{"gene":"CELF2","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2003,"finding":"CUGBP2/CELF2 binds AU-rich sequences (AREs) in the COX-2 3'UTR, stabilizes COX-2 mRNA, but simultaneously inhibits its translation; antisense suppression of CUGBP2 rendered radioprotection via a COX-2-dependent prostaglandin pathway, demonstrating in vivo translation inhibition activity.","method":"Nitrocellulose filter binding, UV cross-linking, chimeric luciferase-COX-2 3'UTR reporter assay, antisense knockdown in cells, in vivo radiation model","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (RNA binding, reporter assay, antisense KD, in vivo) in single study with strong mechanistic controls","pmids":["12535526"],"is_preprint":false},{"year":2001,"finding":"CUGBP2/CELF2 is a component of the apoB mRNA editing holoenzyme; it co-fractionates and co-immunoprecipitates with ACF and apobec-1, binds an AU-rich sequence upstream of the edited cytidine in apoB RNA, and dose-dependently inhibits C-to-U RNA editing in a reconstituted system.","method":"Co-fractionation, immunodepletion/co-precipitation, reconstituted editing system, recombinant protein addition, antisense knockout","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — reconstituted system plus reciprocal co-IP and functional antisense KO, multiple orthogonal methods","pmids":["11577082"],"is_preprint":false},{"year":2002,"finding":"ETR-3/CELF2 binds U/G motifs in conserved intronic muscle-specific elements (MSEs) flanking cardiac troponin T (cTNT) exon 5 and directly activates exon inclusion in vitro; this activation is antagonized by PTB, and dominant-negative mutants demonstrate that endogenous CELF and PTB activities compete for cell-type-specific splicing outcomes.","method":"In vitro splicing assay, dominant-negative mutants, co-transfection with cTNT minigene","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro splicing reconstitution plus dominant-negative genetics, strong mechanistic controls","pmids":["11931771"],"is_preprint":false},{"year":1999,"finding":"ETR-3/CELF2 binds (CUG)8 repeats and is expressed at high levels in heart; both CUG-BP and ETR-3 bind CUG repeats within ETR-3 mRNA itself, suggesting autoregulation of ETR-3 processing.","method":"RNA binding assays, RT-PCR, cDNA library screening, tissue distribution analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct RNA binding demonstrated but single lab, limited functional follow-up","pmids":["9887331"],"is_preprint":false},{"year":2004,"finding":"ETR-3/CELF2 protein contains a strong nuclear localization signal (NLS) overlapping the C-terminal RRM3, nuclear export activity in the divergent domain sensitive to leptomycin B (CRM1-dependent), and additional cytoplasmic localization regions in RRM1/2; the C-terminus and divergent domain are required for splicing activity.","method":"GFP fusion localization, deletion analysis, pyruvate kinase chimera, leptomycin B treatment, cotransfection splicing assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1-2 — systematic domain deletion with functional localization and splicing readouts, multiple orthogonal approaches","pmids":["15226369"],"is_preprint":false},{"year":2005,"finding":"ETR-3/CELF2 preferentially binds UG-rich sequences (UG repeats and UGUU motifs) as identified by SELEX; these motifs are sufficient to confer ETR-3 responsiveness to non-responsive splicing reporters in vivo, and ETR-3 regulates CFTR and MTMR1 alternative splicing via these binding sites.","method":"SELEX (5 rounds), minigene splicing reporters, site-directed mutagenesis of binding sites","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — SELEX identifies consensus binding sequence, validated by mutagenesis and reporter assays","pmids":["15657417"],"is_preprint":false},{"year":2004,"finding":"For ETR-3/CELF2, either RRM1 or RRM2 can independently bind MSE RNA; non-overlapping N- and C-terminal regions both activate MSE-dependent exon inclusion, demonstrating functional redundancy; for CELF4, RRM2 plus 66 amino acids of the divergent domain is sufficient for splicing activation.","method":"Comparative deletion analysis, RNA binding assays, cotransfection splicing assays with cTNT minigene","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — systematic deletion mutagenesis with functional splicing readouts","pmids":["14973222"],"is_preprint":false},{"year":2006,"finding":"CUGBP2/CELF2 and HuR bind COX-2 ARE with similar affinities and compete for binding; they heterodimerize in vitro (GST pulldown and yeast 2-hybrid), colocalize in the nucleus, shuttle between nucleus and cytoplasm, and CUGBP2 competitively inhibits HuR-mediated translation activation of COX-2 mRNA; after radiation, binding switches from HuR to CUGBP2.","method":"Nitrocellulose filter binding, UV cross-linking, GST pulldown, yeast 2-hybrid, immunocytochemistry, heterokaryon nucleocytoplasmic shuttling assay, chimeric luciferase reporter","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal protein interaction methods plus functional translation assay","pmids":["17383427"],"is_preprint":false},{"year":2008,"finding":"CUGBP2/CELF2 binds the Mcl-1 3'UTR (in vitro and in cells), stabilizes Mcl-1 mRNA but inhibits Mcl-1 mRNA translation, leading to reduced Mcl-1 protein and apoptosis during G2-M phase.","method":"RNA immunoprecipitation, chimeric luciferase-Mcl-1 3'UTR reporter, Western blot, flow cytometry, stable CELF2-expressing cell line","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 1-2 — RNA binding plus reporter assay plus functional cell biology with stable expression line","pmids":["18292181"],"is_preprint":false},{"year":2009,"finding":"CUGBP2/CELF2 splicing regulator binds GU-rich motifs at the boundaries (perimeter) of branch sites of the NI exon of NMDA R1 receptor; this perimeter-binding arrangement mechanistically blocks branchpoint formation to silence the exon, and CUGBP2 also autoregulates its own splicing by binding functionally significant motifs surrounding branch sites upstream of CUGBP2 exon 6.","method":"Chemical modification RNA footprinting, in vitro splicing assay, identification of novel target exons with similar motif configuration","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1 — chemical footprinting maps exact binding sites, mechanistic role in branchpoint formation demonstrated in vitro","pmids":["19680430"],"is_preprint":false},{"year":2010,"finding":"ETR-3/CELF2 strongly stimulates CFTR exon 9 skipping by functionally antagonizing U2AF65 binding to the polymorphic U-stretch; the divergent domain of ETR-3 (not present in CUG-BP1) is critical for this skipping activity, demonstrated by deletion and domain-swapping experiments.","method":"Minigene splicing assays, deletion mutants, domain-swapping between ETR-3 and CUG-BP1, competition with U2AF65","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — domain-swap and deletion mutagenesis identifies specific structural determinant, mechanistic competition with U2AF65 shown","pmids":["20631008"],"is_preprint":false},{"year":2011,"finding":"CELF2 directly activates LEF1 exon 