Affinage

CUEDC2

CUE domain-containing protein 2 · UniProt Q9H467

Length
287 aa
Mass
32.0 kDa
Annotated
2026-06-09
32 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2008 High

    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

    PMID:18362886

    Open questions at the time
    • Does not establish what triggers complex disassembly at the molecular level beyond stimulus dependence
    • Stoichiometry and direct vs. indirect IKK contact not resolved
  2. 2011 High

    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

    PMID:21743465

    Open questions at the time
    • Cdk1 phosphosites not fully mapped
    • Mechanism by which CUEDC2 binding displaces Mad2 from APC/C–Cdc20 not structurally defined
  3. 2011 Medium

    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

    PMID:21572428

    Open questions at the time
    • E3 ligase not identified in this study
    • Direct vs. indirect role in ER-α ubiquitination unresolved
  4. 2011 High

    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

    PMID:22084247

    Open questions at the time
    • How CUEDC2 enhances SOCS3–Elongin C association mechanistically not defined
    • Direct binding interface not mapped
  5. 2013 High

    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

    PMID:23776205

    Open questions at the time
    • E3 ligase degrading CUEDC2 after UV not identified
    • Relationship between the mitotic Cdc20-binding and G1 Cdh1-inhibiting roles not unified
  6. 2014 Medium

    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

    PMID:24685480

    Open questions at the time
    • Single lab, two orthogonal methods
    • Physiological consequences of HSP70 inhibition not established
  7. 2016 High

    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

    PMID:27286733

    Open questions at the time
    • Whether CUEDC2 directly bridges TRIM33 and GPX1 not structurally shown
    • Tissue specificity of this axis not defined
  8. 2018 Medium

    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

    PMID:29991678

    Open questions at the time
    • Single lab
    • Binding interface between CUEDC2 and SOCS1 not mapped
  9. 2019 Low

    Linked CUEDC2 to p38 MAPK and chemosensitivity, indicating it negatively regulates p38 in ovarian carcinoma.

    Evidence siRNA knockdown, p38 phosphorylation westerns, cisplatin sensitivity assays

    PMID:31205536

    Open questions at the time
    • Single method (western after knockdown) without mechanistic detail
    • Direct vs. indirect regulation of p38 unknown
  10. 2020 Medium

    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

    PMID:33125618

    Open questions at the time
    • Single lab
    • Whether CUEDC2 is an obligate cofactor or modulator of TRIM21 not resolved
  11. 2020 Medium

    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

    PMID:32393737

    Open questions at the time
    • Single lab
    • Whether bone phenotype is wholly STAT3-dependent vs. multifactorial unresolved
  12. 2022 High

    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

    PMID:36231027

    Open questions at the time
    • Mechanism of how CUE–β-catenin binding promotes nuclear import not defined
    • Relationship to the degradation/scaffold roles of the same CUE domain unclear
  13. 2022 Medium

    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

    PMID:35732909

    Open questions at the time
    • E3 ligase for ER-α still not named
    • Phosphosites and the responsible kinase not fully defined
  14. 2025 Medium

    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

    PMID:41232582

    Open questions at the time
    • Single lab, two orthogonal methods
    • How CUEDC2 binding physically prevents NLRP3 oligomerization not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0060090 molecular adaptor activity 2 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-1640170 Cell Cycle 2 R-HSA-168256 Immune System 2
Partners
CDC20CTNNB1FZR1GADD34IKBKBSOCS1SOCS3TRIM33
Complex memberships
IKK–CUEDC2–PP1(GADD34) complex

