{"gene":"CUEDC2","run_date":"2026-04-28T17:28:53","timeline":{"discoveries":[{"year":2008,"finding":"CUEDC2 acts as an adaptor protein that interacts with both IKKα/IKKβ and the PP1 regulatory subunit GADD34, recruiting PP1 to IKK to promote its dephosphorylation and inactivation, thereby deactivating NF-κB signaling. IKK, CUEDC2, and PP1 exist in a complex, and IKK is released from the complex in response to inflammatory stimuli such as TNF.","method":"Co-immunoprecipitation, complex reconstitution, phosphorylation assays, loss-of-function experiments","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1-2 — reciprocal Co-IP, complex reconstitution, functional phosphorylation assays; highly cited foundational paper","pmids":["18362886"],"is_preprint":false},{"year":2011,"finding":"CUEDC2 modulates ERα protein stability through the ubiquitin-proteasome pathway, leading to ERα downregulation and endocrine resistance in breast cancer.","method":"Ectopic expression, ubiquitin-proteasome pathway assays, Western blotting, breast cancer cell line functional assays","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods in highly cited paper; replicated in subsequent studies","pmids":["21572428"],"is_preprint":false},{"year":2011,"finding":"CUEDC2 is phosphorylated by Cdk1 during mitosis; phosphorylated CUEDC2 binds to Cdc20 (an APC/C activator), promotes release of Mad2 from APC/C-Cdc20, and thereby inactivates the spindle assembly checkpoint and activates APC/C. Depletion of CUEDC2 causes a checkpoint-dependent delay of the metaphase-anaphase transition, while overexpression causes premature APC/C activation, chromosome missegregation, and aneuploidy.","method":"RNAi depletion, Co-immunoprecipitation, phosphorylation assays, time-lapse imaging, mitotic checkpoint assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (Co-IP, phosphorylation assays, live-cell imaging, KD phenotype) in highly cited paper","pmids":["21743465"],"is_preprint":false},{"year":2011,"finding":"CUEDC2 interacts with SOCS3 (via yeast two-hybrid and co-IP), stabilizes SOCS3 by enhancing its association with Elongin C, and cooperates with SOCS3 to inhibit cytokine-induced phosphorylation of JAK1 and STAT3 and subsequent STAT3 transcriptional activity.","method":"Yeast two-hybrid, co-immunoprecipitation, phosphorylation assays, transcriptional reporter assays, SOCS3 stability assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Y2H, reciprocal Co-IP, functional assays) in single study","pmids":["22084247"],"is_preprint":false},{"year":2013,"finding":"CUEDC2 binds to and inhibits APC/C-Cdh1 to stabilize Cyclin A and promote G1-S transition. In response to UV irradiation, CUEDC2 undergoes ERK1/2-dependent phosphorylation and ubiquitin-dependent degradation, leading to APC/C(Cdh1)-mediated Cyclin A destruction, CDK2 inactivation, and G1 arrest. A non-phosphorylatable CUEDC2 mutant is resistant to UV-induced degradation and overrides UV-induced G1-S block.","method":"Co-immunoprecipitation, site-directed mutagenesis, kinase assays (ERK1/2), ubiquitination assays, cell cycle analysis, stable mutant expression","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — reconstitution-level evidence with mutagenesis, multiple orthogonal assays","pmids":["23776205"],"is_preprint":false},{"year":2014,"finding":"CUEDC2 expression is dramatically upregulated during macrophage differentiation; CUEDC2 deficiency results in excessive production of proinflammatory cytokines. The level of CUEDC2 in macrophages is regulated by miR-324-5p. Cuedc2 KO mice show increased susceptibility to DSS-induced colitis and colitis-associated cancer due to macrophage dysfunction.","method":"CUEDC2 knockout mice, macrophage transplantation, DSS colitis model, cytokine measurement, miR-324-5p target validation","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with defined cellular and in vivo phenotype, macrophage transplantation rescue experiment","pmids":["24882011"],"is_preprint":false},{"year":2014,"finding":"CUEDC2 interacts with HSP70; the CUE domain of CUEDC2 mediates binding to the PBD and CT domains of HSP70. CUEDC2 negatively regulates HSP70 chaperone activity, as demonstrated by an intracellular luciferase refolding assay.","method":"Affinity purification with mass spectrometry, co-immunoprecipitation, domain mapping, intracellular luciferase refolding assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with domain mapping and functional chaperone assay, single study","pmids":["24685480"],"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 upregulates GPX1, enhances ROS scavenging, and protects against oxidative stress-induced cardiac injury.","method":"Cuedc2 knockout mice, ubiquitination assays, co-immunoprecipitation, I/R injury model, GPX1 protein stability assays","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 1-2 — ubiquitination reconstitution, KO mouse with in vivo phenotype, multiple orthogonal methods","pmids":["27286733"],"is_preprint":false},{"year":2018,"finding":"CUEDC2 interacts with SOCS1 and attenuates SOCS1 ubiquitination by enhancing SOCS1's association with Elongin C and Cullin-2 (CUL2), thereby stabilizing SOCS1 and suppressing JAK1-STAT3 pathway activation in AML cells.","method":"Co-immunoprecipitation, ubiquitination