6 inclusion by binding to two intronic sequences flanking the regulated exon; CELF2 knockdown reduces exon 6 inclusion, and blocking the exon 6 splice site reduces TCR-alpha mRNA expression, placing CELF2-regulated LEF1 splicing upstream of TCR-alpha expression.","method":"CELF2 knockdown, minigene reporters, CELF2 binding site mutation, TCR-alpha mRNA measurement","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — knockdown with defined molecular phenotype plus binding site mutation establishing pathway position","pmids":["21444716"],"is_preprint":false},{"year":2012,"finding":"miR-196a silences CELF2, and CELF2 directly acts on AR mRNA to enhance its stability; reducing CELF2 via miR-196a delivery decreases AR mRNA stability and ameliorates SBMA phenotypes in a mouse model.","method":"AAV-mediated miR-196a delivery in SBMA mice, CELF2 knockdown/overexpression, AR mRNA stability assay","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — in vivo mouse model with molecular mechanism (CELF2 stabilizes AR mRNA) established by gain/loss-of-function","pmids":["22660636"],"is_preprint":false},{"year":2012,"finding":"CUGBP2/CELF2 has isoform-specific functional consequences: alternative splicing produces a CUGBP2 R3δ isoform lacking part of RRM3; full-length and R3δ have similar effects on ACTN1 SM exon but opposite effects on insulin receptor exon 11 splicing; NMR and molecular dynamics reveal the R3δ third RRM is flexible and unstructured.","method":"Alternative splicing analysis, minigene splicing assays (ACTN1, insulin receptor), NMR spectroscopy, molecular dynamics simulation","journal":"BMC biochemistry","confidence":"High","confidence_rationale":"Tier 1 — NMR structure plus functional splicing assays demonstrates structure-function relationship","pmids":["22433174"],"is_preprint":false},{"year":2015,"finding":"CELF2 expression in T cells is induced by T-cell receptor signaling via NF-κB-dependent transcriptional induction within 6 h, followed by increased CELF2 mRNA stability linked to a change in 3'UTR length; signal-induced CELF2 expression controls dozens of downstream alternative splicing events during T-cell activation and thymic development.","method":"T-cell stimulation, NF-κB inhibitor, transcription inhibition, RNA stability assay, CELF2 knockdown with splicing RNA-seq, human thymus analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods establishing regulation mechanism and downstream functional consequences","pmids":["25870297"],"is_preprint":false},{"year":2015,"finding":"JNK signaling induces CELF2 expression during T-cell activation; CELF2 binds flanking intronic sequences to repress MKK7 exon 2 inclusion, generating an isoform with restored JNK-docking site that enhances JNK pathway activity (c-Jun phosphorylation, TNF-α upregulation), creating a positive feedback loop; ~25% of T-cell receptor-mediated alternative splicing events are JNK- and CELF2-dependent.","method":"JNK inhibitor, CELF2 knockdown, minigene reporters, CELF2 binding site analysis, c-Jun phosphorylation assay, RNA-seq","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis plus binding site analysis plus transcriptome-wide analysis establishes JNK-CELF2 feedback axis","pmids":["26443849"],"is_preprint":false},{"year":2016,"finding":"CLIP-Seq in human T cells demonstrates that CELF2 binding position relative to an exon predicts its effect on splicing: binding upstream promotes exon skipping while binding downstream promotes inclusion; this position-dependence is generalizable across cellular contexts (heart, brain, T cells).","method":"CLIP-Seq, comparison with known functional splicing targets, bioinformatic positional analysis","journal":"RNA biology","confidence":"High","confidence_rationale":"Tier 2 — genome-wide CLIP-Seq with functional validation across multiple targets establishes general position-dependence rule","pmids":["27096301"],"is_preprint":false},{"year":2017,"finding":"CELF2 and hnRNP C directly bind a cis-acting intronic element 340-440 nt upstream of TRAF3 exon 8 and together mediate activation-dependent exon skipping in T cells; CELF2 expression level is the decisive factor while hnRNP C is necessary but not sufficient; CELF2-mediated TRAF3 exon 8 skipping activates non-canonical NF-κB signaling.","method":"siRNA screen, cross-link immunoprecipitation (CLIP), mutational analysis of cis element, minigene with distance-alteration, correlation analysis across model systems","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — CLIP plus mutagenesis identifies binding site with distance-dependence, epistasis placing CELF2 upstream of NF-κB","pmids":["28031331"],"is_preprint":false},{"year":2019,"finding":"CELF2 controls alternative polyadenylation (APA) of its own mRNA and broadly in T cells by competing with core enhancers of the polyadenylation machinery for RNA binding; CELF2 binding overlaps with APA enhancers transcriptome-wide, and ~half of T-cell signaling-induced APA events are CELF2-dependent.","method":"CELF2 knockdown, 3'READS APA profiling, CELF2 CLIP-Seq overlap analysis, competition assay with polyadenylation factors","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — CLIP-seq plus transcriptome-wide APA profiling plus functional competition mechanism","pmids":["31509743"],"is_preprint":false},{"year":2019,"finding":"CELF2 restoration in breast cancer cells with CELF2 promoter hypermethylation has growth-inhibitory effects and restores normal alternative splicing patterns of ULK1 and CARD10; epigenetic silencing via promoter hypermethylation is a mechanism of CELF2 loss in cancer.","method":"Promoter methylation analysis, CELF2 restoration by demethylation/transfection, RNA splicing analysis of downstream targets, cell growth assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 — loss-of-function with defined splicing phenotype, epigenetic mechanism identified, single study","pmids":["31409895"],"is_preprint":false},{"year":2020,"finding":"CELF2 interacts with PREX2 protein and reduces PREX2-PTEN association, thereby upregulating PTEN phosphatase activity; CELF2 overexpression represses Akt phosphorylation and cell proliferation only in the presence of PTEN.","method":"Co-immunoprecipitation, PTEN phosphatase activity assay, CELF2/PREX2 interaction pulldown, Akt phosphorylation assay, PTEN-null cell controls, patient-derived xenograft (PDX) ex vivo","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP plus functional epistasis (PTEN-dependent effect) plus in vivo PDX, single lab","pmids":["31241130"],"is_preprint":false},{"year":2020,"finding":"CELF2 regulates CD44 alternative splicing (CD44s to CD44v conversion) in pancreatic cancer, and this is regulated upstream by ALKBH5-mediated m6A modification leading to CELF2 mRNA degradation via YTHDF2; CELF2-mediated CD44 splicing affects endoplasmic reticulum-associated degradation (ERAD) pathway activity.","method":"m6A modification assay, ALKBH5/YTHDF2 knockdown, CELF2 splicing reporter, RNA-seq of CD44 splicing, ERAD pathway inhibitor rescue","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2-3 — m6A