Affinage

CTBP2

C-terminal-binding protein 2 · UniProt P56545

Length
445 aa
Mass
48.9 kDa
Annotated
2026-06-09
100 papers in source corpus 47 papers cited in narrative 47 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

The CTBP2/RIBEYE locus encodes two functionally distinct proteins: a metabolite-sensing transcriptional regulator (CtBP2) and the structural scaffold of synaptic ribbons (RIBEYE), which share an identical NAD(H)-binding domain (PMID:11163272). As a transcriptional regulator, CtBP2 functions as an NAD(H)- and acyl-CoA-responsive oligomer whose co-repressor activity depends on NAD(H)-regulated homodimerization and tetramerization through its dehydrogenase-like fold (PMID:15037661, PMID:33264605); cellular NAD-saturation and metabolite competition tune this oligomeric state, with malonyl-CoA driving a monomeric configuration (PMID:34997967, PMID:37286039). CtBP2 is recruited to target promoters through PXDLS-type short linear motifs in diverse transcription factors—including deltaEF1/ZEB1, SOX6, OCT1, E2F7, and EVI1—and there it nucleates chromatin-modifying machinery, recruiting HDAC1, the NuRD complex (driving H3K27 deacetylation and downstream PRC2-mediated H3K27me3), or the acetyltransferase p300 depending on context (PMID:10567582, PMID:19181930, PMID:24955216, PMID:38748792, PMID:25944056). Through these interactions CtBP2 acts as both a repressor and a context-dependent co-activator: it represses E-cadherin and drives EMT and cancer cell migration via Tiam1 activation (PMID:33264605, PMID:23264848, PMID:31866012), coactivates RAR/RXR and NEUROD1-dependent insulin transcription (PMID:23775127, PMID:37557182), and serves as a metabolic switch in liver that represses FoxO1-driven gluconeogenesis and PPARα-dependent fatty acid oxidation, such that its activity is regulated reciprocally by NADH and acyl-CoAs (PMID:34728642, PMID:37286039). CtBP2 activity is further controlled post-translationally by p300 acetylation governing nuclear retention and by HIPK2/CDK7-regulated phosphorylation and proteasomal turnover (PMID:16356938, PMID:16999872, PMID:23393140). Ctbp2-null mice die in midgestation with axial patterning and extraembryonic defects, establishing an essential developmental role (PMID:12101226). In its second identity as RIBEYE, the protein assembles synaptic ribbons through multiple self-association interfaces in its unique A-domain together with its NAD(H)-binding B-domain, and tethers ribbons to the active zone and synaptic vesicles by binding Bassoon, Munc119, ArfGAP3, and Piccolino and by redox-regulated lipid binding (PMID:11163272, PMID:15728193, PMID:18685021, PMID:18664567, PMID:24719103, PMID:28202712, PMID:30696732). Genetic deletion of RIBEYE abolishes synaptic ribbons and severely impairs fast and sustained neurotransmitter release at retinal and hair-cell ribbon synapses, where ribbons mediate nano-domain coupling of Ca2+ channels to vesicle exocytosis (PMID:26929012, PMID:21350006, PMID:35153673).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2000 High

    Established that the CTBP2 locus also encodes RIBEYE, identifying the major structural protein of synaptic ribbons and revealing a shared NAD-binding B-domain identical to CtBP2.

    Evidence Partial purification of synaptic ribbons, protein identification, and NAD+ binding assay

    PMID:11163272

    Open questions at the time
    • Did not establish how the A-domain assembles ribbons in vivo
    • Functional role of NAD+ binding unresolved at this stage
  2. 2002 High

    Demonstrated that CtBP2 is essential for embryonic development, moving the gene from an in vitro corepressor to an organismally required regulator with paralog redundancy.

    Evidence Ctbp1/Ctbp2 knockout mouse generation with embryological and transcriptional analysis

    PMID:12101226

    Open questions at the time
    • Specific target genes driving the axial/extraembryonic phenotype not defined
    • Degree of CtBP1 vs CtBP2 functional overlap quantitatively unresolved
  3. 1999 High

    Defined the core recruitment mechanism by which CtBP2 is targeted to promoters: PXDLS-type motifs in transcription factors such as deltaEF1.

    Evidence Yeast two-hybrid, co-IP, Gal4 reporter, and PLDLSL motif mutagenesis

    PMID:10567582

    Open questions at the time
    • Did not identify the chromatin-modifying effectors recruited
    • Generality of the motif across factors not yet shown
  4. 2004 High

    Showed that CtBP2 co-repressor activity is gated by NAD(H)-regulated homodimerization through its dehydrogenase-like fold, linking metabolic state to transcriptional output.

    Evidence Systematic mutagenesis of NAD-binding, substrate, and catalytic residues with transcriptional and dimerization assays

    PMID:15037661

    Open questions at the time
    • Higher-order oligomeric state not resolved
    • Whether NADH acts as a true cellular sensor not addressed
  5. 2006 High

    Established post-translational control of CtBP2 localization, showing p300 acetylation of the unique N-terminal domain enforces nuclear retention and distinguishes CtBP2 from CtBP1.

    Evidence Acetylation assays, deletion mutagenesis, subcellular fractionation, and leptomycin B treatment

    PMID:16356938 PMID:16999872 PMID:17023432

    Open questions at the time
    • Physiological signals controlling acetylation in vivo unclear
    • Functional consequences of cytoplasmic CtBP2 beyond reporter assays limited
  6. 2008 High

    Resolved how RIBEYE builds the ribbon scaffold and recruits active-zone machinery, mapping five self-association sites and NAD-regulated docking plus Munc119 recruitment.

    Evidence Yeast two-hybrid, pulldowns, coaggregation, EM, and point mutagenesis at the B-domain

    PMID:15728193 PMID:18664567 PMID:18685021

    Open questions at the time
    • Stoichiometry of the assembled ribbon not determined
    • How NAD regulation of A-B docking operates in vivo unclear
  7. 2013 Medium

    Expanded CtBP2's regulatory repertoire to context-dependent coactivation and post-translational stabilization, including RAR/RXR coactivation via p300 and CDK7-mediated protection from HIPK2-driven degradation.

