{"gene":"CTBP2","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2000,"finding":"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.","method":"Partial purification of synaptic ribbons, protein identification, domain analysis, NAD+ binding assay","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical purification and reconstitution of ribbon components, NAD+ binding assay, domain functional analysis; foundational study replicated by multiple subsequent labs","pmids":["11163272"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Yeast two-hybrid, co-immunoprecipitation, immunogold electron microscopy, analysis of Bassoon-deficient mice","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction demonstrated by multiple methods, genetic (knockout mouse) validation, replicated in context of ribbon complex dissection","pmids":["15728193"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Yeast two-hybrid, protein pulldowns, synaptic ribbon interaction assays, coaggregation experiments, transmission electron microscopy, immunogold EM","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple independent biochemical methods, structural and functional validation of each interaction domain","pmids":["18685021"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Yeast two-hybrid, protein pulldowns, co-immunoprecipitation, immunofluorescence, point mutagenesis (RE(B)E844Q)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — five independent approaches including mutagenesis to dissect binding sites, functional relevance for synaptic transmission","pmids":["18664567"],"is_preprint":false},{"year":2016,"finding":"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.","method":"RIBEYE knockout mice, paired electrophysiological recordings in acute retina slices, EGTA Ca2+ buffer sensitivity assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — full genetic knockout with rigorous electrophysiological readout and pharmacological dissection of Ca2+ nano-domain coupling","pmids":["26929012"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Morpholino knockdown, transgenic overexpression, electrophysiology, immunofluorescence in zebrafish hair cells","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — complementary loss-of-function and gain-of-function experiments with specific cellular phenotypes and channel localization readouts","pmids":["21350006"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Multiple co-immunoprecipitation, pulldown, yeast two-hybrid, FM1-43 endocytosis assay, overexpression studies","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple independent biochemical approaches, redox-dependent binding mechanism, functional endocytosis assay","pmids":["24719103"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Mutagenesis, subcellular fractionation, leptomycin B treatment, acetylation assay, luciferase reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-directed mutagenesis with nuclear export inhibitor validation and functional transcriptional readout, single lab","pmids":["16356938"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Mutagenesis, transcriptional repression assay, dimerization assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis of multiple functional domains with transcriptional activity readout, single lab","pmids":["15037661"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Cryo-electron microscopy, mutagenesis, cell migration assay, luciferase reporter assay","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct structural determination by cryo-EM combined with functional mutagenesis and multiple cellular readouts, single lab","pmids":["33264605"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Analytical ultracentrifugation, isothermal titration calorimetry","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Moderate — rigorous biophysical measurements with quantitative binding constants, directly refines mechanistic model","pmids":["34997967"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Liver-specific knockout mice, metabolic phenotyping, in vitro binding assays, structural analysis of Rossmann fold metabolite-sensing pocket","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — conditional knockout with metabolic phenotype, biochemical metabolite-sensing assay, structural domain identification, multiple orthogonal methods","pmids":["34728642"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-immunoprecipitation, mutagenesis to shift monomer/dimer equilibrium, metabolic manipulation (malonyl-CoA reduction), liver-specific CtBP2 knockout","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro binding assay with metabolite, mutagenesis, and conditional knockout validation, single lab with multiple methods","pmids":["37286039"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Co-immunoprecipitation, CLIP-Seq, m6Am-Seq, CTBP2 knockout, polysome profiling/translation assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal genomic and biochemical approaches including knockout validation and single-base resolution m6Am mapping","pmids":["37643007"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Co-immunoprecipitation, siRNA depletion, proteasome inhibitor assay, invasion and migration assays, competition binding assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, epistasis experiment between CDK7 and HIPK2, functional migration assay; single lab","pmids":["23393140"],"is_preprint":false},{"year":1999,"finding":"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.","method":"Yeast two-hybrid screen, co-immunoprecipitation, Gal4 reporter assay, transient transfection/repression assay, site-directed mutagenesis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid plus mammalian cell co-IP, mutagenesis of interaction motif, and functional transcription assay; replicated in context of multiple CtBP corepressor studies","pmids":["10567582"],"is_preprint":false},{"year":2001,"finding":"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.","method":"Yeast two-hybrid screen, co-immunoprecipitation in mammalian cells, mutagenesis of PLNLSS motif, luciferase reporter assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid and mammalian cell co-IP, mutagenesis, reporter assay; single lab","pmids":["11504872"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Chromatin immunoprecipitation, luciferase reporter assay, overexpression, site-directed mutagenesis of interaction motifs","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, reporter assay, mutagenesis; single lab","pmids":["19181930"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Deletion mutagenesis, subcellular fractionation, heterologous protein fusions, CtBP1/2 heterodimerization assay","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic mutagenesis and domain swap experiments, single lab","pmids":["16999872"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Co-immunoprecipitation, acetylation assay, transcriptional reporter assay, domain deletion analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus acetylation assay and functional reporter; single lab","pmids":["17023432"],"is_preprint":false},{"year":2015,"finding":"HIPK2 phosphorylates CtBP2 at serine 428; this phosphorylation strengthens the interaction between KLF3 and CtBP2 and increases transcriptional repression by KLF3.","method":"Mass spectrometry identification of phosphorylation site, kinase assay, mutagenesis, co-immunoprecipitation, transcriptional repression assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — MS site identification, kinase assay, mutagenesis, and functional reporter; single lab","pmids":["25659434"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Co-immunoprecipitation, phosphorylation assay, overexpression/knockdown, transcriptional reporter, cell proliferation assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, kinase pathway epistasis, gene-specific transcriptional readout; single lab","pmids":["19668232"],"is_preprint":false},{"year":2013,"finding":"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.","method":"RNAi genetic screen, chromatin immunoprecipitation, co-immunoprecipitation, gene expression analysis, differentiation assay","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — unbiased RNAi screen, ChIP, and co-IP validation; single lab","pmids":["23775127"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Genome-wide ChIP-seq, Ctbp2 knockdown/ablation, H3K27 acetylation and methylation analysis","journal":"Stem cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide epigenetic profiling combined with loss-of-function; single lab","pmids":["25944056"],"is_preprint":false},{"year":2012,"finding":"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.","method":"RNAi knockdown, overexpression, chromatin immunoprecipitation, luciferase reporter assay, migration assay","journal":"Genes & cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, reporter, epistasis via Tiam1 knockdown; single lab","pmids":["23264848"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Chromatin immunoprecipitation, CtBP2 knockdown, gene expression analysis, xenograft tumor model","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP at specific target loci, knockdown, in vivo xenograft; single lab","pmids":["25228652"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Mass spectrometry, co-immunoprecipitation, chromatin immunoprecipitation, CoCl2 treatment, gene expression analysis","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified complex, co-IP, ChIP, and pharmacological rescue; single lab","pmids":["30585266"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Mass