writer/reader identified, splicing target shown, pathway placement via inhibitor, single lab","pmids":["35941702"],"is_preprint":false},{"year":2020,"finding":"CELF2 increases mRNA stability of Beclin-1, ATG5, and ATG12 (autophagy components) and promotes autophagic flux in colorectal cancer cells; CELF2 knockdown abrogates IR-induced autophagy both in vitro and in vivo.","method":"RNA stability assay, immunoblotting, immunofluorescence, autophagic vacuole and electron microscopy analysis, siRNA knockdown, xenograft model","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2-3 — RNA stability assay plus multiple functional autophagy readouts plus in vivo validation, single lab","pmids":["31020708"],"is_preprint":false},{"year":2020,"finding":"CELF2 increases stability of FAM198B mRNA by binding AU/U-rich elements in the FAM198B 3'UTR; CELF2-mediated FAM198B stabilization suppresses ovarian cancer progression via inhibiting MAPK/ERK signaling.","method":"RNA immunoprecipitation, 3'UTR reporter assay, mRNA stability assay, CELF2 knockdown/overexpression, FAM198B rescue experiment","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2-3 — RIP plus stability assay plus functional rescue, single lab","pmids":["33335801"],"is_preprint":false},{"year":2020,"finding":"CELF2 regulates TREM2 exon 3 alternative splicing; only CELF2 (not CELF1) reduces full-length TREM2 protein by promoting exon 3 skipping; a CELF-responsive sequence was mapped to intron 3 of human TREM2 using chimeric human-mouse minigenes.","method":"CELF1/CELF2 overexpression, siRNA knockdown, chimeric human/mouse TREM2 minigenes, Western blot for full-length TREM2","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — minigene mapping of responsive sequence plus protein level functional consequence","pmids":["33093587"],"is_preprint":false},{"year":2020,"finding":"hnRNP C and CELF2 reciprocally regulate each other's expression: loss of hnRNP C reduces CELF2 transcription, while loss of CELF2 decreases hnRNP C translation efficiency; this cross-regulation fine-tunes downstream splicing patterns.","method":"siRNA knockdown of each RBP, transcription assay, polysome fractionation/translation efficiency measurement, downstream splicing RNA-seq","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2-3 — reciprocal knockdown with mechanistically distinct readouts (transcription vs translation), single lab","pmids":["32338744"],"is_preprint":false},{"year":2020,"finding":"De novo CELF2 variants clustering in the C-terminal 20 amino acids (overlapping the nuclear localization signal) cause extranuclear mislocalization of CELF2 in transfected cells, demonstrating that the C-terminus is required for nuclear localization.","method":"Exome sequencing, expression of mutant CELF2 constructs in cells, immunofluorescence localization","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct localization experiment with mutant constructs, consistent with earlier domain studies","pmids":["33131106"],"is_preprint":false},{"year":2021,"finding":"CELF2 undergoes nucleocytoplasmic shuttling that is functionally linked to neural stem cell fate: in self-renewing NPCs CELF2 resides in the cytoplasm where it represses mRNAs encoding cell-fate regulators; translocation to the nucleus releases these mRNAs for translation and triggers NPC differentiation; de novo missense variants disrupting this shuttling cause cortical malformations.","method":"De novo variant identification, transgenic mouse NPC analysis, subcellular fractionation, CELF2 localization imaging, translational reporter assays, patient cortical malformation phenotype","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — subcellular localization directly linked to functional fate outcome in multiple systems (patient variants, mouse model, in vitro NPCs)","pmids":["34107259"],"is_preprint":false},{"year":2020,"finding":"In IL-10-treated macrophages, CELF2 association with pre-miR-155 increases; CRISPR-Cas9 knockdown of CELF2 impairs IL-10's ability to inhibit miR-155 expression and TNF-α expression, placing CELF2 in the IL-10 signaling pathway controlling pre-miR-155 maturation.","method":"RNA immunoprecipitation, CRISPR-Cas9 CELF2 knockdown, miR-155 and TNF-α expression assay, IL-10 treatment","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 — RIP plus CRISPR KD with defined molecular phenotype, single lab","pmids":["32324763"],"is_preprint":false},{"year":2024,"finding":"CELF2 deficiency in hematopoietic cells stabilizes FAT10 mRNA (shown by RIP-Seq) and promotes FAT10 translation, increasing AKT phosphorylation and mTORC1 signaling; loss of Celf2 in mice accelerates AML development in MLL-AF9 models.","method":"RIP-Seq, gene expression profiling, mTORC1 signaling assay, Celf2 conditional KO mice, MLL-AF9 AML model, rapamycin/EPZ-5676 combination treatment","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — RIP-Seq identifies direct mRNA target, in vivo mouse model with defined signaling pathway, pharmacological rescue","pmids":["38514854"],"is_preprint":false},{"year":2024,"finding":"CELF2 undergoes activity-dependent nucleocytoplasmic shuttling in excitatory neurons; cytoplasmic retention of CELF2 (caused by disease-associated variants) causes neuronal hyperexcitability and learning/memory deficits; cytoplasmic CELF2 regulates mRNAs critical for synaptic function; AKT signaling regulates CELF2 shuttling.","method":"iPSC-derived neurons from probands, transgenic mouse models, neuronal excitability recordings, drug screening identifying AKT as regulator, subcellular fractionation","journal":"medRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — multiple model systems (iPSC neurons + transgenic mice) with functional readouts, but preprint","pmids":["40666314"],"is_preprint":true},{"year":2024,"finding":"CELF2 hinge domain contains an intrinsically disordered region (IDR) that mediates CELF2 condensate formation; condensation is required for tau exon 10 splicing regulation; CELF2 co-condenses with NOVA2 and SFPQ to cooperatively regulate tau exon 10 inclusion; a conserved negatively charged residue D388 in the IDR is critical for condensate formation, protein-protein interactions, and splicing function.","method":"TurboID proximity labeling, IDR deletion/swap (with FUS/TAF15 IDRs), D388 mutagenesis, tau exon 10 splicing assay, CELF2 KO mouse brain, live-cell imaging of condensates","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 — mutagenesis plus IDR swap plus in vivo KO, strong mechanistic data but preprint status","pmids":["39553957"],"is_preprint":true},{"year":2024,"finding":"CELF2 binds AU-rich motifs in the CXCL5 3'UTR, reducing CXCL5 mRNA stability and thereby suppressing CXCL5/CXCR2/AKT signaling and bladder cancer cell proliferation and migration.","method":"RNA binding assay (RNA pulldown), mRNA stability assay, CELF2 overexpression/knockdown, AKT phosphorylation assay, cell functional assays, in vivo xenograft","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 — RNA pulldown plus stability assay plus pathway analysis, single lab","pmids":["40154776"],"is_preprint":false},{"year":2025,"finding":"CELF2 