assays, protein stability assays, CUEDC2 overexpression/knockdown","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, ubiquitination assays, single lab","pmids":["29991678"],"is_preprint":false},{"year":2019,"finding":"CUEDC2 knockdown in ovarian serous carcinoma cells increases phosphorylation of p38 MAPK and enhances cisplatin sensitivity, placing CUEDC2 upstream of p38 MAPK signaling in chemoresistance.","method":"siRNA knockdown, Western blotting for p38 MAPK phosphorylation, cell viability assays","journal":"Journal of Cancer","confidence":"Low","confidence_rationale":"Tier 3 — single method (KD + Western blot), single lab, no direct mechanistic reconstitution","pmids":["31205536"],"is_preprint":false},{"year":2020,"finding":"CUEDC2 increases the amount of binding between E3 ligase TRIM21 and the transcription factor CREB, promoting CREB ubiquitination and degradation. Downregulation of CUEDC2 in glioma reduces CREB ubiquitination, leading to CREB accumulation and increased GDNF transcription.","method":"Co-immunoprecipitation, ubiquitination assays, Western blotting, ChIP for GDNF promoter binding","journal":"Neurochemical research","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP and ubiquitination assays, single lab","pmids":["33125618"],"is_preprint":false},{"year":2020,"finding":"CUEDC2 affects STAT3 activation by regulating SOCS3 protein stability; overexpression of CUEDC2 suppresses osteoblast differentiation while knockdown promotes it, and this effect is abolished by STAT3 chemical inhibition, placing CUEDC2 upstream of SOCS3-STAT3 in osteoblast differentiation.","method":"CUEDC2 overexpression and knockdown, SOCS3 stability assays, STAT3 inhibitor experiments, in vivo ectopic bone formation and calvarial defect models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis with chemical inhibitor rescue, in vivo models, single lab","pmids":["32393737"],"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. An 11-amino-acid competitive peptide targeting the CUE domain blocks CUEDC2-β-catenin interaction and abrogates TNBC malignant phenotype.","method":"Co-immunoprecipitation, pull-down, LC-MS/MS, localized surface plasmon resonance, nuclear translocation analysis, competitive peptide inhibition in vitro and in vivo","journal":"Cells","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding confirmed by SPR and pull-down with domain mapping, functional rescue with competitive peptide, in vivo xenograft validation","pmids":["36231027"],"is_preprint":false},{"year":2022,"finding":"CUEDC2 degrades ERα specifically during mitosis using the mitotic ubiquitination machinery, and mitosis-specific phosphorylation of CUEDC2 is required for this process. Upregulated CUEDC2 overrides mitotic arrest and increases aneuploidy.","method":"Co-immunoprecipitation, phosphorylation site analysis, cell cycle synchronization, ubiquitination assays, flow cytometry for aneuploidy","journal":"Cancer gene therapy","confidence":"Medium","confidence_rationale":"Tier 2 — multiple assays but single lab; mechanistically extends prior findings on mitotic CUEDC2 phosphorylation","pmids":["35732909"],"is_preprint":false},{"year":2025,"finding":"CUEDC2 directly interacts with NLRP3 during inflammasome activation, inhibiting IL-1β maturation and caspase-1 activation, thereby suppressing NLRP3 inflammasome-driven pyroptosis in glomerular endothelial cells.","method":"Co-immunoprecipitation, CUEDC2 overexpression/knockdown, caspase-1 activity assays, IL-1β maturation assays, pyroptosis assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with functional assays, single lab, recent paper with 0 citations","pmids":["41232582"],"is_preprint":false}],"current_model":"CUEDC2 is a multifunctional adaptor/scaffold protein whose CUE domain mediates interactions with multiple partners—including IKKα/β (recruiting PP1 for dephosphorylation/inactivation), Cdc20 (releasing Mad2 from APC/C to inactivate the spindle checkpoint after Cdk1-mediated phosphorylation), APC/C-Cdh1 (inhibiting it to stabilize Cyclin A; degraded via ERK1/2-dependent phosphorylation upon UV damage), SOCS3/SOCS1 (stabilizing them via Elongin C/CUL2 to suppress JAK1/STAT3), TRIM33/TRIM21 (promoting ubiquitination of GPX1 and CREB, respectively), β-catenin (promoting its nuclear translocation to activate Wnt targets), NLRP3 (blocking inflammasome activation), and HSP70 (inhibiting chaperone activity)—thereby broadly suppressing inflammatory (NF-κB, JAK/STAT) and cell-cycle (APC/C, SAC) pathways while also regulating protein stability through the ubiquitin-proteasome system."