    Evidence RNAi screen, ChIP, co-IP, and competition/proteasome-inhibitor assays

    PMID:23393140 PMID:23775127

    Open questions at the time
    • Determinants of the repressor-versus-coactivator switch not defined
    • Single-lab findings for the CDK7/HIPK2 axis
  8. 2016 High

    Provided definitive genetic proof that RIBEYE is required for ribbons and for fast/sustained release, linking ribbons mechanistically to Ca2+ nano-domain coupling.

    Evidence RIBEYE knockout mice with paired electrophysiology and EGTA buffering in retina slices

    PMID:21350006 PMID:26929012

    Open questions at the time
    • Molecular basis of channel clustering by RIBEYE not fully resolved
    • Contribution of B-domain redox sensing to release kinetics untested here
  9. 2020 High

    Determined the native functional oligomer of CtBP2 to be an NADH-bound tetramer required for migration and transcriptional activity, refining the long-standing dimer model.

    Evidence Cryo-EM structures with tetramer-destabilizing mutants in migration and reporter assays

    PMID:33264605 PMID:34997967

    Open questions at the time
    • Whether tetramer-dimer equilibrium is dynamically signaled in cells unresolved
    • Biophysics argues against simple NADH sensing, leaving the physiological metabolic input unclear
  10. 2021 High

    Identified CtBP2 as a hepatic metabolic switch sensing NADH and acyl-CoAs, repressing gluconeogenesis and lipogenesis and linking the corepressor directly to metabolic disease.

    Evidence Liver-specific knockout, metabolic phenotyping, in vitro metabolite binding, and structural pocket analysis

    PMID:34728642 PMID:37286039

    Open questions at the time
    • In vivo concentrations of competing acyl-CoAs that switch activity not fully mapped
    • Crosstalk with the tetramer/monomer equilibrium incompletely integrated
  11. 2023 High

    Showed CtBP2 acts as a coactivator that decompacts chromatin at the insulin promoter via NEUROD1, demonstrating a physiological gene-activating role with a metabolic phenotype.

    Evidence Genome-wide ChIP-seq, beta-cell-specific knockout, glucose tolerance, and chromatin accessibility analysis

    PMID:37557182

    Open questions at the time
    • Mechanism by which CtBP2 switches from repressor to chromatin-decompacting coactivator unresolved
    • Effector recruited for chromatin opening at insulin locus not fully defined
  12. 2024 High

    Validated CtBP recruitment via a single PLDLS motif as a therapeutic vulnerability, showing EVI1-CTBP binding is indispensable for leukemic transformation and druggable by competitive peptides.

    Evidence Proteomics, co-IP, and a competitive PLDLS-repeat inhibitor in vitro and in xenotransplant models

    PMID:38748792

    Open questions at the time
    • Genome-wide EVI1-CtBP target program not mapped
    • Specificity of the competitive inhibitor across other PXDLS partners untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single shared NAD(H)-binding domain is partitioned between nuclear transcriptional control and cytoplasmic synaptic ribbon scaffolding, and what physiological metabolic signal actually toggles CtBP2 oligomeric state given near-constitutive NAD saturation, remain unresolved.
  • No unifying model reconciling NAD-saturation biophysics with metabolite-sensing transcriptional switching
  • Tissue-specific determinants of RIBEYE vs CtBP2 isoform production not characterized in the corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0140110 transcription regulator activity 4 GO:0005198 structural molecule activity 3 GO:0140299 molecular sensor activity 3 GO:0008289 lipid binding 1
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-112316 Neuronal System 3 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3 R-HSA-1430728 Metabolism 2 R-HSA-4839726 Chromatin organization 2
Partners
ARFGAP3BSNEP300EVI1HIPK2NEUROD1UNC119ZEB1
Complex memberships
CtBP2-p300 complexNuRD complexsynaptic ribbon