suppresses immunostimulatory endogenous double-stranded RNA ligands in macrophages; CELF2 depletion leads to spontaneous IFN and ISG induction dependent on RIG-I-MAVS pathway; RNA from CELF2-depleted cells can transfer IFN-inducing activity to naïve cells.","method":"CELF2 knockdown in macrophages, IFN/ISG expression assay, RIG-I/MAVS pathway inhibition, RNA transfer experiment, RNase III treatment, dsRNA immunoprecipitation","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods establishing novel innate immune function, but preprint","pmids":[],"is_preprint":true},{"year":2025,"finding":"CELF2 regulates STAT3 alternative splicing by binding UG-rich elements in intron 22 of STAT3 pre-mRNA, modulating the balance between STAT3α and STAT3β isoforms.","method":"Minigene splicing assay, cis-element identification by deletion, CELF2 overexpression, RNA binding to intron 22","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 — minigene plus binding site identification, single study","pmids":["39550869"],"is_preprint":false},{"year":2008,"finding":"CUGBP2/CELF2 variant 1 (but not variants 2 or 3) is predominantly nuclear and inhibits translation of COX-2 mRNA; variants 2 and 3 (with additional N-terminal sequences from alternative promoters) are predominantly cytoplasmic and do not induce G2/M arrest or apoptosis, demonstrating isoform-specific subcellular localization and function.","method":"Identification of splice variants, subcellular localization by immunocytochemistry, COX-2 3'UTR luciferase reporter, cell cycle analysis, apoptosis assays","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2-3 — isoform-specific localization linked to distinct functional phenotypes, single lab","pmids":["18258790"],"is_preprint":false},{"year":2013,"finding":"CUGBP2/CELF2 controls trafficking of COX-2 mRNA to cytoplasmic stress granules in cardiac H9c2 cells in response to pro-inflammatory stimuli; gene silencing experiments demonstrate this is a mechanism for maintaining homeostasis.","method":"Gene silencing, fluorescence microscopy, stress granule co-localization","journal":"Cell biology international","confidence":"Low","confidence_rationale":"Tier 3 — single lab, co-localization without deep mechanistic follow-up","pmids":["23661609"],"is_preprint":false},{"year":2021,"finding":"In spinal cord injury, GAS5 lncRNA recruits CELF2 to the coding region of VAV1 mRNA, increasing VAV1 mRNA stability and expression; GAS5 knockdown reduces CELF2-mediated VAV1 mRNA stabilization and alleviates oxidative stress and cell injury.","method":"RIP assay, mRNA stability assay, GAS5/CELF2 knockdown, OGD cell model, SCI rat model","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 — RIP identifies interaction, functional consequence shown but single lab","pmids":["33574559"],"is_preprint":false}],"current_model":"CELF2 (CUGBP2/ETR-3) is a nucleocytoplasmic RNA-binding protein that recognizes UG-rich and AU-rich sequence motifs through its three RRM domains; it regulates alternative splicing (by binding intronic elements in a position-dependent manner to activate or repress exon inclusion, mechanistically by blocking branchpoint formation or competing with other splicing factors such as PTB and U2AF65), mRNA stability (stabilizing transcripts including COX-2, Mcl-1, AR, and autophagy factors by binding their 3'UTRs), mRNA translation (inhibiting translation of stabilized targets such as COX-2 and Mcl-1 while competing with activators like HuR), alternative polyadenylation (by competing with polyadenylation machinery enhancers), and miRNA processing (regulating pre-miR-155 maturation and strand selection); its activity and localization are regulated by signal-dependent nucleocytoplasmic shuttling (controlled by an NLS in RRM3, CRM1-dependent nuclear export, and AKT signaling), alternative splicing of its own transcript, NF-κB- and JNK-dependent transcriptional induction, and epigenetic promoter methylation, with cytoplasmic CELF2 repressing mRNA translation in neural progenitors and nuclear CELF2 activating splicing programs in T cells and neurons."},"narrative":{"teleology":[{"year":1999,"claim":"Establishing CELF2 as a CUG-repeat-binding RNA-binding protein with high cardiac expression and potential autoregulatory capacity answered the initial question of whether CELF family members beyond CUG-BP1 existed with tissue-specific expression.","evidence":"RNA binding assays and tissue distribution analysis of ETR-3/CELF2","pmids":["9887331"],"confidence":"Medium","gaps":["No functional consequence of CUG-repeat binding demonstrated","Autoregulation inferred from binding but not tested functionally"]},{"year":2001,"claim":"Discovery that CELF2 is a component of the apoB mRNA editing holoenzyme and dose-dependently inhibits C-to-U editing revealed an unexpected role in RNA editing beyond splicing regulation.","evidence":"Co-fractionation, co-immunoprecipitation with ACF/apobec-1, and reconstituted editing assay","pmids":["11577082"],"confidence":"High","gaps":["Whether CELF2 regulates editing of other transcripts beyond apoB is unknown","Structural basis of editing inhibition not determined"]},{"year":2002,"claim":"Demonstrating that CELF2 directly activates exon inclusion via intronic UG-rich muscle-specific elements in competition with PTB established the paradigm that CELF2 and PTB antagonistically regulate tissue-specific splicing.","evidence":"In vitro splicing reconstitution with cTNT minigene plus dominant-negative mutants","pmids":["11931771"],"confidence":"High","gaps":["In vivo relevance in cardiac tissue not yet shown","Direct physical competition between CELF2 and PTB on the same RNA not resolved"]},{"year":2003,"claim":"The discovery that CELF2 simultaneously stabilizes COX-2 mRNA yet inhibits its translation established the dual mRNA stability/translational repression paradigm central to CELF2 cytoplasmic function.","evidence":"UV cross-linking, luciferase-COX-2 3′UTR reporter, antisense knockdown, in vivo radiation model","pmids":["12535526"],"confidence":"High","gaps":["Mechanism of translational inhibition not elucidated","Whether this dual activity applies to other targets was untested"]},{"year":2004,"claim":"Mapping the NLS to RRM3, CRM1-dependent nuclear export to the divergent domain, and cytoplasmic retention signals to RRM1/2 resolved how CELF2 achieves regulated nucleocytoplasmic distribution and linked domain architecture to splicing function.","evidence":"GFP fusion localization, systematic deletion analysis, leptomycin B treatment, cotransfection splicing assay","pmids":["15226369","14973222"],"confidence":"High","gaps":["Signal-dependent regulation of shuttling not identified","Which upstream kinases or pathways control localization was unknown"]},{"year":2005,"claim":"SELEX identification of UG-rich motifs as the CELF2 RNA binding consensus, validated by mutagenesis of CFTR and MTMR1 reporters, provided the sequence rules enabling transcriptome-wide target prediction.","evidence":"SELEX, minigene splicing reporters, site-directed