},"narrative":{"teleology":[{"year":2008,"claim":"Establishing CUEDC2 as a negative regulator of NF-κB signaling answered how IKK is dephosphorylated after inflammatory stimulation: CUEDC2 bridges IKK to the PP1 phosphatase complex via GADD34, and this complex disassembles upon TNF stimulation.","evidence":"Reciprocal co-immunoprecipitation, complex reconstitution, phosphorylation assays, and loss-of-function experiments in mammalian cells","pmids":["18362886"],"confidence":"High","gaps":["Structural basis of the IKK-CUEDC2-PP1 ternary complex is unknown","Whether CUEDC2-PP1 acts on other kinases in the NF-κB pathway is untested","In vivo relevance in conditional knockout models was not shown"]},{"year":2011,"claim":"Three simultaneous discoveries expanded CUEDC2 from an NF-κB regulator to a multi-pathway adaptor: it promotes ERα degradation via the ubiquitin-proteasome system, silences the spindle assembly checkpoint by releasing Mad2 from APC/C-Cdc20 after Cdk1 phosphorylation, and stabilizes SOCS3 to suppress JAK1-STAT3 signaling.","evidence":"Ubiquitin-proteasome assays for ERα degradation in breast cancer cells; RNAi, co-IP, live-cell imaging, and checkpoint assays for Cdc20-Mad2 regulation during mitosis; yeast two-hybrid, co-IP, and reporter assays for SOCS3-Elongin C stabilization","pmids":["21572428","21743465","22084247"],"confidence":"High","gaps":["Whether CUE-domain ubiquitin binding is required for ERα degradation was not tested","Identity of the E3 ligase mediating CUEDC2-dependent ERα ubiquitination was unknown","How Cdk1-phosphorylated CUEDC2 specifically displaces Mad2 from the APC/C-Cdc20 complex structurally is unresolved"]},{"year":2013,"claim":"Revealing that CUEDC2 also inhibits APC/C-Cdh1 to stabilize Cyclin A, and that UV-triggered ERK1/2 phosphorylation targets CUEDC2 for ubiquitin-dependent degradation, established CUEDC2 as a cell-cycle signal integrator whose own turnover controls the G1-S DNA damage checkpoint.","evidence":"Co-IP, ERK1/2 kinase assays, non-phosphorylatable mutant expression, cell cycle analysis after UV irradiation","pmids":["23776205"],"confidence":"High","gaps":["The E3 ligase responsible for CUEDC2 degradation after ERK-dependent phosphorylation is not identified","Whether this mechanism operates in non-transformed cells in vivo is untested"]},{"year":2014,"claim":"In vivo loss-of-function in Cuedc2 knockout mice demonstrated that CUEDC2 is essential for macrophage inflammatory homeostasis and that its absence leads to excessive cytokine production, colitis, and colitis-associated cancer, confirming a non-redundant physiological role.","evidence":"Cuedc2 KO mice, DSS colitis and colitis-associated cancer models, macrophage transplantation rescue, miR-324-5p target validation","pmids":["24882011"],"confidence":"High","gaps":["Which downstream pathway (NF-κB, JAK-STAT, or both) drives the colitis phenotype was not dissected","Tissue-specific conditional knockouts were not reported"]},{"year":2014,"claim":"Identification of HSP70 as a CUE-domain-dependent binding partner revealed that CUEDC2 can negatively regulate protein chaperone activity, extending its functional repertoire beyond signaling and cell cycle.","evidence":"Affinity purification–mass spectrometry, co-IP with domain mapping, intracellular luciferase refolding assay","pmids":["24685480"],"confidence":"Medium","gaps":["Only a single chaperone substrate (luciferase) was tested","Physiological consequence of HSP70 inhibition by CUEDC2 is not established in vivo","No independent replication"]},{"year":2016,"claim":"Demonstrating that CUEDC2 facilitates TRIM33-mediated ubiquitination and degradation of GPX1 in cardiomyocytes established CUEDC2 as a cofactor for TRIM-family E3 ligases and linked it to oxidative stress defense in the heart.","evidence":"Cuedc2 KO mice, ubiquitination reconstitution, ischemia/reperfusion injury model, GPX1 stability assays","pmids":["27286733"],"confidence":"High","gaps":["Whether CUEDC2 is a general TRIM33 cofactor or specific to GPX1 is unclear","Structural basis for CUEDC2-TRIM33 cooperation is unknown"]},{"year":2018,"claim":"Extending the SOCS-stabilization mechanism to SOCS1 via Elongin C/CUL2 in AML cells generalized the principle that CUEDC2 enhances SOCS-box E3 ligase complex assembly to suppress JAK-STAT signaling across cell types.","evidence":"Co-IP, ubiquitination and stability assays, CUEDC2 overexpression/knockdown in AML cell lines","pmids":["29991678"],"confidence":"Medium","gaps":["Whether CUEDC2 engages SOCS proteins directly or via Elongin C is not resolved structurally","Independent replication in primary AML samples is lacking"]},{"year":2020,"claim":"Showing that CUEDC2 promotes TRIM21-mediated ubiquitination of CREB and that this axis controls GDNF transcription in glioma revealed a second TRIM-family partnership and a transcription-factor-degradation role for CUEDC2.","evidence":"Co-IP, ubiquitination assays, ChIP for GDNF promoter CREB occupancy in glioma cells","pmids":["33125618"],"confidence":"Medium","gaps":["Whether CUEDC2-TRIM21 cooperates on substrates beyond CREB is unknown","Single lab, no in vivo validation"]},{"year":2022,"claim":"Mapping the CUE domain interaction with β-catenin ARM repeats 7–9 and blocking it with a competitive peptide demonstrated that CUEDC2 directly promotes β-catenin nuclear translocation and Wnt target gene activation, revealing a new signaling axis targetable therapeutically.","evidence":"Pull-down, SPR binding, LC-MS/MS, nuclear translocation assays, competitive 11-mer peptide inhibition in vitro and in vivo xenografts","pmids":["36231027"],"confidence":"High","gaps":["Whether CUEDC2 competes with APC/Axin destruction complex components for β-catenin binding is untested","Selectivity and pharmacokinetics of the competitive peptide in vivo are preliminary"]},{"year":2022,"claim":"Linking CUEDC2-dependent ERα degradation specifically to mitosis-specific phosphorylation of CUEDC2 