spectrometry, co-immunoprecipitation, chromatin immunoprecipitation, siRNA knockdown, promoter reporter","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified complex, co-IP, ChIP; single lab","pmids":["31929749"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Immunoprecipitation, mass spectrometry, co-IP, chromatin immunoprecipitation, siRNA knockdown","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified complex, co-IP, ChIP; single lab","pmids":["31754335"],"is_preprint":false},{"year":2011,"finding":"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.","method":"siRNA knockdown in neural crest cultures and zebrafish, PKA/proteasome inhibitors, Western blot for CtBP2 protein levels, melanocyte differentiation assay","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in two systems (cell culture + zebrafish), pharmacological dissection of pathway; single lab","pmids":["21199918"],"is_preprint":false},{"year":2014,"finding":"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.","method":"RNAi knockdown in mouse ESCs, LIF withdrawal differentiation assay, mesodermal colony assay","journal":"Mechanisms of development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with defined differentiation phenotype readouts; single lab","pmids":["19825414"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Co-immunoprecipitation, siRNA knockdown, β-catenin stabilization assay, gene expression analysis in ESCs","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and loss-of-function with specific molecular phenotype; single lab","pmids":["29026198"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Co-immunoprecipitation, mutagenesis of CtBP-binding motif in OCT1, EMT marker analysis, TGF-β treatment","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with mutagenesis validation and TGF-β induction; single lab","pmids":["31866012"],"is_preprint":false},{"year":2021,"finding":"CtBP2 forms transcriptional complexes with NRF1 and NRF2 that are required to promote expression of antioxidant genes in response to oxidative insults.","method":"Co-immunoprecipitation, gene expression analysis upon oxidative stress, CtBP2 loss-of-function","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and functional gene expression readout; single lab","pmids":["34052660"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Genome-wide ChIP-Seq, β cell-specific knockout mice, glucose tolerance test, insulin secretion assay, chromatin accessibility analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout, genome-wide binding map, chromatin analysis, and functional metabolic phenotype; multiple orthogonal methods","pmids":["37557182"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Gene targeting/knockout mouse generation, embryological analysis, transcriptional reporter assays in CtBP-deficient cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with defined developmental phenotype and cell-based transcription assay; widely replicated findings","pmids":["12101226"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Mass spectrometry proteomics of CtBP2 complexes, co-immunoprecipitation, mutagenesis of PIDLS motif, transcriptional reporter, cell proliferation assay","journal":"Genes & cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — unbiased proteomics plus co-IP with motif mutagenesis and functional readout; single lab","pmids":["24955216"],"is_preprint":false},{"year":2014,"finding":"Zscan4 directly interacts with both LSD1 and CtBP2 in embryonic stem cell nuclei, as demonstrated by protein interaction analyses.","method":"Co-immunoprecipitation, proximity ligation assay in ESC nuclei","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP without functional follow-up on the CtBP2 interaction specifically; single lab","pmids":["24594919"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Co-immunoprecipitation in embryonic cortex, in utero electroporation of mutant ZEB1, live imaging of neuronal migration","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo co-IP, epistasis by loss-of-function electroporation with defined neuronal phenotype; single lab","pmids":["31116980"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Chromatin immunoprecipitation, siRNA knockdown, reporter assay, PPARγ helix-7 mutagenesis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP at specific promoters, loss-of-function, domain mutagenesis; single lab","pmids":["19564408"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, siRNA knockdown, adipogenesis assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of ternary complex, ChIP at target promoters, knockdown phenotype; single lab","pmids":["30209132"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Protein folding predictions, proteomics, co-immunoprecipitation, competitive inhibitor (4× PLDLS repeat), xenotransplant model","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — proteomics and co-IP for interaction, competitive inhibitor with in vitro and in vivo functional rescue; multiple orthogonal approaches","pmids":["38748792"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Liposome sedimentation assay with defined lipid compositions, synaptic vesicle membrane fraction sedimentation assay","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro lipid-binding assay with defined compositions and redox conditions; single lab","pmids":["28202712"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Knockin mouse genetics (B-domain replacement), immunofluorescence, electron microscopy of ribbon synapses","journal":"Frontiers in molecular neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — precise genetic knockin with complete ribbon loss phenotype, complements RIBEYE A-domain knockout data from same group","pmids":["35153673"],"is_preprint":false},{"year":2017,"finding":"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.","method":"FRAP on transgenic zebrafish larvae expressing GFP/mCherry-tagged Ribeye in hair cells and skin cells","journal":"The Journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo FRAP with quantitative kinetics in two cell types; single lab","pmids":["29086422"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Co-immunoprecipitation, Piccolo/Piccolino-deficient rat model, ultrastructural electron microscopy analysis","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP combined with genetic model and ultrastructural phenotype; single lab","pmids":["30696732"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-immunoprecipitation, gene expression analysis, migration/proliferation assay, xenograft model, interaction-deficient mutant","journal":"Frontiers of medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, interaction-dependency established by mutants, in vitro and in vivo functional validation; single lab","pmids":["36790589"],"is_preprint":false}],"current_model":"CTBP2/RIBEYE is a dual-function locus encoding both a transcriptional corepressor (CtBP2) and the structural scaffold protein of synaptic ribbons (RIBEYE); CtBP2 functions as an NAD(H)/acyl-CoA-sensing obligate tetramer that recruits chromatin-modifying complexes (NuRD, HDAC1, LSD1, p300) to promoters via PXDLS-motif interactions with diverse transcription factors (ZEB1, KLF3, E2F7, OCT1, NEUROD1, AR, RAR/RXR), repressing or co-activating target genes depending on context; RIBEYE uses its A-domain for multiple self-association interactions to scaffold the synaptic ribbon and its NAD(H)-sensing B-domain (identical to CtBP2) to recruit active-zone proteins (Bassoon, Munc119, ArfGAP3, Piccolino) and tether synaptic vesicles via redox-regulated lipid binding, while RIBEYE deletion in mice abolishes ribbons and severely impairs sustained neurotransmitter release."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2000,"claim":"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","pmids":["11163272"],"confidence":"High","gaps":["Did not establish how the A-domain assembles ribbons in vivo","Functional role of NAD+ binding unresolved at this stage"]},{"year":2002,"claim":"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","pmids":["12101226"],"confidence":"High","gaps":["Specific target genes driving the axial/extraembryonic phenotype not defined","Degree of CtBP1 vs CtBP2 functional overlap quantitatively unresolved"]},{"year":1999,"claim":"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","pmids":["10567582"],"confidence":"High","gaps":["Did not identify the chromatin-modifying effectors recruited","Generality of the motif across factors not yet shown"]},{"year":2004,"claim":"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","pmids":["15037661"],"confidence":"High","gaps":["Higher-order oligomeric state not resolved","Whether NADH acts as a true cellular sensor not addressed"]},{"year":2006,"claim":"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","pmids":["16356938","16999872","17023432"],"confidence":"High","gaps":["Physiological signals controlling acetylation in vivo unclear","Functional consequences of cytoplasmic CtBP2 beyond reporter assays limited"]},{"year":2008,"claim":"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","pmids":["18685021","18664567","15728193"],"confidence":"High","gaps":["Stoichiometry of the assembled ribbon not determined","How NAD regulation of A-B docking operates in vivo unclear"]},{"year":2013,"claim":"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","pmids":["23775127","23393140"],"confidence":"Medium","gaps":["Determinants of the repressor-versus-coactivator switch not defined","Single-lab findings for the CDK7/HIPK2 