Evidence

Reading pass · 47 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 RIBEYE (a protein encoded by the CTBP2/RIBEYE locus) is a major structural component of synaptic ribbons, composed of a unique A-domain that mediates assembly into large ribbon structures and a B-domain identical to CtBP2 that binds NAD+ with high affinity, similar to 2-hydroxyacid dehydrogenases. Partial purification of synaptic ribbons, protein identification, domain analysis, NAD+ binding assay Neuron High 11163272
2005 RIBEYE directly interacts with Bassoon at photoreceptor ribbon synapses; this interaction is essential for anchoring the synaptic ribbon to the presynaptic membrane and for the physical integrity of the ribbon complex. Yeast two-hybrid, co-immunoprecipitation, immunogold electron microscopy, analysis of Bassoon-deficient mice The Journal of cell biology High 15728193
2008 RIBEYE self-associates through five distinct interaction sites: three in the A-domain (mediating A-A homodimerization and A-B heterodimerization) and a separate homodimerization interface in the B-domain; NAD+ negatively regulates the A-domain docking site on the B-domain. These multiple RIBEYE-RIBEYE interactions drive assembly of the synaptic ribbon scaffold. Yeast two-hybrid, protein pulldowns, synaptic ribbon interaction assays, coaggregation experiments, transmission electron microscopy, immunogold EM The Journal of neuroscience High 18685021
2008 RIBEYE recruits Munc119 to photoreceptor synaptic ribbons via the PrBP/delta homology domain of Munc119 binding to the NADH-binding region of the RIBEYE B-domain; this interaction does not depend on NADH binding and is distinct from the NADH-binding site. Yeast two-hybrid, protein pulldowns, co-immunoprecipitation, immunofluorescence, point mutagenesis (RE(B)E844Q) The Journal of biological chemistry High 18664567
2016 Full deletion of RIBEYE abolishes all presynaptic ribbons in mouse retina synapses, and loss of RIBEYE severely impairs fast and sustained neurotransmitter release at bipolar neuron/AII amacrine cell synapses; ribbons mediate nano-domain coupling of Ca2+ channels to synaptic vesicle exocytosis. RIBEYE knockout mice, paired electrophysiological recordings in acute retina slices, EGTA Ca2+ buffer sensitivity assay The EMBO journal High 26929012
2011 Ribeye is required in zebrafish hair cells for clustering of presynaptic CaV1.3a calcium channels and for stable afferent innervation; knockdown reduces stimulus-evoked action potentials and CaV1.3a channel clusters, while overexpression produces CaV1.3a co-localized with ectopic Ribeye aggregates. Morpholino knockdown, transgenic overexpression, electrophysiology, immunofluorescence in zebrafish hair cells Development High 21350006
2014 ArfGAP3, a regulator of Golgi vesicle formation, is a component of the photoreceptor synaptic ribbon complex and binds to the RIBEYE B-domain in an NAD(H)-dependent, redox-sensitive manner (NADH promotes, NAD+ inhibits binding); RIBEYE competes with Arf1 for ArfGAP3 binding, and overexpression of ArfGAP3 inhibits endocytic uptake in photoreceptors. Multiple co-immunoprecipitation, pulldown, yeast two-hybrid, FM1-43 endocytosis assay, overexpression studies The Journal of neuroscience High 24719103
2005 Acetylation of CtBP2 by p300 at lysine residues in its unique N-terminal domain (particularly Lys-10) is critical for exclusive nuclear localization; the K10R mutant is predominantly cytoplasmic due to enhanced nuclear export (inhibitable by leptomycin B), and cytoplasmic K10R is more efficient at repressing the E-cadherin promoter. Mutagenesis, subcellular fractionation, leptomycin B treatment, acetylation assay, luciferase reporter assay The Journal of biological chemistry High 16356938
2004 CtBP2 co-repressor function depends on NAD(H)-regulated homodimerization: substitution at Gly189 in the NAD+-binding fold abrogates dimerization and causes dramatic loss of co-repressor activity. Mutations at the substrate-binding domain (Arg272) and catalytic domain (His321) also reduce co-repressor activity. A novel N-terminal repression domain distinct from the dehydrogenase domain was identified. Mutagenesis, transcriptional repression assay, dimerization assays Nucleic acids research High 15037661
2020 Cryo-EM structures of CtBP2 demonstrate that the native state of CtBP2 in the presence of NADH is tetrameric; tetramer-destabilizing mutants are defective for cell migration, transcriptional repression of E-cadherin, and activation of TIAM1, establishing the tetramer as the functional oligomeric form. Cryo-electron microscopy, mutagenesis, cell migration assay, luciferase reporter assay Structure High 33264605
2022 CtBP1 and CtBP2 assemble into tetramers in the presence of saturating NAD+ or NADH (tetramer-to-dimer Kd ~100 nM); NAD(H) binds with Kd 30–500 nM depending on nucleotide and paralog. Given cellular NAD+ concentrations, CtBP is likely constitutively NAD-saturated, suggesting it cannot function as a sensor of NADH levels per se. Analytical ultracentrifugation, isothermal titration calorimetry FEBS letters High 34997967
2021 CtBP2 repressor activity is reciprocally regulated by NADH (activates) and acyl-CoAs (inhibits); CtBP2 directly represses FoxO1-mediated hepatic gluconeogenesis and indirectly represses SREBP1-mediated lipogenesis; liver-specific CtBP2 deletion promotes gluconeogenesis and accelerates steatohepatitis; activation ameliorates diabetes and hepatic steatosis in obese mice. Liver-specific knockout mice, metabolic phenotyping, in vitro binding assays, structural analysis of Rossmann fold metabolite-sensing pocket Nature communications High 34728642
2023 CtBP2 interacts with malonyl-CoA (a metabolic intermediate elevated in obesity) to adopt a monomeric configuration that enhances its interaction with PPARα and represses PPARα transcriptional activity, suppressing fatty acid oxidation; genetic deletion of CtBP2 in liver derepresses PPARα target genes. Co-immunoprecipitation, mutagenesis to shift monomer/dimer equilibrium, metabolic manipulation (malonyl-CoA reduction), liver-specific CtBP2 knockout The Journal of biological chemistry High 37286039
2013 CTBP2 is a cofactor of PCIF1 that facilitates cap mRNA m6Am modification; CTBP2 binds similar mRNAs as PCIF1 (CLIP-Seq), and knockout of CTBP2 reduces PCIF1 occupancy on TET2 mRNA; the PCIF1-CTBP2 complex negatively regulates translation of TET2 mRNA. Co-immunoprecipitation, CLIP-Seq, m6Am-Seq, CTBP2 knockout, polysome profiling/translation assay The Journal of clinical investigation High 37643007
2013 The CCNH/CDK7 complex interacts with CtBP2 in vivo and in vitro, competing with HIPK2 for binding; CCNH/CDK7 inhibits HIPK2-mediated phosphorylation and dimerization of CtBP2, preventing proteasome-dependent CtBP2 degradation and thereby stabilizing CtBP2 to promote cancer cell invasion and migration. Co-immunoprecipitation, siRNA depletion, proteasome inhibitor assay, invasion and migration assays, competition binding assay The Journal of biological chemistry Medium 23393140