unified the earlier ERα and mitotic-checkpoint findings, showing that the same phospho-regulated switch governs both checkpoint silencing and ERα turnover.","evidence":"Cell cycle synchronization, phosphorylation site analysis, co-IP, ubiquitination assays, aneuploidy quantification","pmids":["35732909"],"confidence":"Medium","gaps":["The E3 ligase mediating mitotic ERα ubiquitination downstream of CUEDC2 remains unidentified","Whether mitotic ERα degradation is relevant in normal mammary tissue is unknown"]},{"year":2025,"claim":"Discovery that CUEDC2 directly binds NLRP3 and inhibits inflammasome activation extended its anti-inflammatory repertoire beyond NF-κB and JAK-STAT to the innate immune inflammasome pathway.","evidence":"Co-IP, CUEDC2 overexpression/knockdown, caspase-1 and IL-1β maturation assays in glomerular endothelial cells","pmids":["41232582"],"confidence":"Medium","gaps":["Mechanism of NLRP3 inhibition (oligomerization block vs. ASC recruitment block) is not defined","In vivo relevance in inflammasome-driven disease models is not shown","No independent replication"]},{"year":null,"claim":"A unified structural model explaining how the CUE domain selectively engages its many partners (IKK, Cdc20, SOCS proteins, TRIMs, β-catenin, NLRP3, HSP70, ubiquitin), and how phosphorylation switches redirect CUEDC2 among these interactions, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of CUEDC2 or its complexes exists","Quantitative binding affinities for most partners have not been measured","How the cell prioritizes CUEDC2 allocation among competing interactions is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,7,8,10,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,4,3,8,14]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,12]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,5,14]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2,4,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,8,11,12]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,7,10,13]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[14]}],"complexes":["IKK-CUEDC2-PP1/GADD34","SOCS3-Elongin C-CUL2","APC/C-Cdc20"],"partners":["IKBKB","IKBKA","CDC20","SOCS3","SOCS1","TRIM33","CTNNB1","NLRP3"],"other_free_text":[]},"mechanistic_narrative":"CUEDC2 is a CUE-domain-containing adaptor protein that functions as a broad regulatory hub in inflammation, cell cycle control, and protein stability by scaffolding signaling complexes and directing ubiquitin-proteasome-mediated degradation of diverse substrates. In inflammatory signaling, CUEDC2 recruits PP1 phosphatase to IKKα/IKKβ to terminate NF-κB activation [PMID:18362886], stabilizes SOCS1 and SOCS3 through enhanced Elongin C/CUL2 association to suppress JAK1-STAT3 signaling [PMID:22084247, PMID:29991678], and directly binds NLRP3 to inhibit inflammasome-driven pyroptosis [PMID:41232582]; Cuedc2-knockout mice accordingly exhibit excessive macrophage cytokine production and colitis susceptibility [PMID:24882011]. In cell cycle regulation, Cdk1-dependent phosphorylation of CUEDC2 enables it to bind Cdc20 and release Mad2 from APC/C-Cdc20 to silence the spindle assembly checkpoint [PMID:21743465], while separately CUEDC2 inhibits APC/C-Cdh1 to stabilize Cyclin A and promote G1-S transition, a function terminated by ERK1/2-dependent phosphorylation and degradation of CUEDC2 upon UV damage [PMID:23776205]. CUEDC2 also serves as a cofactor for TRIM-family E3 ligases, promoting TRIM33-mediated ubiquitination of GPX1 in cardiomyocytes [PMID:27286733] and TRIM21-mediated ubiquitination of CREB in glioma cells [PMID:33125618], and its CUE domain directly engages β-catenin to drive its nuclear translocation and Wnt target gene activation [PMID:36231027]."},"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":117,"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 oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28534933","citation_count":19,"is_preprint":false},{"pmid":"30844721","id":"PMC_30844721","title":"CUEDC2: multifunctional roles in carcinogenesis.","date":"2019","source":"Frontiers in bioscience (Landmark edition)","url":"https://pubmed.ncbi.nlm.nih.gov/30844721","citation_count":17,"is_preprint":false},{"pmid":"29991678","id":"PMC_29991678","title":"CUEDC2, a novel interacting partner of the SOCS1 protein, plays important roles in the leukaemogenesis of acute myeloid leukaemia.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/29991678","citation_count":16,"is_preprint":false},{"pmid":"27286733","id":"PMC_27286733","title":"CUEDC2 modulates cardiomyocyte oxidative capacity by regulating GPX1 stability.","date":"2016","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27286733","citation_count":16,"is_preprint":false},{"pmid":"32393737","id":"PMC_32393737","title":"CUEDC2 