axis"]},{"year":2016,"claim":"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","pmids":["26929012","21350006"],"confidence":"High","gaps":["Molecular basis of channel clustering by RIBEYE not fully resolved","Contribution of B-domain redox sensing to release kinetics untested here"]},{"year":2020,"claim":"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","pmids":["33264605","34997967"],"confidence":"High","gaps":["Whether tetramer-dimer equilibrium is dynamically signaled in cells unresolved","Biophysics argues against simple NADH sensing, leaving the physiological metabolic input unclear"]},{"year":2021,"claim":"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","pmids":["34728642","37286039"],"confidence":"High","gaps":["In vivo concentrations of competing acyl-CoAs that switch activity not fully mapped","Crosstalk with the tetramer/monomer equilibrium incompletely integrated"]},{"year":2023,"claim":"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","pmids":["37557182"],"confidence":"High","gaps":["Mechanism by which CtBP2 switches from repressor to chromatin-decompacting coactivator unresolved","Effector recruited for chromatin opening at insulin locus not fully defined"]},{"year":2024,"claim":"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","pmids":["38748792"],"confidence":"High","gaps":["Genome-wide EVI1-CtBP target program not mapped","Specificity of the competitive inhibitor across other PXDLS partners untested"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[8,15,34,11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[15,17,41,36]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,2,43]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[11,12,42]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[42]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7,18,34]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7,18]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[8,15,34,23]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[23,34]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,4,5]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[11,12]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[35,30,31]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[41,25,24]}],"complexes":["synaptic ribbon","NuRD complex","CtBP2-p300 complex"],"partners":["BSN","UNC119","ARFGAP3","ZEB1","EP300","HIPK2","NEUROD1","EVI1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P56545","full_name":"C-terminal-binding protein 2","aliases":[],"length_aa":445,"mass_kda":48.9,"function":"Corepressor targeting diverse transcription regulators. Functions in brown adipose tissue (BAT) differentiation (By similarity) Isoform 2 probably acts as a scaffold for specialized synapses","subcellular_location":"Nucleus; Synapse","url":"https://www.uniprot.org/uniprotkb/P56545/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CTBP2","classification":"Not Classified","n_dependent_lines":199,"n_total_lines":1208,"dependency_fraction":0.16473509933774835},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000175029","cell_line_id":"CID001535","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"nuclear_punctae","grade":2}],"interactors":[{"gene":"CTBP1","stoichiometry":10.0},{"gene":"HDAC2","stoichiometry":4.0},{"gene":"CSNK2A1","stoichiometry":0.2},{"gene":"CSNK2A2","stoichiometry":0.2},{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"ZNF217","stoichiometry":0.2},{"gene":"MBD3","stoichiometry":0.2},{"gene":"ZEB1","stoichiometry":0.2},{"gene":"WIZ","stoichiometry":0.2},{"gene":"NOL4L","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001535","total_profiled":1310},"omim":[{"mim_id":"609392","title":"KLF TRANSCRIPTION FACTOR 3; KLF3","url":"https://www.omim.org/entry/609392"},{"mim_id":"608628","title":"TRANSDUCIN-BETA-LIKE 1 RECEPTOR 1; TBL1XR1","url":"https://www.omim.org/entry/608628"},{"mim_id":"603693","title":"ZINC FINGER PROTEIN, FOG FAMILY MEMBER 2; ZFPM2","url":"https://www.omim.org/entry/603693"},{"mim_id":"603681","title":"OTOFERLIN; OTOF","url":"https://www.omim.org/entry/603681"},{"mim_id":"602619","title":"C-TERMINAL-BINDING PROTEIN 2; CTBP2","url":"https://www.omim.org/entry/602619"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CTBP2"},"hgnc":{"alias_symbol":["ribeye"],"prev_symbol":[]},"alphafold":{"accession":"P56545","domains":[{"cath_id":"3.40.50.720","chopping":"22-128_327-360","consensus_level":"high","plddt":94.1477,"start":22,"end":360},{"cath_id":"3.40.50.720","chopping":"131-317","consensus_level":"high","plddt":98.0909,"start":131,"end":317}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P56545","model_url":"https://alphafold.ebi.ac.uk/files/AF-P56545-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P56545-F1-predicted_aligned_error_v6.png","plddt_mean":83.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CTBP2","jax_strain_url":"https://www.jax.org/strain/search?query=CTBP2"},"sequence":{"accession":"P56545","fasta_url":"https://rest.uniprot.org/uniprotkb/P56545.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P56545/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P56545"}},"corpus_meta":[{"pmid":"11163272","id":"PMC_11163272","title":"RIBEYE, a component of synaptic ribbons: a protein's journey through evolution provides insight into synaptic ribbon function.","date":"2000","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/11163272","citation_count":449,"is_preprint":false},{"pmid":"24012420","id":"PMC_24012420","title":"Myeloid-derived suppressor cells enhance stemness of cancer cells by inducing microRNA101 and suppressing the corepressor CtBP2.","date":"2013","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/24012420","citation_count":371,"is_preprint":false},{"pmid":"15728193","id":"PMC_15728193","title":"Molecular dissection of the photoreceptor ribbon synapse: physical interaction of Bassoon and RIBEYE is essential for the assembly of the ribbon complex.","date":"2005","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/15728193","citation_count":336,"is_preprint":false},{"pmid":"12101226","id":"PMC_12101226","title":"Overlapping and unique roles for C-terminal binding protein 1 (CtBP1) and CtBP2 during mouse development.","date":"2002","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12101226","citation_count":255,"is_preprint":false},{"pmid":"19564408","id":"PMC_19564408","title":"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.","date":"2009","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19564408","citation_count":167,"is_preprint":false},{"pmid":"10567582","id":"PMC_10567582","title":"Identification of CtBP1 and CtBP2 as corepressors of zinc finger-homeodomain factor deltaEF1.","date":"1999","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/10567582","citation_count":116,"is_preprint":false},{"pmid":"26929012","id":"PMC_26929012","title":"How to make a synaptic ribbon: RIBEYE deletion abolishes ribbons in retinal synapses and disrupts neurotransmitter release.","date":"2016","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/26929012","citation_count":105,"is_preprint":false},{"pmid":"21350006","id":"PMC_21350006","title":"Ribeye is required for presynaptic Ca(V)1.3a channel localization and afferent innervation of sensory hair cells.","date":"2011","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/21350006","citation_count":102,"is_preprint":false},{"pmid":"18685021","id":"PMC_18685021","title":"Multiple RIBEYE-RIBEYE interactions create a dynamic scaffold for the formation of synaptic ribbons.","date":"2008","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/18685021","citation_count":101,"is_preprint":false},{"pmid":"19181930","id":"PMC_19181930","title":"The transcription repressor, ZEB1, cooperates with CtBP2 and HDAC1 to suppress IL-2 gene activation in T cells.","date":"2009","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19181930","citation_count":92,"is_preprint":false},{"pmid":"29147064","id":"PMC_29147064","title":"LncRNA NEAT1 Regulates Cell Viability and Invasion in Esophageal Squamous Cell Carcinoma through the miR-129/CTBP2 Axis.","date":"2017","source":"Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/29147064","citation_count":74,"is_preprint":false},{"pmid":"16356938","id":"PMC_16356938","title":"Acetylation by p300 regulates nuclear localization and function of the transcriptional corepressor CtBP2.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16356938","citation_count":70,"is_preprint":false},{"pmid":"23393140","id":"PMC_23393140","title":"Interaction with cyclin H/cyclin-dependent kinase 7 (CCNH/CDK7) stabilizes C-terminal binding protein 2 (CtBP2) and promotes cancer cell migration.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23393140","citation_count":68,"is_preprint":false},{"pmid":"15673675","id":"PMC_15673675","title":"Two ribeye genes in teleosts: the role of Ribeye in ribbon formation and bipolar cell development.","date":"2005","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/15673675","citation_count":64,"is_preprint":false},{"pmid":"11504872","id":"PMC_11504872","title":"SOX6 binds CtBP2 to repress transcription from the Fgf-3 promoter.","date":"2001","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/11504872","citation_count":64,"is_preprint":false},{"pmid":"9479502","id":"PMC_9479502","title":"A novel C-terminal binding protein (CTBP2) is closely related to CTBP1, an adenovirus E1A-binding protein, and maps to human chromosome 21q21.3.","date":"1998","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9479502","citation_count":62,"is_preprint":false},{"pmid":"27292637","id":"PMC_27292637","title":"Synaptic Ribbons Require Ribeye for Electron Density, Proper Synaptic Localization, and Recruitment of Calcium Channels.