mutagenesis","pmids":["15657417"],"confidence":"High","gaps":["Context-dependent binding preferences (structural RNA features) not addressed","Affinity measurements for different motif variants not determined"]},{"year":2007,"claim":"Demonstrating that CELF2 and HuR compete for COX-2 ARE binding with opposite translational outcomes, and that radiation shifts occupancy from HuR to CELF2, established a signal-responsive competitive binding model for translational control.","evidence":"Nitrocellulose filter binding, GST pulldown, yeast two-hybrid, heterokaryon shuttling assay, luciferase reporter","pmids":["17383427"],"confidence":"High","gaps":["Whether CELF2-HuR competition operates on other shared mRNA targets was untested","The signal transduction pathway mediating the switch was not identified"]},{"year":2008,"claim":"Extension of the dual stabilize-but-repress-translation mechanism to Mcl-1 mRNA, with consequent apoptosis during G2-M, generalized the paradigm beyond COX-2 and linked it to cell fate decisions.","evidence":"RNA immunoprecipitation, Mcl-1 3′UTR reporter, flow cytometry in stable CELF2-expressing cells","pmids":["18292181","18258790"],"confidence":"High","gaps":["Mechanism of translational repression still unresolved","Whether CELF2 recruits specific deadenylation or ribosome-stalling factors unknown"]},{"year":2009,"claim":"Chemical footprinting revealed that CELF2 binds GU-rich motifs at the perimeter of branchpoint sequences to block spliceosome assembly, providing the first direct mechanistic explanation for CELF2-mediated exon silencing and demonstrating autoregulation of its own exon 6.","evidence":"Chemical modification RNA footprinting, in vitro splicing with NMDA R1 NI exon and CELF2 exon 6","pmids":["19680430"],"confidence":"High","gaps":["Whether branchpoint blocking applies to all CELF2-silenced exons or only a subset is unknown","Structural basis of branchpoint occlusion not resolved"]},{"year":2010,"claim":"Domain-swap experiments showing that the divergent domain unique to CELF2 (not shared with CUG-BP1) is required for CFTR exon 9 skipping via competition with U2AF65 established paralog-specific functional determinants within the CELF family.","evidence":"Minigene splicing assays, ETR-3/CUG-BP1 domain swapping, U2AF65 competition","pmids":["20631008"],"confidence":"High","gaps":["Structural basis of divergent domain function not determined","Whether the divergent domain mediates all paralog-specific effects is untested"]},{"year":2012,"claim":"Identification that CELF2 stabilizes AR mRNA and that miR-196a-mediated CELF2 silencing ameliorates SBMA phenotypes in mice placed CELF2 in a disease-relevant mRNA stability pathway and demonstrated therapeutic potential of targeting CELF2 indirectly.","evidence":"AAV-mediated miR-196a delivery in SBMA mice, CELF2 gain/loss-of-function, AR mRNA stability assay","pmids":["22660636"],"confidence":"High","gaps":["Whether CELF2-AR mRNA interaction is direct (specific binding site) was not mapped","Contribution of CELF2 to AR mRNA stability in normal physiology unknown"]},{"year":2012,"claim":"NMR characterization of a CELF2 splice isoform (R3δ) lacking part of RRM3 revealed an unstructured, flexible third RRM with target-specific functional consequences (opposite effects on insulin receptor vs. ACTN1 splicing), demonstrating that alternative splicing of CELF2 itself tunes its regulatory output.","evidence":"NMR spectroscopy, molecular dynamics, minigene splicing assays for ACTN1 and insulin receptor","pmids":["22433174"],"confidence":"High","gaps":["Which isoform predominates in specific tissues/developmental stages was not determined","Crystal structure of full-length CELF2 remains unavailable"]},{"year":2015,"claim":"Establishing that TCR signaling induces CELF2 via NF-κB-dependent transcription followed by 3′UTR shortening-mediated mRNA stabilization, with CELF2 controlling dozens of downstream splicing events during T-cell activation and thymic development, defined CELF2 as a signal-responsive master splicing regulator in the immune system.","evidence":"T-cell stimulation with NF-κB inhibitor, transcription/stability assays, CELF2 knockdown with splicing RNA-seq, human thymus samples","pmids":["25870297"],"confidence":"High","gaps":["Direct NF-κB binding site in CELF2 promoter not mapped","Full T-cell splicing network architecture downstream of CELF2 not resolved"]},{"year":2015,"claim":"Discovery of a JNK→CELF2→MKK7 splicing→JNK positive feedback loop revealed that CELF2 amplifies T-cell activation signaling, with ~25% of TCR-mediated splicing events being JNK- and CELF2-dependent.","evidence":"JNK inhibitor, CELF2 knockdown, minigene reporters, c-Jun phosphorylation, RNA-seq","pmids":["26443849"],"confidence":"High","gaps":["How the feedback loop is terminated to prevent runaway signaling is unknown","Whether similar feedback operates in non-immune contexts untested"]},{"year":2016,"claim":"Genome-wide CLIP-Seq in T cells established the position-dependent splicing rule—upstream binding promotes skipping, downstream binding promotes inclusion—as a general principle across tissues (heart, brain, T cells), providing a predictive framework for CELF2 splicing regulation.","evidence":"CLIP-Seq in human T cells with bioinformatic positional analysis validated against known targets","pmids":["27096301"],"confidence":"High","gaps":["Exceptions to the positional rule not systematically catalogued","Whether position-dependence reflects distinct co-factor recruitment is unknown"]},{"year":2017,"claim":"Identification of CELF2 and hnRNP C as co-regulators binding a defined intronic element upstream of TRAF3 exon 8 demonstrated combinatorial splicing control, with CELF2 expression level as the rate-limiting factor controlling non-canonical NF-κB activation.","evidence":"siRNA screen, CLIP, cis-element mutagenesis with distance alteration, minigene reporters","pmids":["28031331"],"confidence":"High","gaps":["Whether CELF2-hnRNP C co-regulation extends beyond TRAF3 is partially addressed but incomplete","Structural basis of cooperative binding not determined"]},{"year":2019,"claim":"Revealing that CELF2 controls alternative polyadenylation by competing with polyadenylation machinery enhancers for RNA binding expanded CELF2's regulatory repertoire beyond splicing and translation to 3′ end processing, with ~half of T-cell signaling-induced APA events being CELF2-dependent.","evidence":"CELF2 knockdown, 3′READS APA profiling, CLIP-Seq overlap analysis, competition assay","pmids":["31509743"],"confidence":"High","gaps":["Which specific polyadenylation factors CELF2 competes with directly was not fully resolved","Functional consequences of individual APA events not characterized"]},{"year":2020,"claim":"Multiple studies expanded CELF2's mRNA stability targets (autophagy factors Beclin-1/ATG5/ATG12, FAM198B, CXCL5) and identified upstream regulation of CELF2 itself by m6A modification (ALKBH5/YTHDF2 axis), reciprocal regulation with hnRNP C, and promoter hypermethylation in cancer, building a picture of CELF2 as a broadly acting mRNA stability regulator under multilayered