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":13,"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":"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":"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":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":"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":"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":9,"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":"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":"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":"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":"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":"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":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":"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},{"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}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17286,"output_tokens":3738,"usd":0.053964},"stage2":{"model":"claude-opus-4-6","input_tokens":7212,"output_tokens":3525,"usd":0.186278},"total_usd":0.240242,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","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 interacts with both IKKα/IKKβ and the PP1 regulatory subunit GADD34, recruiting PP1 to IKK to promote its dephosphorylation and inactivation, thereby deactivating NF-κB signaling. IKK, CUEDC2, and PP1 exist in a complex, and IKK is released from the complex in response to inflammatory stimuli such as TNF.\",\n      \"method\": \"Co-immunoprecipitation, complex reconstitution, phosphorylation assays, loss-of-function experiments\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal Co-IP, complex reconstitution, functional phosphorylation assays; highly cited foundational paper\",\n      \"pmids\": [\"18362886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CUEDC2 modulates ERα protein stability through the ubiquitin-proteasome pathway, leading to ERα downregulation and endocrine resistance in breast cancer.\",\n      \"method\": \"Ectopic expression, ubiquitin-proteasome pathway assays, Western blotting, breast cancer cell line functional assays\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in highly cited paper; replicated in subsequent studies\",\n      \"pmids\": [\"21572428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CUEDC2 is phosphorylated by Cdk1 during mitosis; phosphorylated CUEDC2 binds to Cdc20 (an APC/C activator), promotes release of Mad2 from APC/C-Cdc20, and thereby inactivates the spindle assembly checkpoint and activates APC/C. Depletion of CUEDC2 causes a checkpoint-dependent delay of the metaphase-anaphase transition, while overexpression causes premature APC/C activation, chromosome missegregation, and aneuploidy.\",\n      \"method\": \"RNAi depletion, Co-immunoprecipitation, phosphorylation assays, time-lapse imaging, mitotic checkpoint assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (Co-IP, phosphorylation assays, live-cell imaging, KD phenotype) in highly cited paper\",\n      \"pmids\": [\"21743465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CUEDC2 interacts with SOCS3 (via yeast two-hybrid and co-IP), stabilizes SOCS3 by enhancing its association with Elongin C, and cooperates with SOCS3 to inhibit cytokine-induced phosphorylation of JAK1 and STAT3 and subsequent STAT3 transcriptional activity.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, phosphorylation assays, transcriptional reporter assays, SOCS3 stability assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Y2H, reciprocal Co-IP, functional assays) in single study\",\n      \"pmids\": [\"22084247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CUEDC2 binds to and inhibits APC/C-Cdh1 to stabilize Cyclin A and promote G1-S transition. In response to UV irradiation, CUEDC2 undergoes ERK1/2-dependent phosphorylation and ubiquitin-dependent degradation, leading to APC/C(Cdh1)-mediated Cyclin A destruction, CDK2 inactivation, and G1 arrest. A non-phosphorylatable CUEDC2 mutant is resistant to UV-induced degradation and overrides UV-induced G1-S block.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis, kinase assays (ERK1/2), ubiquitination assays, cell cycle analysis, stable mutant expression\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution-level evidence with mutagenesis, multiple orthogonal assays\",\n      \"pmids\": [\"23776205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CUEDC2 expression is dramatically upregulated during macrophage differentiation; CUEDC2 deficiency results in excessive production of proinflammatory cytokines. The level of CUEDC2 in macrophages is regulated by miR-324-5p. Cuedc2 KO mice show increased susceptibility to DSS-induced colitis and colitis-associated cancer due to macrophage dysfunction.\",\n      \"method\": \"CUEDC2 knockout mice, macrophage transplantation, DSS colitis model, cytokine measurement, miR-324-5p target validation\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined cellular and in vivo phenotype, macrophage transplantation rescue experiment\",\n      \"pmids\": [\"24882011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CUEDC2 interacts with HSP70; the CUE domain of CUEDC2 mediates binding to the PBD and CT domains of HSP70. CUEDC2 negatively regulates HSP70 chaperone activity, as demonstrated by an intracellular luciferase refolding assay.\",\n      \"method\": \"Affinity purification with 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 — Co-IP with domain mapping and functional chaperone assay, single study\",\n      \"pmids\": [\"24685480\"],\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 upregulates GPX1, enhances ROS scavenging, and protects against oxidative stress-induced cardiac injury.