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27292637","citation_count":61,"is_preprint":false},{"pmid":"34781990","id":"PMC_34781990","title":"Circular RNA circHERC4 as a novel oncogenic driver to promote tumor metastasis via the miR-556-5p/CTBP2/E-cadherin axis in colorectal cancer.","date":"2021","source":"Journal of hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34781990","citation_count":57,"is_preprint":false},{"pmid":"25228652","id":"PMC_25228652","title":"CtBP2 modulates the androgen receptor to promote prostate cancer progression.","date":"2014","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/25228652","citation_count":56,"is_preprint":false},{"pmid":"31116980","id":"PMC_31116980","title":"ZEB1 Represses Neural Differentiation and Cooperates with CTBP2 to Dynamically Regulate Cell Migration during Neocortex Development.","date":"2019","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/31116980","citation_count":55,"is_preprint":false},{"pmid":"25944056","id":"PMC_25944056","title":"Ctbp2 Modulates NuRD-Mediated Deacetylation of H3K27 and Facilitates PRC2-Mediated H3K27me3 in Active Embryonic Stem Cell Genes During Exit from Pluripotency.","date":"2015","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/25944056","citation_count":55,"is_preprint":false},{"pmid":"18664567","id":"PMC_18664567","title":"RIBEYE recruits Munc119, a mammalian ortholog of the Caenorhabditis elegans protein unc119, to synaptic ribbons of photoreceptor synapses.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18664567","citation_count":54,"is_preprint":false},{"pmid":"25895816","id":"PMC_25895816","title":"Obesity-Associated MiR-342-3p Promotes Adipogenesis of Mesenchymal Stem Cells by Suppressing CtBP2 and Releasing C/EBPα from CtBP2 Binding.","date":"2015","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/25895816","citation_count":54,"is_preprint":false},{"pmid":"23264848","id":"PMC_23264848","title":"CtBP2 Promotes Human Cancer Cell Migration by Transcriptional Activation of Tiam1.","date":"2012","source":"Genes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/23264848","citation_count":53,"is_preprint":false},{"pmid":"15037661","id":"PMC_15037661","title":"The CtBP2 co-repressor is regulated by NADH-dependent dimerization and possesses a novel N-terminal repression domain.","date":"2004","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/15037661","citation_count":53,"is_preprint":false},{"pmid":"30619490","id":"PMC_30619490","title":"miR-144-3p Promotes Adipogenesis Through Releasing C/EBPα From Klf3 and CtBP2.","date":"2018","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30619490","citation_count":44,"is_preprint":false},{"pmid":"19597856","id":"PMC_19597856","title":"Porcine muscle sensory attributes associate with major changes in gene networks involving CAPZB, ANKRD1, and CTBP2.","date":"2009","source":"Functional & integrative genomics","url":"https://pubmed.ncbi.nlm.nih.gov/19597856","citation_count":39,"is_preprint":false},{"pmid":"24835310","id":"PMC_24835310","title":"CtBP2 could promote prostate cancer cell proliferation through c-Myc signaling.","date":"2014","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/24835310","citation_count":37,"is_preprint":false},{"pmid":"30209132","id":"PMC_30209132","title":"The TEA domain family transcription factor TEAD4 represses murine adipogenesis by recruiting the cofactors VGLL4 and CtBP2 into a transcriptional complex.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30209132","citation_count":37,"is_preprint":false},{"pmid":"30696732","id":"PMC_30696732","title":"A Multiple Piccolino-RIBEYE Interaction Supports Plate-Shaped Synaptic Ribbons in Retinal Neurons.","date":"2019","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/30696732","citation_count":33,"is_preprint":false},{"pmid":"16999872","id":"PMC_16999872","title":"Role of the unique N-terminal domain of CtBP2 in determining the subcellular localisation of CtBP family proteins.","date":"2006","source":"BMC cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16999872","citation_count":33,"is_preprint":false},{"pmid":"24594919","id":"PMC_24594919","title":"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.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24594919","citation_count":32,"is_preprint":false},{"pmid":"31929749","id":"PMC_31929749","title":"Transforming growth factor beta (TGF-β) is activated by the CtBP2-p300-AP1 transcriptional complex in chronic renal failure.","date":"2020","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31929749","citation_count":31,"is_preprint":false},{"pmid":"32866716","id":"PMC_32866716","title":"The Monocyte-Derived Exosomal CLMAT3 Activates the CtBP2-p300-NF-κB Transcriptional Complex to Induce Proinflammatory Cytokines in ALI.","date":"2020","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/32866716","citation_count":30,"is_preprint":false},{"pmid":"25132384","id":"PMC_25132384","title":"A self-organizing miR-132/Ctbp2 circuit regulates bimodal notch signals and glial progenitor fate choice during spinal cord maturation.","date":"2014","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/25132384","citation_count":30,"is_preprint":false},{"pmid":"23255392","id":"PMC_23255392","title":"CtBP2 contributes to malignant development of human esophageal squamous cell carcinoma by regulation of p16INK4A.","date":"2013","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23255392","citation_count":29,"is_preprint":false},{"pmid":"30585266","id":"PMC_30585266","title":"The intracellular NADH level regulates atrophic nonunion pathogenesis through the CtBP2-p300-Runx2 transcriptional complex.","date":"2018","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30585266","citation_count":27,"is_preprint":false},{"pmid":"25820824","id":"PMC_25820824","title":"Interaction with CCNH/CDK7 facilitates CtBP2 promoting esophageal squamous cell carcinoma (ESCC) metastasis via upregulating epithelial-mesenchymal transition (EMT) progression.","date":"2015","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25820824","citation_count":27,"is_preprint":false},{"pmid":"31754335","id":"PMC_31754335","title":"Downregulation of miR-199a-3p mediated by the CtBP2-HDAC1-FOXP3 transcriptional complex contributes to acute lung injury by targeting NLRP1.","date":"2019","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31754335","citation_count":27,"is_preprint":false},{"pmid":"22832038","id":"PMC_22832038","title":"High-resolution optical imaging of zebrafish larval ribbon synapse protein RIBEYE, RIM2, and CaV 1.4 by stimulation emission depletion microscopy.","date":"2012","source":"Microscopy and microanalysis : the official journal of Microscopy Society of America, Microbeam Analysis Society, Microscopical Society of Canada","url":"https://pubmed.ncbi.nlm.nih.gov/22832038","citation_count":27,"is_preprint":false},{"pmid":"28438897","id":"PMC_28438897","title":"Downregulation of miR-200a-3p, Targeting CtBP2 Complex, Is Involved in the Hypoproduction of IL-2 in Systemic Lupus Erythematosus-Derived T Cells.","date":"2017","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/28438897","citation_count":26,"is_preprint":false},{"pmid":"37643007","id":"PMC_37643007","title":"The CTBP2-PCIF1 complex regulates m6Am modification of mRNA in head and neck squamous cell carcinoma.","date":"2023","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/37643007","citation_count":25,"is_preprint":false},{"pmid":"34728642","id":"PMC_34728642","title":"The transcriptional corepressor CtBP2 serves as a metabolite sensor orchestrating hepatic glucose and lipid homeostasis.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34728642","citation_count":25,"is_preprint":false},{"pmid":"11576649","id":"PMC_11576649","title":"Dual use of the transcriptional repressor (CtBP2)/ribbon synapse (RIBEYE) gene: how prevalent are multifunctional genes?","date":"2001","source":"Trends in neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/11576649","citation_count":24,"is_preprint":false},{"pmid":"24719103","id":"PMC_24719103","title":"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.","date":"2014","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/24719103","citation_count":24,"is_preprint":false},{"pmid":"33264605","id":"PMC_33264605","title":"Cryo-EM structure of CtBP2 confirms tetrameric architecture.","date":"2020","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/33264605","citation_count":23,"is_preprint":false},{"pmid":"30334447","id":"PMC_30334447","title":"CtBP2 promotes proliferation and reduces drug sensitivity in non-small cell lung cancer via the Wnt/β-catenin pathway.","date":"2018","source":"Neoplasma","url":"https://pubmed.ncbi.nlm.nih.gov/30334447","citation_count":23,"is_preprint":false},{"pmid":"21315774","id":"PMC_21315774","title":"Ataxin-1 occupies the promoter region of E-cadherin in vivo and activates CtBP2-repressed promoter.","date":"2011","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/21315774","citation_count":23,"is_preprint":false},{"pmid":"31351181","id":"PMC_31351181","title":"Transcriptome profiling of muscle in Nelore cattle phenotypically divergent for the ribeye muscle area.","date":"2019","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/31351181","citation_count":22,"is_preprint":false},{"pmid":"25659434","id":"PMC_25659434","title":"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.