1999 CtBP2 binds deltaEF1 via the PLDLSL sequence in the medial domain of deltaEF1 and acts as a corepressor; Gal4-CtBP2 fusions exhibit transcriptional repression activity, and CtBP2 enhancement of deltaEF1 repression is abolished by mutation of the PLDLSL motif. Yeast two-hybrid screen, co-immunoprecipitation, Gal4 reporter assay, transient transfection/repression assay, site-directed mutagenesis Molecular and cellular biology High 10567582
2001 SOX6 recruits CtBP2 as a corepressor via a PLNLSS motif to repress transcription from the Fgf-3 promoter through the PS4A enhancer element; mutation of the PLNLSS motif abolishes both CtBP2 binding and SOX6 responsiveness to CtBP2. Yeast two-hybrid screen, co-immunoprecipitation in mammalian cells, mutagenesis of PLNLSS motif, luciferase reporter assay Nucleic acids research Medium 11504872
2009 ZEB1 recruits CtBP2 and HDAC1 to form a repressor complex on the IL-2 promoter; ZEB1-mediated repression of IL-2 depends on both the ZEB-binding site at -100 and the PXDLS interaction motif of CtBP2. Chromatin immunoprecipitation, luciferase reporter assay, overexpression, site-directed mutagenesis of interaction motifs International immunology Medium 19181930
2006 The unique N-terminal domain (aa 4-14) of CtBP2 acts as a p300 acetyltransferase-dependent nuclear retention sequence that directs CtBP2 to an almost exclusively nuclear distribution; a region within aa 1-119 cooperates with aa 4-14 for nuclear accumulation; CtBP1 can be recruited to the nucleus through heterodimerization with CtBP2. Deletion mutagenesis, subcellular fractionation, heterologous protein fusions, CtBP1/2 heterodimerization assay BMC cell biology Medium 16999872
2006 Adenovirus E1A enhances acetylation of CtBP2 by recruiting p300 to the CtBP2 complex; E1A also displaces histone methyltransferase G9a and the E-box repressor ZEB from the CtBP2 complex via the C-terminal CtBP-binding domain; the unique N-terminal domain of CtBP2 specifically inhibits E1A transcriptional activation activity, distinguishing CtBP2 from CtBP1. Co-immunoprecipitation, acetylation assay, transcriptional reporter assay, domain deletion analysis The Journal of biological chemistry Medium 17023432
2015 HIPK2 phosphorylates CtBP2 at serine 428; this phosphorylation strengthens the interaction between KLF3 and CtBP2 and increases transcriptional repression by KLF3. Mass spectrometry identification of phosphorylation site, kinase assay, mutagenesis, co-immunoprecipitation, transcriptional repression assay The Journal of biological chemistry Medium 25659434
2009 CtBP2 binds acinus in a phosphorylation-dependent manner regulated by NGF/TrkA/Akt signaling: NGF promotes Akt-mediated phosphorylation of acinus, which enhances CtBP2-acinus interaction; CtBP2-acinus complex suppresses cyclin A1 (but not cyclin A2) transcription, inhibiting leukemia cell proliferation. Co-immunoprecipitation, phosphorylation assay, overexpression/knockdown, transcriptional reporter, cell proliferation assay Oncogene Medium 19668232
2013 CTBP2 functions as a coactivator of RAR/RXR nuclear receptor complexes for retinoic acid (RA)-induced transcription: CTBP2 associates with RAR/RXR at RA target gene promoters and is required for transactivation by recruiting histone acetyltransferase p300 to create a permissive chromatin environment. RNAi genetic screen, chromatin immunoprecipitation, co-immunoprecipitation, gene expression analysis, differentiation assay Molecular and cellular biology Medium 23775127
2015 Ctbp2 facilitates NuRD complex-mediated deacetylation of H3K27 and subsequent PRC2-mediated H3K27me3 at active embryonic stem cell genes to enable exit from pluripotency; ablation of Ctbp2 sustains high H3K27ac and impedes H3K27me3, causing inappropriate gene silencing failure in ESCs. Genome-wide ChIP-seq, Ctbp2 knockdown/ablation, H3K27 acetylation and methylation analysis Stem cells Medium 25944056
2012 CtBP2 promotes cancer cell migration via transcriptional activation of Tiam1 (a Rac GEF): CtBP2 occupies the Tiam1 promoter in a KLF8-dependent manner, KLF8+CtBP2 co-expression activates a Tiam1 promoter reporter, and Tiam1 knockdown abolishes CtBP2-stimulated migration. RNAi knockdown, overexpression, chromatin immunoprecipitation, luciferase reporter assay, migration assay Genes & cancer Medium 23264848
2014 CtBP2 represses tumor-suppressor genes (NCOR, RIP140) and AR corepressors in prostate cancer cells by binding with androgen receptor (AR) to their promoter enhancers, and CtBP2 silencing increases AR interactions with corepressors that limit histone modification. Chromatin immunoprecipitation, CtBP2 knockdown, gene expression analysis, xenograft tumor model Cancer research Medium 25228652
2017 The intracellular NADH level regulates CtBP2 dimerization: lower NADH disrupts CtBP2 dimerization and enhances formation of the CtBP2-p300-Runx2 complex, which blocks Runx2 access to bone-related target gene promoters; this mechanism operates in atrophic nonunion, and forcing NADH increase with CoCl2 rescues target gene expression. Mass spectrometry, co-immunoprecipitation, chromatin immunoprecipitation, CoCl2 treatment, gene expression analysis International journal of biological sciences Medium 30585266
2020 CtBP2 forms a transcriptional complex with p300 and AP-1 subunits (c-Jun and c-FOS) that binds the TGFB1 promoter and activates TGF-β expression; knockdown of CtBP2 decreases TGFB1 expression and reduces p300/AP-1 occupancy at the promoter. Mass spectrometry, co-immunoprecipitation, chromatin immunoprecipitation, siRNA knockdown, promoter reporter International journal of biological sciences Medium 31929749
2019 CtBP2 forms a transcriptional complex with HDAC1 and FOXP3 that binds the miR-199a-3p promoter and represses its expression, leading to NLRP1 inflammasome activation and IL-1β/IL-18 secretion in acute lung injury. Immunoprecipitation, mass spectrometry, co-IP, chromatin immunoprecipitation, siRNA knockdown International journal of biological sciences Medium 31754335
2011 cAMP/PKA promotes CtBP2 proteasomal degradation via HIPK2, leading to de-repression of Mitf and REST expression and enhanced melanocyte differentiation in neural crest cells; knockdown of CtBP2 (but not CtBP1) derepresses Mitf and REST and enhances melanocyte differentiation, while HIPK2 knockdown increases CtBP2 levels and suppresses melanocyte fate. siRNA knockdown in neural crest cultures and zebrafish, PKA/proteasome inhibitors, Western blot for CtBP2 protein levels, melanocyte differentiation assay Molecular and cellular biology Medium 21199918