\",\n      \"method\": \"Cuedc2 knockout mice, ubiquitination assays, co-immunoprecipitation, I/R injury model, GPX1 protein stability assays\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ubiquitination reconstitution, KO mouse with in vivo phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"27286733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CUEDC2 interacts with SOCS1 and attenuates SOCS1 ubiquitination by enhancing SOCS1's association with Elongin C and Cullin-2 (CUL2), thereby stabilizing SOCS1 and suppressing JAK1-STAT3 pathway activation in AML cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, protein stability assays, CUEDC2 overexpression/knockdown\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ubiquitination assays, single lab\",\n      \"pmids\": [\"29991678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CUEDC2 knockdown in ovarian serous carcinoma cells increases phosphorylation of p38 MAPK and enhances cisplatin sensitivity, placing CUEDC2 upstream of p38 MAPK signaling in chemoresistance.\",\n      \"method\": \"siRNA knockdown, Western blotting for p38 MAPK phosphorylation, cell viability assays\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single method (KD + Western blot), single lab, no direct mechanistic reconstitution\",\n      \"pmids\": [\"31205536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CUEDC2 increases the amount of binding between E3 ligase TRIM21 and the transcription factor CREB, promoting CREB ubiquitination and degradation. Downregulation of CUEDC2 in glioma reduces CREB ubiquitination, leading to CREB accumulation and increased GDNF transcription.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, Western blotting, ChIP for GDNF promoter binding\",\n      \"journal\": \"Neurochemical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and ubiquitination assays, single lab\",\n      \"pmids\": [\"33125618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CUEDC2 affects STAT3 activation by regulating SOCS3 protein stability; overexpression of CUEDC2 suppresses osteoblast differentiation while knockdown promotes it, and this effect is abolished by STAT3 chemical inhibition, placing CUEDC2 upstream of SOCS3-STAT3 in osteoblast differentiation.\",\n      \"method\": \"CUEDC2 overexpression and knockdown, SOCS3 stability assays, STAT3 inhibitor experiments, in vivo ectopic bone formation and calvarial defect models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis with chemical inhibitor rescue, in vivo models, single lab\",\n      \"pmids\": [\"32393737\"],\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. An 11-amino-acid competitive peptide targeting the CUE domain blocks CUEDC2-β-catenin interaction and abrogates TNBC malignant phenotype.\",\n      \"method\": \"Co-immunoprecipitation, pull-down, LC-MS/MS, localized surface plasmon resonance, nuclear translocation analysis, competitive peptide inhibition in vitro and in vivo\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding confirmed by SPR and pull-down with domain mapping, functional rescue with competitive peptide, in vivo xenograft validation\",\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, and mitosis-specific phosphorylation of CUEDC2 is required for this process. Upregulated CUEDC2 overrides mitotic arrest and increases aneuploidy.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation site analysis, cell cycle synchronization, ubiquitination assays, flow cytometry for aneuploidy\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple assays but single lab; mechanistically extends prior findings on mitotic CUEDC2 phosphorylation\",\n      \"pmids\": [\"35732909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CUEDC2 directly interacts with NLRP3 during inflammasome activation, inhibiting IL-1β maturation and caspase-1 activation, thereby suppressing NLRP3 inflammasome-driven pyroptosis in glomerular endothelial cells.\",\n      \"method\": \"Co-immunoprecipitation, CUEDC2 overexpression/knockdown, caspase-1 activity assays, IL-1β maturation assays, pyroptosis assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with functional assays, single lab, recent paper with 0 citations\",\n      \"pmids\": [\"41232582\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CUEDC2 is a multifunctional adaptor/scaffold protein whose CUE domain mediates interactions with multiple partners—including IKKα/β (recruiting PP1 for dephosphorylation/inactivation), Cdc20 (releasing Mad2 from APC/C to inactivate the spindle checkpoint after Cdk1-mediated phosphorylation), APC/C-Cdh1 (inhibiting it to stabilize Cyclin A; degraded via ERK1/2-dependent phosphorylation upon UV damage), SOCS3/SOCS1 (stabilizing them via Elongin C/CUL2 to suppress JAK1/STAT3), TRIM33/TRIM21 (promoting ubiquitination of GPX1 and CREB, respectively), β-catenin (promoting its nuclear translocation to activate Wnt targets), NLRP3 (blocking inflammasome activation), and HSP70 (inhibiting chaperone activity)—thereby broadly suppressing inflammatory (NF-κB, JAK/STAT) and cell-cycle (APC/C, SAC) pathways while also regulating protein stability through the ubiquitin-proteasome system.