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 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). Co-immunoprecipitation, complex reconstitution, phosphorylation assays, identification of GADD34 interaction by yeast two-hybrid/Co-IP Nature immunology High 18362886
2011 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. Kinase assay (Cdk1 phosphorylation), Co-immunoprecipitation (CUEDC2–Cdc20, Mad2 release), siRNA depletion with mitotic timing assays, overexpression with chromosomal instability readouts Nature cell biology High 21743465
2011 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. 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 Nature medicine Medium 21572428
2011 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. Yeast two-hybrid, co-immunoprecipitation, STAT3 transcriptional activity assays, SOCS3 stability/ubiquitination assays, Elongin C interaction analysis The Journal of biological chemistry High 22084247
2013 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. Co-immunoprecipitation (CUEDC2–APC/C(Cdh1)), kinase assay (ERK1/2 phosphorylation), ubiquitination assay, phosphomutant rescue experiments, Cyclin A stability assays Proceedings of the National Academy of Sciences of the United States of America High 23776205
2016 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. CUEDC2 knockout mice, ubiquitination assay (TRIM33-GPX1), western blot for GPX1 levels, I/R injury model with infarct size measurement, ROS quantification EMBO molecular medicine High 27286733
2014 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. Affinity purification/mass spectrometry, co-immunoprecipitation, domain mapping, intracellular luciferase refolding assay Biochemical and biophysical research communications Medium 24685480
2018 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. Co-immunoprecipitation (CUEDC2–SOCS1), ubiquitination assay, Elongin C/CUL2 interaction analysis, JAK1-STAT3 phosphorylation assays, overexpression/knockdown with proliferation and cell-cycle readouts Cell death & disease Medium 29991678
2020 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. Co-immunoprecipitation (CUEDC2–TRIM21–CREB), ubiquitination assay, western blot for CREB levels, GDNF promoter binding assay, CUEDC2 knockdown/overexpression Neurochemical research Medium 33125618
2022 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. Co-immunoprecipitation, pull-down, LC-MS/MS, localized surface plasmon resonance (direct binding), nuclear translocation analysis, competitive peptide inhibition, xenograft model Cells High 36231027
2022 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. Western blot for ERα levels during mitotic progression, phosphorylation-dependent degradation assays, mitotic arrest override assays, aneuploidy quantification Cancer gene therapy Medium 35732909
2019 CUEDC2 knockdown increases phosphorylation of p38 MAPK in ovarian serous carcinoma cells, contributing to cisplatin sensitization, suggesting CUEDC2 negatively regulates p38 MAPK signaling. siRNA knockdown of CUEDC2, western blot for p38 MAPK phosphorylation, cisplatin sensitivity assays Journal of Cancer Low 31205536
2025 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. Co-immunoprecipitation (CUEDC2–NLRP3), caspase-1 activity assay, IL-1β maturation assay, CUEDC2 overexpression/inhibition in GEC pyroptosis model Cellular signalling Medium 41232582
2020 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. Overexpression/knockdown in osteoblast precursor cells, SOCS3 stability assay, STAT3 phosphorylation assay, ectopic bone formation model in vivo, calvarial defect repair model Cell death & disease Medium 32393737