control.","evidence":"RNA stability assays, RIP, 3′UTR reporters, CELF2 overexpression/knockdown, m6A modification assays, polysome fractionation, promoter methylation analysis across multiple cancer cell systems","pmids":["31020708","33335801","35941702","32338744","31409895","40154776"],"confidence":"Medium","gaps":["Most mRNA stability targets characterized in single labs without independent replication","Relative contributions of splicing vs. stability regulation in cancer phenotypes not disentangled","Direct binding sites on most stability targets not mapped at nucleotide resolution"]},{"year":2020,"claim":"Studies of CELF2 in miRNA biology and non-canonical protein interactions revealed that CELF2 regulates pre-miR-155 maturation downstream of IL-10 in macrophages and interacts with PREX2 to relieve PTEN inhibition, extending CELF2 function to innate immune regulation and signaling pathway modulation.","evidence":"RIP for pre-miR-155, CRISPR-Cas9 CELF2 knockdown in macrophages, co-IP of CELF2-PREX2, PTEN phosphatase activity assay in PTEN-null controls","pmids":["32324763","31241130"],"confidence":"Medium","gaps":["Mechanism by which CELF2 binding affects pre-miR-155 processing not determined","CELF2-PREX2 interaction not independently confirmed","Whether CELF2 broadly regulates miRNA biogenesis or is specific to miR-155 is unknown"]},{"year":2021,"claim":"Linking CELF2 nucleocytoplasmic shuttling to neural progenitor fate decisions—cytoplasmic CELF2 represses translation to maintain self-renewal, nuclear translocation releases mRNAs for differentiation—and demonstrating that de novo variants disrupting shuttling cause cortical malformations established CELF2 as a critical regulator of brain development with direct disease relevance.","evidence":"De novo variant identification in patients, transgenic mouse NPC analysis, subcellular fractionation, translational reporter assays","pmids":["34107259"],"confidence":"High","gaps":["Identity of the full set of mRNAs repressed by cytoplasmic CELF2 in NPCs not catalogued","Whether cortical malformation phenotype is primarily due to splicing or translation defects is unresolved"]},{"year":2024,"claim":"Discovery that CELF2 loss stabilizes FAT10 mRNA and activates AKT/mTORC1 signaling to accelerate AML in mice established CELF2 as a tumor suppressor in hematopoietic malignancy through a defined mRNA target-signaling axis.","evidence":"RIP-Seq in hematopoietic cells, Celf2 conditional KO mice, MLL-AF9 AML model, rapamycin/EPZ-5676 rescue","pmids":["38514854"],"confidence":"High","gaps":["Whether CELF2 destabilizes or translationally represses FAT10 mRNA not fully distinguished","Contribution of other CELF2 targets to the AML phenotype not assessed"]},{"year":null,"claim":"Key unresolved questions include: the structural basis of CELF2's dual stabilize-but-repress-translation mechanism; how condensate formation via the intrinsically disordered hinge region integrates with splicing regulation in vivo; the full scope of CELF2's role in suppressing immunostimulatory dsRNA; and the precise kinase cascades controlling signal-dependent nucleocytoplasmic shuttling across different cell types.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of full-length CELF2 or CELF2-RNA complex","Condensate-dependent splicing regulation shown only in preprint, awaits peer review","dsRNA suppression function shown only in preprint, awaits independent confirmation","Complete upstream signaling pathway for CELF2 shuttling not mapped in any single system"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,2,3,5,7,8,9,16]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[1]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,8,29]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,7,8,20,28]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,26,27,35]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,27,35]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2,5,9,10,11,14,15,16,17,18]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[14,15,17,28]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,7,8,29]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[22]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[27]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[15,20,29]}],"complexes":["apoB mRNA editing holoenzyme"],"partners":["PTB","HUR","HNRNP C","U2AF65","ACF","APOBEC1","PREX2"],"other_free_text":[]},"mechanistic_narrative":"CELF2 is a multifunctional RNA-binding protein that coordinates post-transcriptional gene regulation through alternative splicing, mRNA stability control, translational repression, and alternative polyadenylation across diverse cell types including T cells, neurons, and macrophages. Its three RRM domains recognize UG-rich and AU-rich RNA elements, and it regulates alternative splicing in a position-dependent manner—binding upstream of an exon promotes skipping while binding downstream promotes inclusion—mechanistically by blocking branchpoint formation or competing with U2AF65 and PTB [PMID:27096301, PMID:19680430, PMID:11931771, PMID:20631008]. In the cytoplasm, CELF2 binds 3′UTR AU-rich elements to stabilize target mRNAs (COX-2, Mcl-1, AR, autophagy factors) while simultaneously inhibiting their translation, competing with the translational activator HuR [PMID:12535526, PMID:18292181, PMID:17383427]. Signal-dependent nucleocytoplasmic shuttling—controlled by an NLS in RRM3, CRM1-dependent export, and AKT signaling—serves as a functional switch: cytoplasmic CELF2 represses translation to maintain neural progenitor self-renewal, while nuclear translocation releases targets and activates splicing programs during T-cell activation and neuronal differentiation, and de novo variants disrupting this shuttling cause cortical malformations [PMID:34107259, PMID:15226369, PMID:25870297]."},"prefetch_data":{"uniprot":{"accession":"O95319","full_name":"CUGBP Elav-like family member 2","aliases":["Bruno-like protein 3","CUG triplet repeat RNA-binding protein 2","CUG-BP2","CUG-BP- and ETR-3-like factor 2","ELAV-type RNA-binding protein 3","ETR-3","Neuroblastoma apoptosis-related RNA-binding protein","hNAPOR","RNA-binding protein BRUNOL-3"],"length_aa":508,"mass_kda":54.3,"function":"RNA-binding protein implicated in the regulation of several post-transcriptional events. Involved in pre-mRNA alternative splicing, mRNA translation and stability. Mediates exon inclusion and/or exclusion in pre-mRNA that are subject to tissue-specific and developmentally regulated alternative splicing. Specifically activates exon 5 inclusion of TNNT2 in embryonic, but not adult, skeletal muscle. Activates TNNT2 exon 5 inclusion by antagonizing the repressive effect of PTB. Acts both as an activator and as a repressor of a pair of coregulated exons: promotes inclusion of the smooth muscle (SM) exon but exclusion of the non-muscle (NM) exon in actinin pre-mRNAs. Promotes inclusion of exonS 21 and exclusion of exon 5 of the NMDA receptor R1 pre-mRNA. Involved in the apoB RNA editing activity. Increases COX2 mRNA stability and inhibits COX2 mRNA translation in epithelial