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CUEDC2 is a CUE-domain-containing adaptor protein that functions as a broad regulatory hub in inflammation, cell cycle control, and protein stability by scaffolding signaling complexes and directing ubiquitin-proteasome-mediated degradation of diverse substrates. In inflammatory signaling, CUEDC2 recruits PP1 phosphatase to IKKα/IKKβ to terminate NF-κB activation [PMID:18362886], stabilizes SOCS1 and SOCS3 through enhanced Elongin C/CUL2 association to suppress JAK1-STAT3 signaling [PMID:22084247, PMID:29991678], and directly binds NLRP3 to inhibit inflammasome-driven pyroptosis [PMID:41232582]; Cuedc2-knockout mice accordingly exhibit excessive macrophage cytokine production and colitis susceptibility [PMID:24882011]. In cell cycle regulation, Cdk1-dependent phosphorylation of CUEDC2 enables it to bind Cdc20 and release Mad2 from APC/C-Cdc20 to silence the spindle assembly checkpoint [PMID:21743465], while separately CUEDC2 inhibits APC/C-Cdh1 to stabilize Cyclin A and promote G1-S transition, a function terminated by ERK1/2-dependent phosphorylation and degradation of CUEDC2 upon UV damage [PMID:23776205]. CUEDC2 also serves as a cofactor for TRIM-family E3 ligases, promoting TRIM33-mediated ubiquitination of GPX1 in cardiomyocytes [PMID:27286733] and TRIM21-mediated ubiquitination of CREB in glioma cells [PMID:33125618], and its CUE domain directly engages β-catenin to drive its nuclear translocation and Wnt target gene activation [PMID:36231027].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Establishing CUEDC2 as a negative regulator of NF-κB signaling answered how IKK is dephosphorylated after inflammatory stimulation: CUEDC2 bridges IKK to the PP1 phosphatase complex via GADD34, and this complex disassembles upon TNF stimulation.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, complex reconstitution, phosphorylation assays, and loss-of-function experiments in mammalian cells\",\n      \"pmids\": [\"18362886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the IKK-CUEDC2-PP1 ternary complex is unknown\", \"Whether CUEDC2-PP1 acts on other kinases in the NF-κB pathway is untested\", \"In vivo relevance in conditional knockout models was not shown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Three simultaneous discoveries expanded CUEDC2 from an NF-κB regulator to a multi-pathway adaptor: it promotes ERα degradation via the ubiquitin-proteasome system, silences the spindle assembly checkpoint by releasing Mad2 from APC/C-Cdc20 after Cdk1 phosphorylation, and stabilizes SOCS3 to suppress JAK1-STAT3 signaling.\",\n      \"evidence\": \"Ubiquitin-proteasome assays for ERα degradation in breast cancer cells; RNAi, co-IP, live-cell imaging, and checkpoint assays for Cdc20-Mad2 regulation during mitosis; yeast two-hybrid, co-IP, and reporter assays for SOCS3-Elongin C stabilization\",\n      \"pmids\": [\"21572428\", \"21743465\", \"22084247\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CUE-domain ubiquitin binding is required for ERα degradation was not tested\", \"Identity of the E3 ligase mediating CUEDC2-dependent ERα ubiquitination was unknown\", \"How Cdk1-phosphorylated CUEDC2 specifically displaces Mad2 from the APC/C-Cdc20 complex structurally is unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealing that CUEDC2 also inhibits APC/C-Cdh1 to stabilize Cyclin A, and that UV-triggered ERK1/2 phosphorylation targets CUEDC2 for ubiquitin-dependent degradation, established CUEDC2 as a cell-cycle signal integrator whose own turnover controls the G1-S DNA damage checkpoint.\",\n      \"evidence\": \"Co-IP, ERK1/2 kinase assays, non-phosphorylatable mutant expression, cell cycle analysis after UV irradiation\",\n      \"pmids\": [\"23776205\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The E3 ligase responsible for CUEDC2 degradation after ERK-dependent phosphorylation is not identified\", \"Whether this mechanism operates in non-transformed cells in vivo is untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"In vivo loss-of-function in Cuedc2 knockout mice demonstrated that CUEDC2 is essential for macrophage inflammatory homeostasis and that its absence leads to excessive cytokine production, colitis, and colitis-associated cancer, confirming a non-redundant physiological role.\",\n      \"evidence\": \"Cuedc2 KO mice, DSS colitis and colitis-associated cancer models, macrophage transplantation rescue, miR-324-5p target validation\",\n      \"pmids\": [\"24882011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which downstream pathway (NF-κB, JAK-STAT, or both) drives the colitis phenotype was not dissected\", \"Tissue-specific conditional knockouts were not reported\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identification of HSP70 as a CUE-domain-dependent binding partner revealed that CUEDC2 can negatively regulate protein chaperone activity, extending its functional repertoire beyond signaling and cell cycle.\",\n      \"evidence\": \"Affinity purification–mass spectrometry, co-IP with domain mapping, intracellular luciferase refolding assay\",\n      \"pmids\": [\"24685480\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Only a single chaperone substrate (luciferase) was tested\", \"Physiological consequence of HSP70 inhibition by CUEDC2 is not established in vivo\", \"No independent replication\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating that CUEDC2 facilitates TRIM33-mediated ubiquitination and degradation of GPX1 in cardiomyocytes established CUEDC2 as a cofactor for TRIM-family E3 ligases and linked it to oxidative stress defense in the heart.