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25659434","citation_count":22,"is_preprint":false},{"pmid":"19668232","id":"PMC_19668232","title":"NGF inhibits human leukemia proliferation by downregulating cyclin A1 expression through promoting acinus/CtBP2 association.","date":"2009","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/19668232","citation_count":22,"is_preprint":false},{"pmid":"17023432","id":"PMC_17023432","title":"Changes in C-terminal binding protein 2 (CtBP2) corepressor complex induced by E1A and modulation of E1A transcriptional activity by CtBP2.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17023432","citation_count":20,"is_preprint":false},{"pmid":"26788097","id":"PMC_26788097","title":"CtBP2 overexpression is associated with tumorigenesis and poor clinical outcome of prostate cancer.","date":"2015","source":"Archives of medical science : AMS","url":"https://pubmed.ncbi.nlm.nih.gov/26788097","citation_count":20,"is_preprint":false},{"pmid":"23775127","id":"PMC_23775127","title":"The corepressor CTBP2 is a coactivator of retinoic acid receptor/retinoid X receptor in retinoic acid signaling.","date":"2013","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/23775127","citation_count":19,"is_preprint":false},{"pmid":"24332637","id":"PMC_24332637","title":"Expression patterns of candidate susceptibility genes HNF1β and CtBP2 in prostate cancer: association with tumor progression.","date":"2013","source":"Urologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/24332637","citation_count":18,"is_preprint":false},{"pmid":"21199918","id":"PMC_21199918","title":"CtBP2 downregulation during neural crest specification induces expression of Mitf and REST, resulting in melanocyte differentiation and sympathoadrenal lineage suppression.","date":"2011","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21199918","citation_count":18,"is_preprint":false},{"pmid":"28111233","id":"PMC_28111233","title":"CtBP2 ameliorates palmitate-induced insulin resistance in HepG2 cells through ROS mediated JNK pathway.","date":"2017","source":"General and comparative endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/28111233","citation_count":18,"is_preprint":false},{"pmid":"38748792","id":"PMC_38748792","title":"Oncogene EVI1 drives acute myeloid leukemia via a targetable interaction with CTBP2.","date":"2024","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/38748792","citation_count":17,"is_preprint":false},{"pmid":"16258936","id":"PMC_16258936","title":"Expression of avian C-terminal binding proteins (Ctbp1 and Ctbp2) during embryonic development.","date":"2006","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/16258936","citation_count":17,"is_preprint":false},{"pmid":"23076816","id":"PMC_23076816","title":"Different functions of HIPK2 and CtBP2 in traumatic brain injury.","date":"2012","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/23076816","citation_count":17,"is_preprint":false},{"pmid":"30098506","id":"PMC_30098506","title":"Antimony enhances c-Myc stability in prostate cancer via activating CtBP2-ROCK1 signaling pathway.","date":"2018","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/30098506","citation_count":17,"is_preprint":false},{"pmid":"25208216","id":"PMC_25208216","title":"Characterization of Ribeye subunits in zebrafish hair cells reveals that exogenous Ribeye B-domain and CtBP1 localize to the basal ends of synaptic ribbons.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25208216","citation_count":16,"is_preprint":false},{"pmid":"37286039","id":"PMC_37286039","title":"Obesity-induced metabolic imbalance allosterically modulates CtBP2 to inhibit PPAR-alpha transcriptional activity.","date":"2023","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37286039","citation_count":16,"is_preprint":false},{"pmid":"24955216","id":"PMC_24955216","title":"CtBP2 proteome: Role of CtBP in E2F7-mediated repression and cell proliferation.","date":"2014","source":"Genes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/24955216","citation_count":16,"is_preprint":false},{"pmid":"33972635","id":"PMC_33972635","title":"Endoplasmic reticulum stress regulates the intestinal stem cell state through CtBP2.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33972635","citation_count":15,"is_preprint":false},{"pmid":"19825414","id":"PMC_19825414","title":"Delayed differentiation in embryonic stem cells and mesodermal progenitors in the absence of CtBP2.","date":"2009","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/19825414","citation_count":15,"is_preprint":false},{"pmid":"28826173","id":"PMC_28826173","title":"MiR-338 suppresses cell proliferation and invasion by targeting CTBP2 in glioma.","date":"2017","source":"Cancer biomarkers : section A of Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/28826173","citation_count":14,"is_preprint":false},{"pmid":"29026198","id":"PMC_29026198","title":"Ctbp2-mediated β-catenin regulation is required for exit from pluripotency.","date":"2017","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29026198","citation_count":14,"is_preprint":false},{"pmid":"28785118","id":"PMC_28785118","title":"In Vivo Ribbon Mobility and Turnover of Ribeye at Zebrafish Hair Cell Synapses.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28785118","citation_count":14,"is_preprint":false},{"pmid":"36331689","id":"PMC_36331689","title":"CTBP1 and CTBP2 mutations underpinning neurological disorders: a systematic review.","date":"2022","source":"Neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/36331689","citation_count":13,"is_preprint":false},{"pmid":"26681554","id":"PMC_26681554","title":"CtBP2 Regulates TGFβ2-Induced Epithelial-Mesenchymal Transition Through Notch Signaling Pathway in Lens Epithelial Cells.","date":"2015","source":"Current eye research","url":"https://pubmed.ncbi.nlm.nih.gov/26681554","citation_count":13,"is_preprint":false},{"pmid":"35153673","id":"PMC_35153673","title":"RIBEYE B-Domain Is Essential for RIBEYE A-Domain Stability and Assembly of Synaptic Ribbons.","date":"2022","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/35153673","citation_count":12,"is_preprint":false},{"pmid":"33531645","id":"PMC_33531645","title":"microRNA-133a exerts tumor suppressive role in oral squamous cell carcinoma through the Notch signaling pathway via downregulation of CTBP2.","date":"2021","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33531645","citation_count":12,"is_preprint":false},{"pmid":"32169478","id":"PMC_32169478","title":"The corepressor CtBP2 is required for proper development of the mouse cerebral cortex.","date":"2020","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/32169478","citation_count":12,"is_preprint":false},{"pmid":"29086422","id":"PMC_29086422","title":"Ribeye protein is intrinsically dynamic but is stabilized in the context of the ribbon synapse.","date":"2018","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/29086422","citation_count":10,"is_preprint":false},{"pmid":"34997967","id":"PMC_34997967","title":"NADH/NAD+ binding and linked tetrameric assembly of the oncogenic transcription factors CtBP1 and CtBP2.","date":"2022","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/34997967","citation_count":10,"is_preprint":false},{"pmid":"22426895","id":"PMC_22426895","title":"Involvement of CtBP2 in LPS-induced microglial activation.","date":"2012","source":"Journal of molecular histology","url":"https://pubmed.ncbi.nlm.nih.gov/22426895","citation_count":10,"is_preprint":false},{"pmid":"34052660","id":"PMC_34052660","title":"CtBP2 confers protection against oxidative stress through interactions with NRF1 and NRF2.","date":"2021","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/34052660","citation_count":10,"is_preprint":false},{"pmid":"25447313","id":"PMC_25447313","title":"Oxygen-dependent acetylation and dimerization of the corepressor CtBP2 in neural stem cells.","date":"2014","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/25447313","citation_count":10,"is_preprint":false},{"pmid":"32434298","id":"PMC_32434298","title":"NSM00158 Specifically Disrupts the CtBP2-p300 Interaction to Reverse CtBP2-Mediated Transrepression and Prevent the Occurrence of Nonunion.","date":"2020","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/32434298","citation_count":9,"is_preprint":false},{"pmid":"35113002","id":"PMC_35113002","title":"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).","date":"2022","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/35113002","citation_count":9,"is_preprint":false},{"pmid":"31866012","id":"PMC_31866012","title":"Transcriptional co-repressor CtBP2 orchestrates epithelial-mesenchymal transition through a novel transcriptional holocomplex with OCT1.