2014 Ctbp2 is required for proper exit from pluripotency in embryonic stem cells; knockdown of Ctbp2 increases ESC self-renewal, delays differentiation induced by LIF withdrawal, and introduces developmental changes in mesodermal differentiation. RNAi knockdown in mouse ESCs, LIF withdrawal differentiation assay, mesodermal colony assay Mechanisms of development Medium 19825414
2017 Ctbp2 associates with β-catenin destruction complex components in ESCs, limiting β-catenin accessibility to core pluripotency transcription factors; Ctbp2 knockdown stabilizes β-catenin, which then interacts with core pluripotency factors, causing incomplete exit from pluripotency. Co-immunoprecipitation, siRNA knockdown, β-catenin stabilization assay, gene expression analysis in ESCs Experimental & molecular medicine Medium 29026198
2019 CtBP2 directly interacts with OCT1 (POU2F1) and this CtBP2-OCT1 complex orchestrates EMT; mutation of the CtBP-binding motif in OCT1 diminishes EMT promotion; TGF-β promotes CtBP2/OCT1 complex formation. Co-immunoprecipitation, mutagenesis of CtBP-binding motif in OCT1, EMT marker analysis, TGF-β treatment Biochemical and biophysical research communications Medium 31866012
2021 CtBP2 forms transcriptional complexes with NRF1 and NRF2 that are required to promote expression of antioxidant genes in response to oxidative insults. Co-immunoprecipitation, gene expression analysis upon oxidative stress, CtBP2 loss-of-function Biochemical and biophysical research communications Medium 34052660
2023 CtBP2 coactivates insulin gene expression in pancreatic β cells through interaction with NEUROD1; CtBP2 decompacts chromatin at the insulin gene promoter; β cell-specific CtBP2-deficient mice develop glucose intolerance with impaired insulin secretion. Genome-wide ChIP-Seq, β cell-specific knockout mice, glucose tolerance test, insulin secretion assay, chromatin accessibility analysis Cell reports High 37557182
2002 Ctbp2-null mice show defects in axial patterning and die by E10.5 due to aberrant extraembryonic development; compound Ctbp1/Ctbp2 mutant mice display dosage-sensitive developmental defects in many processes; transcription assays with CtBP-deficient cells confirm overlapping roles in regulating gene expression. Gene targeting/knockout mouse generation, embryological analysis, transcriptional reporter assays in CtBP-deficient cells Molecular and cellular biology High 12101226
2014 CtBP2 proteomics identified E2F7 as a novel CtBP2-interacting protein: E2F7 interacts with the hydrophobic cleft of CtBP1 and CtBP2 via a PIDLS motif, represses E2F1 transcription and inhibits cell proliferation in a CtBP-dependent manner. Mass spectrometry proteomics of CtBP2 complexes, co-immunoprecipitation, mutagenesis of PIDLS motif, transcriptional reporter, cell proliferation assay Genes & cancer Medium 24955216
2014 Zscan4 directly interacts with both LSD1 and CtBP2 in embryonic stem cell nuclei, as demonstrated by protein interaction analyses. Co-immunoprecipitation, proximity ligation assay in ESC nuclei PloS one Low 24594919
2019 ZEB1 interaction with CTBP2 in embryonic cortical neural progenitors is required for ZEB1-induced multipolar-to-bipolar transition of differentiating neurons but is not required for ZEB1 suppression of Neurod1, revealing distinct mechanisms for ZEB1's two functions. Co-immunoprecipitation in embryonic cortex, in utero electroporation of mutant ZEB1, live imaging of neuronal migration Cell reports Medium 31116980
2009 C/EBPα recruits CtBP1 and CtBP2 to the promoters of visceral white adipose genes (resistin, angiotensinogen) in response to PPARγ ligands, mediating their repression during induction of the brown phenotype in white adipocytes. Chromatin immunoprecipitation, siRNA knockdown, reporter assay, PPARγ helix-7 mutagenesis Molecular and cellular biology Medium 19564408
2018 TEAD4 forms a ternary transcriptional repressor complex with VGLL4 (as adaptor) and CtBP2 to suppress adipogenesis; VGLL4 enhances the TEAD4-CtBP2 interaction; TEAD4 directly targets PPARγ and Adipoq promoters; this complex functions independently of YAP/TAZ. Co-immunoprecipitation, chromatin immunoprecipitation, siRNA knockdown, adipogenesis assay The Journal of biological chemistry Medium 30209132
2024 EVI1 interacts with CTBP1 and CTBP2 via a single PLDLS motif, and this interaction is indispensable for EVI1-driven leukemic transformation; a competitive PLDLS repeat construct disrupts EVI1-CTBP binding and inhibits proliferation of 3q26/MECOM-rearranged AML in vitro and in xenotransplant models. Protein folding predictions, proteomics, co-immunoprecipitation, competitive inhibitor (4× PLDLS repeat), xenotransplant model Science advances High 38748792
2017 RIBEYE B-domain binds lipid components of synaptic vesicles directly (particularly lysophospholipids) in an NAD(H)-dependent, redox-sensitive manner: NADH (reduced form) enhances and NAD+ (oxidized form) inhibits this lipid binding, providing a mechanism for NAD(H)-regulated vesicle attachment to ribbons. Liposome sedimentation assay with defined lipid compositions, synaptic vesicle membrane fraction sedimentation assay The Biochemical journal Medium 28202712
2022 The RIBEYE B-domain is essential for RIBEYE A-domain stability and synaptic ribbon assembly: knockin mice in which the RIBEYE B-domain is replaced by a fluorescent protein module show complete loss of synaptic ribbons, indicating the B-domain is required for the A-domain to assemble into ribbons. Knockin mouse genetics (B-domain replacement), immunofluorescence, electron microscopy of ribbon synapses Frontiers in molecular neuroscience High 35153673
2017 RIBEYE is intrinsically dynamic but is stabilized within the ribbon synapse: FRAP experiments show Ribeye a exchanges rapidly in non-synaptic skin cells (t½ ~3.2 min) but exchanges an order of magnitude slower at hair cell ribbons (t½ ~95–126 min), indicating ribbon context stabilizes RIBEYE. FRAP on transgenic zebrafish larvae expressing GFP/mCherry-tagged Ribeye in hair cells and skin cells The Journal of physiology Medium 29086422
2019 Piccolino (ribbon-specific splice variant of Piccolo) interacts with RIBEYE via multiple PxDLS-like motifs at its C-terminus, connecting multiple RIBEYE molecules; loss of Piccolino destabilizes the plate-shaped superstructure of synaptic ribbons in rod photoreceptors. Co-immunoprecipitation, Piccolo/Piccolino-deficient rat model, ultrastructural electron microscopy analysis The Journal of neuroscience Medium 30696732
2023 ALDOB inhibits CtBP2-mediated transcriptional repression in renal cell carcinoma by acting as a scaffold that brings acireductone dioxygenase 1 (ADI1) into proximity with CtBP2, potentiating ADI1-mediated synthesis of an endogenous CtBP2 inhibitor (4-methylthio 2-oxobutyric acid); this scaffolding is independent of ALDOB enzymatic activity and decreases cancer cell proliferation and migration. Co-immunoprecipitation, gene expression analysis, migration/proliferation assay, xenograft model, interaction-deficient mutant Frontiers of medicine Medium 36790589

