances SOCS3\\u2013Elongin C association mechanistically not defined\", \"Direct binding interface not mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved an opposing cell-cycle role, showing CUEDC2 inhibits APC/C(Cdh1) in G1 and that its DNA-damage-triggered degradation enforces G1 arrest.\",\n      \"evidence\": \"CUEDC2\\u2013APC/C(Cdh1) Co-IP, ERK1/2 kinase assay, ubiquitination assay, phosphomutant rescue, Cyclin A stability readouts\",\n      \"pmids\": [\"23776205\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase degrading CUEDC2 after UV not identified\", \"Relationship between the mitotic Cdc20-binding and G1 Cdh1-inhibiting roles not unified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified a chaperone-regulatory function, showing the CUE domain binds HSP70 and dampens its refolding activity.\",\n      \"evidence\": \"AP-MS, Co-IP, domain mapping, intracellular luciferase refolding assay\",\n      \"pmids\": [\"24685480\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, two orthogonal methods\", \"Physiological consequences of HSP70 inhibition not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected CUEDC2 to redox protection in vivo by showing it directs TRIM33-mediated degradation of GPX1 and that its loss protects the heart from oxidative injury.\",\n      \"evidence\": \"CUEDC2 knockout mice, TRIM33\\u2013GPX1 ubiquitination assay, GPX1 westerns, I/R infarct and ROS measurements\",\n      \"pmids\": [\"27286733\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CUEDC2 directly bridges TRIM33 and GPX1 not structurally shown\", \"Tissue specificity of this axis not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Generalized the SOCS-stabilization mechanism to SOCS1/CUL2 in leukemia, reinforcing CUEDC2 as a brake on JAK1-STAT3.\",\n      \"evidence\": \"CUEDC2\\u2013SOCS1 Co-IP, ubiquitination assay, Elongin C/CUL2 interaction, JAK1-STAT3 phosphorylation and proliferation readouts\",\n      \"pmids\": [\"29991678\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Binding interface between CUEDC2 and SOCS1 not mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked CUEDC2 to p38 MAPK and chemosensitivity, indicating it negatively regulates p38 in ovarian carcinoma.\",\n      \"evidence\": \"siRNA knockdown, p38 phosphorylation westerns, cisplatin sensitivity assays\",\n      \"pmids\": [\"31205536\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single method (western after knockdown) without mechanistic detail\", \"Direct vs. indirect regulation of p38 unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed CUEDC2 directs TRIM21-mediated CREB degradation, controlling GDNF transcription in glioma.\",\n      \"evidence\": \"CUEDC2\\u2013TRIM21\\u2013CREB Co-IP, ubiquitination assay, CREB westerns, GDNF promoter binding assays\",\n      \"pmids\": [\"33125618\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Whether CUEDC2 is an obligate cofactor or modulator of TRIM21 not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated the SOCS3/STAT3 axis governs a developmental output, with CUEDC2 restraining osteoblast differentiation.\",\n      \"evidence\": \"Gain/loss-of-function in osteoblast precursors, SOCS3 stability and STAT3 phosphorylation assays, in vivo bone formation and calvarial repair with STAT3-inhibitor rescue\",\n      \"pmids\": [\"32393737\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Whether bone phenotype is wholly STAT3-dependent vs. multifactorial unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided direct biophysical evidence for a CUE-domain interaction with \\u03b2-catenin driving Wnt activation, and a druggable peptide interface.\",\n      \"evidence\": \"Co-IP, pull-down, LC-MS/MS, SPR direct-binding, nuclear translocation assay, competitive peptide and xenograft in TNBC\",\n      \"pmids\": [\"36231027\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of how CUE\\u2013\\u03b2-catenin binding promotes nuclear import not defined\", \"Relationship to the degradation/scaffold roles of the same CUE domain unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Refined the ER-\\u03b1 degradation mechanism by showing it is mitosis-restricted and dependent on mitotic phosphorylation of CUEDC2.\",\n      \"evidence\": \"ER\\u03b1 westerns across mitotic progression, phosphorylation-dependent degradation and mitotic-arrest override assays, aneuploidy quantification\",\n      \"pmids\": [\"35732909\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase for ER-\\u03b1 still not named\", \"Phosphosites and the responsible kinase not fully defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Added an inflammasome-suppressive role, showing CUEDC2 binds NLRP3 to block assembly and limit pyroptosis.\",\n      \"evidence\": \"CUEDC2\\u2013NLRP3 Co-IP, caspase-1 activity and IL-1\\u03b2 maturation assays in glomerular endothelial cell pyroptosis model\",\n      \"pmids\": [\"41232582\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, two orthogonal methods\", \"How CUEDC2 binding physically prevents NLRP3 oligomerization not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single CUE-domain adaptor selects among its many partners (PP1/IKK, Cdc20, Cdh1, SOCS1/3, multiple TRIM ligases, \\u03b2-catenin, NLRP3) and switches between stabilizing, degrading, and scaffolding modes remains unresolved.\",\n      \"evidence\": \"No structural or competitive-binding study in the timeline addresses how partner selection and functional mode are coordinated\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of CUEDC2 or its complexes\", \"No systematic mapping of which interactions are mutually exclusive\", \"Upstream signals controlling mode-switching incompletely defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3, 7, 6]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [5, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [9, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 12]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5, 8, 2]}\n    ],\n    \"complexes\": [\"IKK\\u2013CUEDC2\\u2013PP1(GADD34) complex\"],\n    \"partners\": [\"IKBKB\", \"GADD34\", \"CDC20\", \"FZR1\", \"SOCS3\", \"SOCS1\", \"TRIM33\", \"CTNNB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}