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/31866012","citation_count":9,"is_preprint":false},{"pmid":"36790589","id":"PMC_36790589","title":"Aldolase B attenuates clear cell renal cell carcinoma progression by inhibiting CtBP2.","date":"2023","source":"Frontiers of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36790589","citation_count":8,"is_preprint":false},{"pmid":"32971103","id":"PMC_32971103","title":"CtBP2 interacts with ZBTB18 to promote malignancy of glioblastoma.","date":"2020","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32971103","citation_count":8,"is_preprint":false},{"pmid":"25170565","id":"PMC_25170565","title":"Changes in the numbers of ribbon synapses and expression of RIBEYE in salicylate-induced tinnitus.","date":"2014","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/25170565","citation_count":8,"is_preprint":false},{"pmid":"21334379","id":"PMC_21334379","title":"Ribeye a-mCherry fusion protein: a novel tool for labeling synaptic ribbons of the hair cell.","date":"2011","source":"Journal of neuroscience methods","url":"https://pubmed.ncbi.nlm.nih.gov/21334379","citation_count":8,"is_preprint":false},{"pmid":"28677795","id":"PMC_28677795","title":"CtBP2 is associated with angiogenesis and regulates the apoptosis of prostate cancer cells.","date":"2017","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/28677795","citation_count":8,"is_preprint":false},{"pmid":"28179207","id":"PMC_28179207","title":"Down-regulation of C-terminal binding protein 2 (CtBP2) inhibits proliferation, migration, and invasion of human SHSY5Y cells in vitro.","date":"2017","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/28179207","citation_count":8,"is_preprint":false},{"pmid":"31518606","id":"PMC_31518606","title":"Brn4 promotes the differentiation of radial glial cells into neurons by inhibiting CtBP2.","date":"2019","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31518606","citation_count":8,"is_preprint":false},{"pmid":"34878149","id":"PMC_34878149","title":"CtBP2 interacts with TGIF to promote the progression of esophageal squamous cell cancer through the Wnt/β‑catenin pathway.","date":"2021","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/34878149","citation_count":7,"is_preprint":false},{"pmid":"36715854","id":"PMC_36715854","title":"ZFX-mediated upregulation of CEBPA-AS1 contributes to acute myeloid leukemia progression through miR-24-3p/CTBP2 axis.","date":"2023","source":"Cell biology and toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/36715854","citation_count":7,"is_preprint":false},{"pmid":"38698344","id":"PMC_38698344","title":"Patient-derived castration-resistant prostate cancer model revealed CTBP2 upregulation mediated by OCT1 and androgen receptor.","date":"2024","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/38698344","citation_count":6,"is_preprint":false},{"pmid":"35095414","id":"PMC_35095414","title":"Temporal and Isoform-Specific Expression of CTBP2 Is Evolutionarily Conserved Between the Developing Chick and Human Retina.","date":"2022","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/35095414","citation_count":6,"is_preprint":false},{"pmid":"25627828","id":"PMC_25627828","title":"Role of CtBP2 in the Apoptosis of Retinal Ganglion Cells.","date":"2015","source":"Cellular and molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/25627828","citation_count":6,"is_preprint":false},{"pmid":"37932697","id":"PMC_37932697","title":"Differential expressions of FASN, SCD, and FABP4 genes in the ribeye muscle of omega-3 oil-supplemented Tattykeel Australian White lambs.","date":"2023","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/37932697","citation_count":6,"is_preprint":false},{"pmid":"40381776","id":"PMC_40381776","title":"A novel DNA binding protein encoded by circZNF131 inhibits the growth of gastric cancer by suppressing CTBP2 transcription.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/40381776","citation_count":5,"is_preprint":false},{"pmid":"37557182","id":"PMC_37557182","title":"Loss of CtBP2 may be a mechanistic link between metabolic derangements and progressive impairment of pancreatic β cell function.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/37557182","citation_count":5,"is_preprint":false},{"pmid":"39318101","id":"PMC_39318101","title":"BBOX1-AS1 promotes gastric cardia adenocarcinoma progression via interaction with CtBP2 to facilitate the epithelial-mesenchymal transition process.","date":"2024","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/39318101","citation_count":5,"is_preprint":false},{"pmid":"18490918","id":"PMC_18490918","title":"Inhibition of transcriptional activation and cell proliferation activities of adenovirus E1A by the unique N-terminal domain of CtBP2.","date":"2008","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/18490918","citation_count":5,"is_preprint":false},{"pmid":"28202712","id":"PMC_28202712","title":"RIBEYE(B)-domain binds to lipid components of synaptic vesicles in an NAD(H)-dependent, redox-sensitive manner.","date":"2017","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/28202712","citation_count":5,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50428,"output_tokens":10895,"usd":0.157355,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":21760,"output_tokens":4691,"usd":0.113037,"stage2_stop_reason":"end_turn"},"total_usd":0.270392,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"Partial purification of synaptic ribbons, protein identification, domain analysis, NAD+ binding assay\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical purification and reconstitution of ribbon components, NAD+ binding assay, domain functional analysis; foundational study replicated by multiple subsequent labs\",\n      \"pmids\": [\"11163272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, immunogold electron microscopy, analysis of Bassoon-deficient mice\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction demonstrated by multiple methods, genetic (knockout mouse) validation, replicated in context of ribbon complex dissection\",\n      \"pmids\": [\"15728193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid, protein pulldowns, synaptic ribbon interaction assays, coaggregation experiments, transmission electron microscopy, immunogold EM\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple independent biochemical methods, structural and functional validation of each interaction domain\",\n      \"pmids\": [\"18685021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid, protein pulldowns, co-immunoprecipitation, immunofluorescence, point mutagenesis (RE(B)E844Q)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — five independent approaches including mutagenesis to dissect binding sites, functional relevance for synaptic transmission\",\n      \"pmids\": [\"18664567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"RIBEYE knockout mice, paired electrophysiological recordings in acute retina slices, EGTA Ca2+ buffer sensitivity assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — full genetic knockout with rigorous electrophysiological readout and pharmacological dissection of Ca2+ nano-domain coupling\",\n      \"pmids\": [\"26929012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Morpholino knockdown, transgenic overexpression, electrophysiology, immunofluorescence in zebrafish hair cells\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — complementary loss-of-function and gain-of-function experiments with specific cellular phenotypes and channel localization readouts\",\n      \"pmids\": [\"21350006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Multiple co-immunoprecipitation, pulldown, yeast two-hybrid, FM1-43 endocytosis assay, overexpression studies\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple independent biochemical approaches, redox-dependent binding mechanism, functional endocytosis assay\",\n      \"pmids\": [\"24719103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Mutagenesis, subcellular fractionation, leptomycin B treatment, acetylation assay, luciferase reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-directed mutagenesis with nuclear export inhibitor validation and functional transcriptional readout, single lab\",\n      \"pmids\": [\"16356938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Mutagenesis, transcriptional repression assay, dimerization assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis of multiple functional domains with transcriptional activity readout, single lab\",\n      \"pmids\": [\"15037661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Cryo-electron microscopy, mutagenesis, cell migration assay, luciferase reporter assay\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct structural determination by cryo-EM combined with functional mutagenesis and multiple cellular readouts, single lab\",\n      \"pmids\": [\"33264605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Analytical ultracentrifugation, isothermal titration calorimetry\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — rigorous biophysical measurements with quantitative binding constants, directly refines mechanistic model\",\n      \"pmids\": [\"34997967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Liver-specific knockout mice, metabolic phenotyping, in vitro binding assays, structural analysis of Rossmann fold metabolite-sensing pocket\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — conditional knockout with metabolic phenotype, biochemical metabolite-sensing assay, structural domain identification, multiple orthogonal methods\",\n      \"pmids\": [\"34728642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis to shift monomer/dimer equilibrium, metabolic manipulation (malonyl-CoA reduction), liver-specific CtBP2 knockout\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro binding assay with metabolite, mutagenesis, and conditional knockout validation, single lab with multiple methods\",\n      \"pmids\": [\"37286039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, CLIP-Seq, m6Am-Seq, CTBP2 knockout, polysome profiling/translation assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal genomic and biochemical approaches including knockout validation and single-base resolution m6Am mapping\",\n      \"pmids\": [\"37643007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, siRNA depletion, proteasome inhibitor assay, invasion and migration assays, competition binding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, epistasis experiment between CDK7 and HIPK2, functional migration assay; single lab\",\n      \"pmids\": [\"23393140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, Gal4 