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 RIBEYE, a component of synaptic ribbons: a protein's journey through evolution provides insight into synaptic ribbon function. Neuron 449 11163272
2013 Myeloid-derived suppressor cells enhance stemness of cancer cells by inducing microRNA101 and suppressing the corepressor CtBP2. Immunity 371 24012420
2005 Molecular dissection of the photoreceptor ribbon synapse: physical interaction of Bassoon and RIBEYE is essential for the assembly of the ribbon complex. The Journal of cell biology 336 15728193
2002 Overlapping and unique roles for C-terminal binding protein 1 (CtBP1) and CtBP2 during mouse development. Molecular and cellular biology 255 12101226
2009 C/EBPalpha and the corepressors CtBP1 and CtBP2 regulate repression of select visceral white adipose genes during induction of the brown phenotype in white adipocytes by peroxisome proliferator-activated receptor gamma agonists. Molecular and cellular biology 167 19564408
1999 Identification of CtBP1 and CtBP2 as corepressors of zinc finger-homeodomain factor deltaEF1. Molecular and cellular biology 116 10567582
2016 How to make a synaptic ribbon: RIBEYE deletion abolishes ribbons in retinal synapses and disrupts neurotransmitter release. The EMBO journal 105 26929012
2011 Ribeye is required for presynaptic Ca(V)1.3a channel localization and afferent innervation of sensory hair cells. Development (Cambridge, England) 102 21350006
2008 Multiple RIBEYE-RIBEYE interactions create a dynamic scaffold for the formation of synaptic ribbons. The Journal of neuroscience : the official journal of the Society for Neuroscience 101 18685021
2009 The transcription repressor, ZEB1, cooperates with CtBP2 and HDAC1 to suppress IL-2 gene activation in T cells. International immunology 92 19181930
2017 LncRNA NEAT1 Regulates Cell Viability and Invasion in Esophageal Squamous Cell Carcinoma through the miR-129/CTBP2 Axis. Disease markers 74 29147064
2005 Acetylation by p300 regulates nuclear localization and function of the transcriptional corepressor CtBP2. The Journal of biological chemistry 70 16356938
2013 Interaction with cyclin H/cyclin-dependent kinase 7 (CCNH/CDK7) stabilizes C-terminal binding protein 2 (CtBP2) and promotes cancer cell migration. The Journal of biological chemistry 68 23393140
2005 Two ribeye genes in teleosts: the role of Ribeye in ribbon formation and bipolar cell development. The Journal of neuroscience : the official journal of the Society for Neuroscience 64 15673675
2001 SOX6 binds CtBP2 to repress transcription from the Fgf-3 promoter. Nucleic acids research 64 11504872
1998 A novel C-terminal binding protein (CTBP2) is closely related to CTBP1, an adenovirus E1A-binding protein, and maps to human chromosome 21q21.3. Genomics 62 9479502
2016 Synaptic Ribbons Require Ribeye for Electron Density, Proper Synaptic Localization, and Recruitment of Calcium Channels. Cell reports 61 27292637
2021 Circular RNA circHERC4 as a novel oncogenic driver to promote tumor metastasis via the miR-556-5p/CTBP2/E-cadherin axis in colorectal cancer. Journal of hematology & oncology 57 34781990
2014 CtBP2 modulates the androgen receptor to promote prostate cancer progression. Cancer research 56 25228652
2019 ZEB1 Represses Neural Differentiation and Cooperates with CTBP2 to Dynamically Regulate Cell Migration during Neocortex Development. Cell reports 55 31116980
2015 Ctbp2 Modulates NuRD-Mediated Deacetylation of H3K27 and Facilitates PRC2-Mediated H3K27me3 in Active Embryonic Stem Cell Genes During Exit from Pluripotency. Stem cells (Dayton, Ohio) 55 25944056
2015 Obesity-Associated MiR-342-3p Promotes Adipogenesis of Mesenchymal Stem Cells by Suppressing CtBP2 and Releasing C/EBPα from CtBP2 Binding. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 54 25895816
2008 RIBEYE recruits Munc119, a mammalian ortholog of the Caenorhabditis elegans protein unc119, to synaptic ribbons of photoreceptor synapses. The Journal of biological chemistry 54 18664567
2012 CtBP2 Promotes Human Cancer Cell Migration by Transcriptional Activation of Tiam1. Genes & cancer 53 23264848
2004 The CtBP2 co-repressor is regulated by NADH-dependent dimerization and possesses a novel N-terminal repression domain. Nucleic acids research 53 15037661
2018 miR-144-3p Promotes Adipogenesis Through Releasing C/EBPα From Klf3 and CtBP2. Frontiers in genetics 44 30619490
2009 Porcine muscle sensory attributes associate with major changes in gene networks involving CAPZB, ANKRD1, and CTBP2. Functional & integrative genomics 39 19597856
2018 The TEA domain family transcription factor TEAD4 represses murine adipogenesis by recruiting the cofactors VGLL4 and CtBP2 into a transcriptional complex. The Journal of biological chemistry 37 30209132
2014 CtBP2 could promote prostate cancer cell proliferation through c-Myc signaling. Gene 37 24835310
2019 A Multiple Piccolino-RIBEYE Interaction Supports Plate-Shaped Synaptic Ribbons in Retinal Neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 33 30696732
2006 Role of the unique N-terminal domain of CtBP2 in determining the subcellular localisation of CtBP family proteins. BMC cell biology 33 16999872
2014 Zscan4 is regulated by PI3-kinase and DNA-damaging agents and directly interacts with the transcriptional repressors LSD1 and CtBP2 in mouse embryonic stem cells. PloS one 32 24594919
2020 Transforming growth factor beta (TGF-β) is activated by the CtBP2-p300-AP1 transcriptional complex in chronic renal failure. International journal of biological sciences 31 31929749