cells after radiation injury (By similarity). Modulates the cellular apoptosis program by regulating COX2-mediated prostaglandin E2 (PGE2) expression (By similarity). Binds to (CUG)n triplet repeats in the 3'-UTR of transcripts such as DMPK. Binds to the muscle-specific splicing enhancer (MSE) intronic sites flanking the TNNT2 alternative exon 5. Binds preferentially to UG-rich sequences, in particular UG repeat and UGUU motifs. Binds to apoB mRNA, specifically to AU-rich sequences located immediately upstream of the edited cytidine. Binds AU-rich sequences in the 3'-UTR of COX2 mRNA (By similarity). Binds to an intronic RNA element responsible for the silencing of exon 21 splicing (By similarity). Binds to (CUG)n repeats (By similarity). May be a specific regulator of miRNA biogenesis. Binds to primary microRNA pri-MIR140 and, with CELF1, negatively regulates the processing to mature miRNA (PubMed:28431233)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O95319/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CELF2","classification":"Not Classified","n_dependent_lines":12,"n_total_lines":1208,"dependency_fraction":0.009933774834437087},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CELF2","total_profiled":1310},"omim":[{"mim_id":"619561","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 97; DEE97","url":"https://www.omim.org/entry/619561"},{"mim_id":"602538","title":"CUGBP- AND ELAV-LIKE FAMILY, MEMBER 2; CELF2","url":"https://www.omim.org/entry/602538"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Midbody ring","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":73.5}],"url":"https://www.proteinatlas.org/search/CELF2"},"hgnc":{"alias_symbol":["Etr-3","NAPOR-2","BRUNOL3"],"prev_symbol":["CUGBP2"]},"alphafold":{"accession":"O95319","domains":[{"cath_id":"3.30.70.330","chopping":"39-120","consensus_level":"high","plddt":86.589,"start":39,"end":120},{"cath_id":"3.30.70.330","chopping":"125-213","consensus_level":"high","plddt":84.6512,"start":125,"end":213},{"cath_id":"3.30.70.330","chopping":"423-497","consensus_level":"high","plddt":88.5508,"start":423,"end":497}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95319","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95319-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95319-F1-predicted_aligned_error_v6.png","plddt_mean":64.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CELF2","jax_strain_url":"https://www.jax.org/strain/search?query=CELF2"},"sequence":{"accession":"O95319","fasta_url":"https://rest.uniprot.org/uniprotkb/O95319.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95319/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95319"}},"corpus_meta":[{"pmid":"21379329","id":"PMC_21379329","title":"Genome-wide association of familial late-onset Alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE.","date":"2011","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21379329","citation_count":202,"is_preprint":false},{"pmid":"12535526","id":"PMC_12535526","title":"Coupled mRNA stabilization and translational silencing of cyclooxygenase-2 by a novel RNA binding protein, CUGBP2.","date":"2003","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/12535526","citation_count":191,"is_preprint":false},{"pmid":"11931771","id":"PMC_11931771","title":"Dynamic antagonism between ETR-3 and PTB regulates cell type-specific alternative splicing.","date":"2002","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/11931771","citation_count":155,"is_preprint":false},{"pmid":"22660636","id":"PMC_22660636","title":"Viral delivery of miR-196a ameliorates the SBMA phenotype via the silencing of CELF2.","date":"2012","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22660636","citation_count":118,"is_preprint":false},{"pmid":"9887331","id":"PMC_9887331","title":"Cardiac elav-type RNA-binding protein (ETR-3) binds to RNA CUG repeats expanded in myotonic dystrophy.","date":"1999","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9887331","citation_count":97,"is_preprint":false},{"pmid":"11577082","id":"PMC_11577082","title":"Novel role for RNA-binding protein CUGBP2 in mammalian RNA editing. 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antisense suppression of CUGBP2 rendered radioprotection via a COX-2-dependent prostaglandin pathway, demonstrating in vivo translation inhibition activity.\",\n      \"method\": \"Nitrocellulose filter binding, UV cross-linking, chimeric luciferase-COX-2 3'UTR reporter assay, antisense knockdown in cells, in vivo radiation model\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (RNA binding, reporter assay, antisense KD, in vivo) in single study with strong mechanistic controls\",\n      \"pmids\": [\"12535526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CUGBP2/CELF2 is a component of the apoB mRNA editing holoenzyme; it co-fractionates and co-immunoprecipitates with ACF and apobec-1, binds an AU-rich sequence upstream of the edited cytidine in apoB RNA, and dose-dependently inhibits C-to-U RNA editing in a reconstituted system.\",\n      \"method\": \"Co-fractionation, immunodepletion/co-precipitation, reconstituted editing system, recombinant protein addition, antisense knockout\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstituted system plus reciprocal co-IP and functional antisense KO, multiple orthogonal methods\",\n      \"pmids\": [\"11577082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"ETR-3/CELF2 binds U/G motifs in conserved intronic muscle-specific elements (MSEs) flanking cardiac troponin T (cTNT) exon 5 and directly activates exon inclusion in vitro; this activation is antagonized by PTB, and dominant-negative mutants demonstrate that endogenous CELF and PTB activities compete for cell-type-specific splicing outcomes.\",\n      \"method\": \"In vitro splicing assay, dominant-negative mutants, co-transfection with cTNT minigene\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro splicing reconstitution plus dominant-negative genetics, strong mechanistic controls\",\n      \"pmids\": [\"11931771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"ETR-3/CELF2 binds (CUG)8 repeats and is expressed at high levels in heart; both CUG-BP and ETR-3 bind CUG repeats within ETR-3 mRNA itself, suggesting autoregulation of ETR-3 processing.\",\n      \"method\": \"RNA binding assays, RT-PCR, cDNA library screening, tissue distribution analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct RNA binding demonstrated but single lab, limited functional follow-up\",\n      \"pmids\": [\"9887331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ETR-3/CELF2 protein contains a strong nuclear localization signal (NLS) overlapping the C-terminal RRM3, nuclear export activity in the divergent domain sensitive to leptomycin B (CRM1-dependent), and additional cytoplasmic localization regions in RRM1/2; the C-terminus and divergent domain are required for splicing activity.