reporter assay, transient transfection/repression assay, site-directed mutagenesis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid plus mammalian cell co-IP, mutagenesis of interaction motif, and functional transcription assay; replicated in context of multiple CtBP corepressor studies\",\n      \"pmids\": [\"10567582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation in mammalian cells, mutagenesis of PLNLSS motif, luciferase reporter assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid and mammalian cell co-IP, mutagenesis, reporter assay; single lab\",\n      \"pmids\": [\"11504872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Chromatin immunoprecipitation, luciferase reporter assay, overexpression, site-directed mutagenesis of interaction motifs\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, reporter assay, mutagenesis; single lab\",\n      \"pmids\": [\"19181930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Deletion mutagenesis, subcellular fractionation, heterologous protein fusions, CtBP1/2 heterodimerization assay\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic mutagenesis and domain swap experiments, single lab\",\n      \"pmids\": [\"16999872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, acetylation assay, transcriptional reporter assay, domain deletion analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus acetylation assay and functional reporter; single lab\",\n      \"pmids\": [\"17023432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HIPK2 phosphorylates CtBP2 at serine 428; this phosphorylation strengthens the interaction between KLF3 and CtBP2 and increases transcriptional repression by KLF3.\",\n      \"method\": \"Mass spectrometry identification of phosphorylation site, kinase assay, mutagenesis, co-immunoprecipitation, transcriptional repression assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — MS site identification, kinase assay, mutagenesis, and functional reporter; single lab\",\n      \"pmids\": [\"25659434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assay, overexpression/knockdown, transcriptional reporter, cell proliferation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, kinase pathway epistasis, gene-specific transcriptional readout; single lab\",\n      \"pmids\": [\"19668232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"RNAi genetic screen, chromatin immunoprecipitation, co-immunoprecipitation, gene expression analysis, differentiation assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased RNAi screen, ChIP, and co-IP validation; single lab\",\n      \"pmids\": [\"23775127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Genome-wide ChIP-seq, Ctbp2 knockdown/ablation, H3K27 acetylation and methylation analysis\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide epigenetic profiling combined with loss-of-function; single lab\",\n      \"pmids\": [\"25944056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"RNAi knockdown, overexpression, chromatin immunoprecipitation, luciferase reporter assay, migration assay\",\n      \"journal\": \"Genes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, reporter, epistasis via Tiam1 knockdown; single lab\",\n      \"pmids\": [\"23264848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Chromatin immunoprecipitation, CtBP2 knockdown, gene expression analysis, xenograft tumor model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at specific target loci, knockdown, in vivo xenograft; single lab\",\n      \"pmids\": [\"25228652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, chromatin immunoprecipitation, CoCl2 treatment, gene expression analysis\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified complex, co-IP, ChIP, and pharmacological rescue; single lab\",\n      \"pmids\": [\"30585266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, chromatin immunoprecipitation, siRNA knockdown, promoter reporter\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified complex, co-IP, ChIP; single lab\",\n      \"pmids\": [\"31929749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry, co-IP, chromatin immunoprecipitation, siRNA knockdown\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified complex, co-IP, ChIP; single lab\",\n      \"pmids\": [\"31754335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown in neural crest cultures and zebrafish, PKA/proteasome inhibitors, Western blot for CtBP2 protein levels, melanocyte differentiation assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in two systems (cell culture + zebrafish), pharmacological dissection of pathway; single lab\",\n      \"pmids\": [\"21199918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"RNAi knockdown in mouse ESCs, LIF withdrawal differentiation assay, mesodermal colony assay\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with defined differentiation phenotype readouts; single lab\",\n      \"pmids\": [\"19825414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, β-catenin stabilization assay, gene expression analysis in ESCs\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and loss-of-function with specific molecular phenotype; single lab\",\n      \"pmids\": [\"29026198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis of CtBP-binding motif in OCT1, EMT marker analysis, TGF-β treatment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with mutagenesis validation and TGF-β induction; single lab\",\n      \"pmids\": [\"31866012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CtBP2 forms transcriptional complexes with NRF1 and NRF2 that are required to promote expression of antioxidant genes in response to oxidative insults.\",\n      \"method\": \"Co-immunoprecipitation, gene expression analysis upon oxidative stress, CtBP2 loss-of-function\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and functional gene expression readout; single lab\",\n      \"pmids\": [\"34052660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Genome-wide ChIP-Seq, β cell-specific knockout mice, glucose tolerance test, insulin secretion assay, chromatin accessibility analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout, genome-wide binding map, chromatin analysis, and functional metabolic phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"37557182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Gene targeting/knockout mouse generation, embryological analysis, transcriptional reporter assays in CtBP-deficient cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with defined developmental phenotype and cell-based transcription assay; widely replicated findings\",\n      \"pmids\": [\"12101226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Mass spectrometry proteomics of CtBP2 complexes, co-immunoprecipitation, mutagenesis of PIDLS motif, transcriptional reporter, cell proliferation assay\",\n      \"journal\": \"Genes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased proteomics plus co-IP with motif mutagenesis and functional readout; single lab\",\n      \"pmids\": [\"24955216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Zscan4 directly interacts with both LSD1 and CtBP2 in embryonic stem cell nuclei, as demonstrated by protein interaction analyses.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay in ESC nuclei\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP without functional follow-up on the CtBP2 interaction specifically; single lab\",\n      \"pmids\": [\"24594919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation in embryonic cortex, in utero electroporation of mutant ZEB1, live imaging of neuronal migration\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo co-IP, epistasis by loss-of-function electroporation with defined neuronal phenotype; single lab\",\n      \"pmids\": [\"31116980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Chromatin immunoprecipitation, siRNA knockdown, reporter assay, PPARγ helix-7 mutagenesis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at specific promoters, loss-of-function, domain mutagenesis; single lab\",\n      \"pmids\": [\"19564408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, siRNA knockdown, adipogenesis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of ternary complex, ChIP at target promoters, knockdown phenotype; single lab\",\n      \"pmids\": [\"30209132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Protein folding predictions, proteomics, co-immunoprecipitation, competitive inhibitor (4× PLDLS repeat), xenotransplant model\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — proteomics and co-IP for interaction, competitive inhibitor with in vitro and in vivo functional rescue; multiple orthogonal approaches\",\n      \"pmids\": [\"38748792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Liposome sedimentation assay with defined lipid compositions, synaptic vesicle membrane fraction sedimentation assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro lipid-binding assay with defined compositions and redox conditions; single lab\",\n      \"pmids\": [\"28202712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Knockin mouse genetics (B-domain replacement), immunofluorescence, electron microscopy of ribbon synapses\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — precise genetic knockin with complete ribbon loss phenotype, complements RIBEYE A-domain knockout data from same group\",\n      \"pmids\": [\"35153673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"FRAP on transgenic zebrafish larvae expressing GFP/mCherry-tagged Ribeye in hair cells and skin