2020 The Monocyte-Derived Exosomal CLMAT3 Activates the CtBP2-p300-NF-κB Transcriptional Complex to Induce Proinflammatory Cytokines in ALI. Molecular therapy. Nucleic acids 30 32866716
2014 A self-organizing miR-132/Ctbp2 circuit regulates bimodal notch signals and glial progenitor fate choice during spinal cord maturation. Developmental cell 30 25132384
2013 CtBP2 contributes to malignant development of human esophageal squamous cell carcinoma by regulation of p16INK4A. Journal of cellular biochemistry 29 23255392
2019 Downregulation of miR-199a-3p mediated by the CtBP2-HDAC1-FOXP3 transcriptional complex contributes to acute lung injury by targeting NLRP1. International journal of biological sciences 27 31754335
2018 The intracellular NADH level regulates atrophic nonunion pathogenesis through the CtBP2-p300-Runx2 transcriptional complex. International journal of biological sciences 27 30585266
2015 Interaction with CCNH/CDK7 facilitates CtBP2 promoting esophageal squamous cell carcinoma (ESCC) metastasis via upregulating epithelial-mesenchymal transition (EMT) progression. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 27 25820824
2012 High-resolution optical imaging of zebrafish larval ribbon synapse protein RIBEYE, RIM2, and CaV 1.4 by stimulation emission depletion microscopy. Microscopy and microanalysis : the official journal of Microscopy Society of America, Microbeam Analysis Society, Microscopical Society of Canada 27 22832038
2017 Downregulation of miR-200a-3p, Targeting CtBP2 Complex, Is Involved in the Hypoproduction of IL-2 in Systemic Lupus Erythematosus-Derived T Cells. Journal of immunology (Baltimore, Md. : 1950) 26 28438897
2023 The CTBP2-PCIF1 complex regulates m6Am modification of mRNA in head and neck squamous cell carcinoma. The Journal of clinical investigation 25 37643007
2021 The transcriptional corepressor CtBP2 serves as a metabolite sensor orchestrating hepatic glucose and lipid homeostasis. Nature communications 25 34728642
2014 ArfGAP3 is a component of the photoreceptor synaptic ribbon complex and forms an NAD(H)-regulated, redox-sensitive complex with RIBEYE that is important for endocytosis. The Journal of neuroscience : the official journal of the Society for Neuroscience 24 24719103
2001 Dual use of the transcriptional repressor (CtBP2)/ribbon synapse (RIBEYE) gene: how prevalent are multifunctional genes? Trends in neurosciences 24 11576649
2020 Cryo-EM structure of CtBP2 confirms tetrameric architecture. Structure (London, England : 1993) 23 33264605
2018 CtBP2 promotes proliferation and reduces drug sensitivity in non-small cell lung cancer via the Wnt/β-catenin pathway. Neoplasma 23 30334447
2011 Ataxin-1 occupies the promoter region of E-cadherin in vivo and activates CtBP2-repressed promoter. Biochimica et biophysica acta 23 21315774
2019 Transcriptome profiling of muscle in Nelore cattle phenotypically divergent for the ribeye muscle area. Genomics 22 31351181
2015 Phosphorylation of Krüppel-like factor 3 (KLF3/BKLF) and C-terminal binding protein 2 (CtBP2) by homeodomain-interacting protein kinase 2 (HIPK2) modulates KLF3 DNA binding and activity. The Journal of biological chemistry 22 25659434
2009 NGF inhibits human leukemia proliferation by downregulating cyclin A1 expression through promoting acinus/CtBP2 association. Oncogene 22 19668232
2015 CtBP2 overexpression is associated with tumorigenesis and poor clinical outcome of prostate cancer. Archives of medical science : AMS 20 26788097
2006 Changes in C-terminal binding protein 2 (CtBP2) corepressor complex induced by E1A and modulation of E1A transcriptional activity by CtBP2. The Journal of biological chemistry 20 17023432
2013 The corepressor CTBP2 is a coactivator of retinoic acid receptor/retinoid X receptor in retinoic acid signaling. Molecular and cellular biology 19 23775127
2017 CtBP2 ameliorates palmitate-induced insulin resistance in HepG2 cells through ROS mediated JNK pathway. General and comparative endocrinology 18 28111233
2013 Expression patterns of candidate susceptibility genes HNF1β and CtBP2 in prostate cancer: association with tumor progression. Urologic oncology 18 24332637
2011 CtBP2 downregulation during neural crest specification induces expression of Mitf and REST, resulting in melanocyte differentiation and sympathoadrenal lineage suppression. Molecular and cellular biology 18 21199918
2024 Oncogene EVI1 drives acute myeloid leukemia via a targetable interaction with CTBP2. Science advances 17 38748792
2018 Antimony enhances c-Myc stability in prostate cancer via activating CtBP2-ROCK1 signaling pathway. Ecotoxicology and environmental safety 17 30098506
2012 Different functions of HIPK2 and CtBP2 in traumatic brain injury. Journal of molecular neuroscience : MN 17 23076816
2006 Expression of avian C-terminal binding proteins (Ctbp1 and Ctbp2) during embryonic development. Developmental dynamics : an official publication of the American Association of Anatomists 17 16258936
2023 Obesity-induced metabolic imbalance allosterically modulates CtBP2 to inhibit PPAR-alpha transcriptional activity. The Journal of biological chemistry 16 37286039
2014 CtBP2 proteome: Role of CtBP in E2F7-mediated repression and cell proliferation. Genes & cancer 16 24955216
2014 Characterization of Ribeye subunits in zebrafish hair cells reveals that exogenous Ribeye B-domain and CtBP1 localize to the basal ends of synaptic ribbons. PloS one 16 25208216