\",\n      \"evidence\": \"Cuedc2 KO mice, ubiquitination reconstitution, ischemia/reperfusion injury model, GPX1 stability assays\",\n      \"pmids\": [\"27286733\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CUEDC2 is a general TRIM33 cofactor or specific to GPX1 is unclear\", \"Structural basis for CUEDC2-TRIM33 cooperation is unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extending the SOCS-stabilization mechanism to SOCS1 via Elongin C/CUL2 in AML cells generalized the principle that CUEDC2 enhances SOCS-box E3 ligase complex assembly to suppress JAK-STAT signaling across cell types.\",\n      \"evidence\": \"Co-IP, ubiquitination and stability assays, CUEDC2 overexpression/knockdown in AML cell lines\",\n      \"pmids\": [\"29991678\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CUEDC2 engages SOCS proteins directly or via Elongin C is not resolved structurally\", \"Independent replication in primary AML samples is lacking\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showing that CUEDC2 promotes TRIM21-mediated ubiquitination of CREB and that this axis controls GDNF transcription in glioma revealed a second TRIM-family partnership and a transcription-factor-degradation role for CUEDC2.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, ChIP for GDNF promoter CREB occupancy in glioma cells\",\n      \"pmids\": [\"33125618\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CUEDC2-TRIM21 cooperates on substrates beyond CREB is unknown\", \"Single lab, no in vivo validation\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapping the CUE domain interaction with β-catenin ARM repeats 7–9 and blocking it with a competitive peptide demonstrated that CUEDC2 directly promotes β-catenin nuclear translocation and Wnt target gene activation, revealing a new signaling axis targetable therapeutically.\",\n      \"evidence\": \"Pull-down, SPR binding, LC-MS/MS, nuclear translocation assays, competitive 11-mer peptide inhibition in vitro and in vivo xenografts\",\n      \"pmids\": [\"36231027\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CUEDC2 competes with APC/Axin destruction complex components for β-catenin binding is untested\", \"Selectivity and pharmacokinetics of the competitive peptide in vivo are preliminary\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linking CUEDC2-dependent ERα degradation specifically to mitosis-specific phosphorylation of CUEDC2 unified the earlier ERα and mitotic-checkpoint findings, showing that the same phospho-regulated switch governs both checkpoint silencing and ERα turnover.\",\n      \"evidence\": \"Cell cycle synchronization, phosphorylation site analysis, co-IP, ubiquitination assays, aneuploidy quantification\",\n      \"pmids\": [\"35732909\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The E3 ligase mediating mitotic ERα ubiquitination downstream of CUEDC2 remains unidentified\", \"Whether mitotic ERα degradation is relevant in normal mammary tissue is unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovery that CUEDC2 directly binds NLRP3 and inhibits inflammasome activation extended its anti-inflammatory repertoire beyond NF-κB and JAK-STAT to the innate immune inflammasome pathway.\",\n      \"evidence\": \"Co-IP, CUEDC2 overexpression/knockdown, caspase-1 and IL-1β maturation assays in glomerular endothelial cells\",\n      \"pmids\": [\"41232582\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of NLRP3 inhibition (oligomerization block vs. ASC recruitment block) is not defined\", \"In vivo relevance in inflammasome-driven disease models is not shown\", \"No independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unified structural model explaining how the CUE domain selectively engages its many partners (IKK, Cdc20, SOCS proteins, TRIMs, β-catenin, NLRP3, HSP70, ubiquitin), and how phosphorylation switches redirect CUEDC2 among these interactions, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of CUEDC2 or its complexes exists\", \"Quantitative binding affinities for most partners have not been measured\", \"How the cell prioritizes CUEDC2 allocation among competing interactions is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 7, 8, 10, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 4, 3, 8, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 12]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 5, 14]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2, 4, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 8, 11, 12]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 7, 10, 13]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"complexes\": [\n      \"IKK-CUEDC2-PP1/GADD34\",\n      \"SOCS3-Elongin C-CUL2\",\n      \"APC/C-Cdc20\"\n    ],\n    \"partners\": [\n      \"IKBKB\",\n      \"IKBKA\",\n      \"CDC20\",\n      \"SOCS3\",\n      \"SOCS1\",\n      \"TRIM33\",\n      \"CTNNB1\",\n      \"NLRP3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}