cells\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo FRAP with quantitative kinetics in two cell types; single lab\",\n      \"pmids\": [\"29086422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, Piccolo/Piccolino-deficient rat model, ultrastructural electron microscopy analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP combined with genetic model and ultrastructural phenotype; single lab\",\n      \"pmids\": [\"30696732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, gene expression analysis, migration/proliferation assay, xenograft model, interaction-deficient mutant\",\n      \"journal\": \"Frontiers of medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, interaction-dependency established by mutants, in vitro and in vivo functional validation; single lab\",\n      \"pmids\": [\"36790589\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CTBP2/RIBEYE is a dual-function locus encoding both a transcriptional corepressor (CtBP2) and the structural scaffold protein of synaptic ribbons (RIBEYE); CtBP2 functions as an NAD(H)/acyl-CoA-sensing obligate tetramer that recruits chromatin-modifying complexes (NuRD, HDAC1, LSD1, p300) to promoters via PXDLS-motif interactions with diverse transcription factors (ZEB1, KLF3, E2F7, OCT1, NEUROD1, AR, RAR/RXR), repressing or co-activating target genes depending on context; RIBEYE uses its A-domain for multiple self-association interactions to scaffold the synaptic ribbon and its NAD(H)-sensing B-domain (identical to CtBP2) to recruit active-zone proteins (Bassoon, Munc119, ArfGAP3, Piccolino) and tether synaptic vesicles via redox-regulated lipid binding, while RIBEYE deletion in mice abolishes ribbons and severely impairs sustained neurotransmitter release.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0]. 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 [#8, #9]; cellular NAD-saturation and metabolite competition tune this oligomeric state, with malonyl-CoA driving a monomeric configuration [#10, #12]. 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 [#15, #17, #36, #41, #23]. 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 [#9, #24, #32], coactivates RAR/RXR and NEUROD1-dependent insulin transcription [#22, #34], 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 [#11, #12]. CtBP2 activity is further controlled post-translationally by p300 acetylation governing nuclear retention and by HIPK2/CDK7-regulated phosphorylation and proteasomal turnover [#7, #18, #14]. Ctbp2-null mice die in midgestation with axial patterning and extraembryonic defects, establishing an essential developmental role [#35]. 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 [#0, #1, #2, #3, #6, #42, #45]. 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 [#4, #5, #43].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"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.\",\n      \"evidence\": \"Partial purification of synaptic ribbons, protein identification, and NAD+ binding assay\",\n      \"pmids\": [\"11163272\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish how the A-domain assembles ribbons in vivo\", \"Functional role of NAD+ binding unresolved at this stage\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrated that CtBP2 is essential for embryonic development, moving the gene from an in vitro corepressor to an organismally required regulator with paralog redundancy.\",\n      \"evidence\": \"Ctbp1/Ctbp2 knockout mouse generation with embryological and transcriptional analysis\",\n      \"pmids\": [\"12101226\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific target genes driving the axial/extraembryonic phenotype not defined\", \"Degree of CtBP1 vs CtBP2 functional overlap quantitatively unresolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined the core recruitment mechanism by which CtBP2 is targeted to promoters: PXDLS-type motifs in transcription factors such as deltaEF1.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, Gal4 reporter, and PLDLSL motif mutagenesis\",\n      \"pmids\": [\"10567582\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the chromatin-modifying effectors recruited\", \"Generality of the motif across factors not yet shown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed that CtBP2 co-repressor activity is gated by NAD(H)-regulated homodimerization through its dehydrogenase-like fold, linking metabolic state to transcriptional output.\",\n      \"evidence\": \"Systematic mutagenesis of NAD-binding, substrate, and catalytic residues with transcriptional and dimerization assays\",\n      \"pmids\": [\"15037661\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Higher-order oligomeric state not resolved\", \"Whether NADH acts as a true cellular sensor not addressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Established post-translational control of CtBP2 localization, showing p300 acetylation of the unique N-terminal domain enforces nuclear retention and distinguishes CtBP2 from CtBP1.\",\n      \"evidence\": \"Acetylation assays, deletion mutagenesis, subcellular fractionation, and leptomycin B treatment\",\n      \"pmids\": [\"16356938\", \"16999872\", \"17023432\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological signals controlling acetylation in vivo unclear\", \"Functional consequences of cytoplasmic CtBP2 beyond reporter assays limited\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved how RIBEYE builds the ribbon scaffold and recruits active-zone machinery, mapping five self-association sites and NAD-regulated docking plus Munc119 recruitment.\",\n      \"evidence\": \"Yeast two-hybrid, pulldowns, coaggregation, EM, and point mutagenesis at the B-domain\",\n      \"pmids\": [\"18685021\", \"18664567\", \"15728193\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the assembled ribbon not determined\", \"How NAD regulation of A-B docking operates in vivo unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"evidence\": \"RNAi screen, ChIP, co-IP, and competition/proteasome-inhibitor assays\",\n      \"pmids\": [\"23775127\", \"23393140\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinants of the repressor-versus-coactivator switch not defined\", \"Single-lab findings for the CDK7/HIPK2 axis\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided definitive genetic proof that RIBEYE is required for ribbons and for fast/sustained release, linking ribbons mechanistically to Ca2+ nano-domain coupling.\",\n      \"evidence\": \"RIBEYE knockout mice with paired electrophysiology and EGTA buffering in retina slices\",\n      \"pmids\": [\"26929012\", \"21350006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of channel clustering by RIBEYE not fully resolved\", \"Contribution of B-domain redox sensing to release kinetics untested here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"Cryo-EM structures with tetramer-destabilizing mutants in migration and reporter assays\",\n      \"pmids\": [\"33264605\", \"34997967\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether tetramer-dimer equilibrium is dynamically signaled in cells unresolved\", \"Biophysics argues against simple NADH sensing, leaving the physiological metabolic input unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified CtBP2 as a hepatic metabolic switch sensing NADH and acyl-CoAs, repressing gluconeogenesis and lipogenesis and linking the corepressor directly to metabolic disease.\",\n      \"evidence\": \"Liver-specific knockout, metabolic phenotyping, in vitro metabolite binding, and structural pocket analysis\",\n      \"pmids\": [\"34728642\", \"37286039\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo concentrations of competing acyl-CoAs that switch activity not fully mapped\", \"Crosstalk with the tetramer/monomer equilibrium incompletely integrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"Genome-wide ChIP-seq, beta-cell-specific knockout, glucose tolerance, and chromatin accessibility analysis\",\n      \"pmids\": [\"37557182\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CtBP2 switches from repressor to chromatin-decompacting coactivator unresolved\", \"Effector recruited for chromatin opening at insulin locus not fully defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Proteomics, co-IP, and a competitive PLDLS-repeat inhibitor in vitro and in xenotransplant models\",\n      \"pmids\": [\"38748792\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide EVI1-CtBP target program not mapped\", \"Specificity of the competitive inhibitor across other PXDLS partners untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [8, 15, 34, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [15, 17, 41, 36]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2, 43]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [11, 12, 42]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [42]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7, 18, 34]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [8, 15, 34, 23]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [23, 34]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 4, 5]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [11, 12]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [35, 30, 31]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [41, 25, 24]}\n    ],\n    \"complexes\": [\n      \"synaptic ribbon\",\n      \"NuRD complex\",\n      \"CtBP2-p300 complex\"\n    ],\n    \"partners\": [\n      \"BSN\",\n      \"UNC119\",\n      \"ARFGAP3\",\n      \"ZEB1\",\n      \"EP300\",\n      \"HIPK2\",\n      \"NEUROD1\",\n      \"EVI1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}