2021 Endoplasmic reticulum stress regulates the intestinal stem cell state through CtBP2. Scientific reports 15 33972635
2009 Delayed differentiation in embryonic stem cells and mesodermal progenitors in the absence of CtBP2. Mechanisms of development 15 19825414
2017 In Vivo Ribbon Mobility and Turnover of Ribeye at Zebrafish Hair Cell Synapses. Scientific reports 14 28785118
2017 MiR-338 suppresses cell proliferation and invasion by targeting CTBP2 in glioma. Cancer biomarkers : section A of Disease markers 14 28826173
2017 Ctbp2-mediated β-catenin regulation is required for exit from pluripotency. Experimental & molecular medicine 14 29026198
2022 CTBP1 and CTBP2 mutations underpinning neurological disorders: a systematic review. Neurogenetics 13 36331689
2015 CtBP2 Regulates TGFβ2-Induced Epithelial-Mesenchymal Transition Through Notch Signaling Pathway in Lens Epithelial Cells. Current eye research 13 26681554
2022 RIBEYE B-Domain Is Essential for RIBEYE A-Domain Stability and Assembly of Synaptic Ribbons. Frontiers in molecular neuroscience 12 35153673
2021 microRNA-133a exerts tumor suppressive role in oral squamous cell carcinoma through the Notch signaling pathway via downregulation of CTBP2. Cancer gene therapy 12 33531645
2020 The corepressor CtBP2 is required for proper development of the mouse cerebral cortex. Molecular and cellular neurosciences 12 32169478
2022 NADH/NAD+ binding and linked tetrameric assembly of the oncogenic transcription factors CtBP1 and CtBP2. FEBS letters 10 34997967
2021 CtBP2 confers protection against oxidative stress through interactions with NRF1 and NRF2. Biochemical and biophysical research communications 10 34052660
2018 Ribeye protein is intrinsically dynamic but is stabilized in the context of the ribbon synapse. The Journal of physiology 10 29086422
2014 Oxygen-dependent acetylation and dimerization of the corepressor CtBP2 in neural stem cells. Experimental cell research 10 25447313
2012 Involvement of CtBP2 in LPS-induced microglial activation. Journal of molecular histology 10 22426895
2022 Knockdown of receptor interacting protein 140 (RIP140) alleviated lipopolysaccharide-induced inflammation, apoptosis and permeability in pulmonary microvascular endothelial cells by regulating C-terminal binding protein 2 (CTBP2). Bioengineered 9 35113002
2020 NSM00158 Specifically Disrupts the CtBP2-p300 Interaction to Reverse CtBP2-Mediated Transrepression and Prevent the Occurrence of Nonunion. Molecules and cells 9 32434298
2019 Transcriptional co-repressor CtBP2 orchestrates epithelial-mesenchymal transition through a novel transcriptional holocomplex with OCT1. Biochemical and biophysical research communications 9 31866012
2023 Aldolase B attenuates clear cell renal cell carcinoma progression by inhibiting CtBP2. Frontiers of medicine 8 36790589
2020 CtBP2 interacts with ZBTB18 to promote malignancy of glioblastoma. Life sciences 8 32971103
2019 Brn4 promotes the differentiation of radial glial cells into neurons by inhibiting CtBP2. Life sciences 8 31518606
2017 Down-regulation of C-terminal binding protein 2 (CtBP2) inhibits proliferation, migration, and invasion of human SHSY5Y cells in vitro. Neuroscience letters 8 28179207
2017 CtBP2 is associated with angiogenesis and regulates the apoptosis of prostate cancer cells. Oncology reports 8 28677795
2014 Changes in the numbers of ribbon synapses and expression of RIBEYE in salicylate-induced tinnitus. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 8 25170565
2011 Ribeye a-mCherry fusion protein: a novel tool for labeling synaptic ribbons of the hair cell. Journal of neuroscience methods 8 21334379
2023 ZFX-mediated upregulation of CEBPA-AS1 contributes to acute myeloid leukemia progression through miR-24-3p/CTBP2 axis. Cell biology and toxicology 7 36715854
2021 CtBP2 interacts with TGIF to promote the progression of esophageal squamous cell cancer through the Wnt/β‑catenin pathway. Oncology reports 7 34878149
2024 Patient-derived castration-resistant prostate cancer model revealed CTBP2 upregulation mediated by OCT1 and androgen receptor. BMC cancer 6 38698344
2023 Differential expressions of FASN, SCD, and FABP4 genes in the ribeye muscle of omega-3 oil-supplemented Tattykeel Australian White lambs. BMC genomics 6 37932697
2022 Temporal and Isoform-Specific Expression of CTBP2 Is Evolutionarily Conserved Between the Developing Chick and Human Retina. Frontiers in molecular neuroscience 6 35095414
2015 Role of CtBP2 in the Apoptosis of Retinal Ganglion Cells. Cellular and molecular neurobiology 6 25627828
2025 A novel DNA binding protein encoded by circZNF131 inhibits the growth of gastric cancer by suppressing CTBP2 transcription. International journal of biological macromolecules 5 40381776
2024 BBOX1-AS1 promotes gastric cardia adenocarcinoma progression via interaction with CtBP2 to facilitate the epithelial-mesenchymal transition process. Cancer science 5 39318101
2023 Loss of CtBP2 may be a mechanistic link between metabolic derangements and progressive impairment of pancreatic β cell function. Cell reports 5 37557182
2017 RIBEYE(B)-domain binds to lipid components of synaptic vesicles in an NAD(H)-dependent, redox-sensitive manner. The Biochemical journal 5 28202712
2008 Inhibition of transcriptional activation and cell proliferation activities of adenovirus E1A by the unique N-terminal domain of CtBP2. Oncogene 5 18490918

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