Source papers

Stage 0 corpus · 32 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Deactivation of the kinase IKK by CUEDC2 through recruitment of the phosphatase PP1. Nature immunology 118 18362886
2011 Elevated expression of CUEDC2 protein confers endocrine resistance in breast cancer. Nature medicine 114 21572428
2020 LncRNA BCYRN1 inhibits glioma tumorigenesis by competitively binding with miR-619-5p to regulate CUEDC2 expression and the PTEN/AKT/p21 pathway. Oncogene 87 32978519
2015 Sinomenine inhibits breast cancer cell invasion and migration by suppressing NF-κB activation mediated by IL-4/miR-324-5p/CUEDC2 axis. Biochemical and biophysical research communications 75 26166821
2011 Cdk1-phosphorylated CUEDC2 promotes spindle checkpoint inactivation and chromosomal instability. Nature cell biology 70 21743465
2014 Dysregulation of the miR-324-5p-CUEDC2 axis leads to macrophage dysfunction and is associated with colon cancer. Cell reports 54 24882011
2018 MicroRNA hsa-miR-324-5p Suppresses H5N1 Virus Replication by Targeting the Viral PB1 and Host CUEDC2. Journal of virology 43 30045983
2011 CUEDC2: an emerging key player in inflammation and tumorigenesis. Protein & cell 26 21976060
2011 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. The Journal of biological chemistry 23 22084247
2017 CUEDC2 suppresses glioma tumorigenicity by inhibiting the activation of STAT3 and NF-κB signaling pathway. International journal of oncology 19 28534933
2019 CUEDC2: multifunctional roles in carcinogenesis. Frontiers in bioscience (Landmark edition) 17 30844721
2018 CUEDC2, a novel interacting partner of the SOCS1 protein, plays important roles in the leukaemogenesis of acute myeloid leukaemia. Cell death & disease 16 29991678
2016 CUEDC2 modulates cardiomyocyte oxidative capacity by regulating GPX1 stability. EMBO molecular medicine 16 27286733
2020 CUEDC2 controls osteoblast differentiation and bone formation via SOCS3-STAT3 pathway. Cell death & disease 14 32393737
2021 CUEDC2 ablation enhances the efficacy of mesenchymal stem cells in ameliorating cerebral ischemia/reperfusion insult. Aging 13 33494071
2013 Phosphorylation-triggered CUEDC2 degradation promotes UV-induced G1 arrest through APC/C(Cdh1) regulation. Proceedings of the National Academy of Sciences of the United States of America 13 23776205
2021 MicroRNA-324-5p-CUEDC2 Axis Mediates Gain-of-Function Mutant p53-Driven Cancer Stemness. Molecular cancer research : MCR 12 34257080
2019 CUEDC2 Contributes to Cisplatin-Based Chemotherapy Resistance in Ovarian Serious Carcinoma by Regulating p38 MAPK Signaling. Journal of Cancer 11 31205536
2020 Kawasaki disease: SOCS2-AS1/miR-324-5p/CUEDC2 axis regulates the progression of human umbilical vein endothelial cells. Pediatric research 10 32688371
2020 Down-Regulated CUEDC2 Increases GDNF Expression by Stabilizing CREB Through Reducing Its Ubiquitination in Glioma. Neurochemical research 10 33125618
2013 CUEDC2 sensitizes chronic myeloid leukemic cells to imatinib treatment. Leukemia research 10 24125838
2022 CUEDC2 Drives β-Catenin Nuclear Translocation and Promotes Triple-Negative Breast Cancer Tumorigenesis. Cells 6 36231027
2025 Dandelion extract suppresses the stem-like properties of triple-negative breast cancer cells by regulating CUEDC2/β-catenin/OCT4 signaling axis. Journal of ethnopharmacology 5 39864604
2023 Long Noncoding RNA AROD Inhibits Host Antiviral Innate Immunity via the miR-324-5p-CUEDC2 Axis. Microbiology spectrum 5 37036350
2019 Expression of CUEDC2 in colorectal cancer with different invasion and migration abilities. The Journal of international medical research 5 30651016
2018 Downregulation of CUEDC2 prevents doxorubicin‑induced cardiotoxicity in H9c2 cells. Molecular medicine reports 5 29845245
2015 CUEDC2 Protects Against Experimental Colitis and Suppresses Excessive Proliferation of Intestinal Mucosa. Digestive diseases and sciences 4 26182901
2024 miRNA-7145-cuedc2 axis controls hematopoiesis through JAK1/STAT3 signaling pathway. Cell death discovery 3 38697957
2022 Molecular crosstalk between CUEDC2 and ERα influences the clinical outcome by regulating mitosis in breast cancer. Cancer gene therapy 2 35732909
2014 CUEDC2 interacts with heat shock protein 70 and negatively regulates its chaperone activity. Biochemical and biophysical research communications 1 24685480
2025 CUEDC2 improves pyroptosis and kidney damage in diabetic kidney disease by inhibiting NLRP3 inflammasome activation. Cellular signalling 0 41232582
2020 Comparison of ADAM19 and CUEDC2 expression in EHCC and their clinicopathological significance. Biomarkers in medicine 0 32960074

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