\",\n      \"method\": \"GFP fusion localization, deletion analysis, pyruvate kinase chimera, leptomycin B treatment, cotransfection splicing assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — systematic domain deletion with functional localization and splicing readouts, multiple orthogonal approaches\",\n      \"pmids\": [\"15226369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ETR-3/CELF2 preferentially binds UG-rich sequences (UG repeats and UGUU motifs) as identified by SELEX; these motifs are sufficient to confer ETR-3 responsiveness to non-responsive splicing reporters in vivo, and ETR-3 regulates CFTR and MTMR1 alternative splicing via these binding sites.\",\n      \"method\": \"SELEX (5 rounds), minigene splicing reporters, site-directed mutagenesis of binding sites\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — SELEX identifies consensus binding sequence, validated by mutagenesis and reporter assays\",\n      \"pmids\": [\"15657417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"For ETR-3/CELF2, either RRM1 or RRM2 can independently bind MSE RNA; non-overlapping N- and C-terminal regions both activate MSE-dependent exon inclusion, demonstrating functional redundancy; for CELF4, RRM2 plus 66 amino acids of the divergent domain is sufficient for splicing activation.\",\n      \"method\": \"Comparative deletion analysis, RNA binding assays, cotransfection splicing assays with cTNT minigene\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic deletion mutagenesis with functional splicing readouts\",\n      \"pmids\": [\"14973222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CUGBP2/CELF2 and HuR bind COX-2 ARE with similar affinities and compete for binding; they heterodimerize in vitro (GST pulldown and yeast 2-hybrid), colocalize in the nucleus, shuttle between nucleus and cytoplasm, and CUGBP2 competitively inhibits HuR-mediated translation activation of COX-2 mRNA; after radiation, binding switches from HuR to CUGBP2.\",\n      \"method\": \"Nitrocellulose filter binding, UV cross-linking, GST pulldown, yeast 2-hybrid, immunocytochemistry, heterokaryon nucleocytoplasmic shuttling assay, chimeric luciferase reporter\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal protein interaction methods plus functional translation assay\",\n      \"pmids\": [\"17383427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CUGBP2/CELF2 binds the Mcl-1 3'UTR (in vitro and in cells), stabilizes Mcl-1 mRNA but inhibits Mcl-1 mRNA translation, leading to reduced Mcl-1 protein and apoptosis during G2-M phase.\",\n      \"method\": \"RNA immunoprecipitation, chimeric luciferase-Mcl-1 3'UTR reporter, Western blot, flow cytometry, stable CELF2-expressing cell line\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — RNA binding plus reporter assay plus functional cell biology with stable expression line\",\n      \"pmids\": [\"18292181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CUGBP2/CELF2 splicing regulator binds GU-rich motifs at the boundaries (perimeter) of branch sites of the NI exon of NMDA R1 receptor; this perimeter-binding arrangement mechanistically blocks branchpoint formation to silence the exon, and CUGBP2 also autoregulates its own splicing by binding functionally significant motifs surrounding branch sites upstream of CUGBP2 exon 6.\",\n      \"method\": \"Chemical modification RNA footprinting, in vitro splicing assay, identification of novel target exons with similar motif configuration\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — chemical footprinting maps exact binding sites, mechanistic role in branchpoint formation demonstrated in vitro\",\n      \"pmids\": [\"19680430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ETR-3/CELF2 strongly stimulates CFTR exon 9 skipping by functionally antagonizing U2AF65 binding to the polymorphic U-stretch; the divergent domain of ETR-3 (not present in CUG-BP1) is critical for this skipping activity, demonstrated by deletion and domain-swapping experiments.\",\n      \"method\": \"Minigene splicing assays, deletion mutants, domain-swapping between ETR-3 and CUG-BP1, competition with U2AF65\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — domain-swap and deletion mutagenesis identifies specific structural determinant, mechanistic competition with U2AF65 shown\",\n      \"pmids\": [\"20631008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CELF2 directly activates LEF1 exon 6 inclusion by binding to two intronic sequences flanking the regulated exon; CELF2 knockdown reduces exon 6 inclusion, and blocking the exon 6 splice site reduces TCR-alpha mRNA expression, placing CELF2-regulated LEF1 splicing upstream of TCR-alpha expression.\",\n      \"method\": \"CELF2 knockdown, minigene reporters, CELF2 binding site mutation, TCR-alpha mRNA measurement\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — knockdown with defined molecular phenotype plus binding site mutation establishing pathway position\",\n      \"pmids\": [\"21444716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"miR-196a silences CELF2, and CELF2 directly acts on AR mRNA to enhance its stability; reducing CELF2 via miR-196a delivery decreases AR mRNA stability and ameliorates SBMA phenotypes in a mouse model.\",\n      \"method\": \"AAV-mediated miR-196a delivery in SBMA mice, CELF2 knockdown/overexpression, AR mRNA stability assay\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo mouse model with molecular mechanism (CELF2 stabilizes AR mRNA) established by gain/loss-of-function\",\n      \"pmids\": [\"22660636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CUGBP2/CELF2 has isoform-specific functional consequences: alternative splicing produces a CUGBP2 R3δ isoform lacking part of RRM3; full-length and R3δ have similar effects on ACTN1 SM exon but opposite effects on insulin receptor exon 11 splicing; NMR and molecular dynamics reveal the R3δ third RRM is flexible and unstructured.\",\n      \"method\": \"Alternative splicing analysis, minigene splicing assays (ACTN1, insulin receptor), NMR spectroscopy, molecular dynamics simulation\",\n      \"journal\": \"BMC biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure plus functional splicing assays demonstrates structure-function relationship\",\n      \"pmids\": [\"22433174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CELF2 expression in T cells is induced by T-cell receptor signaling via NF-κB-dependent transcriptional induction within 6 h, followed by increased CELF2 mRNA stability linked to a change in 3'UTR length; signal-induced CELF2 expression controls dozens of downstream alternative splicing events during T-cell activation and thymic development.\",\n      \"method\": \"T-cell stimulation, NF-κB inhibitor, transcription inhibition, RNA stability assay, CELF2 knockdown with splicing RNA-seq, human thymus analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods establishing regulation mechanism and downstream functional consequences\",\n      \"pmids\": [\"25870297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"JNK signaling induces CELF2 expression during T-cell activation; CELF2 binds flanking intronic sequences to repress MKK7 exon 2 inclusion, generating an isoform with restored JNK-docking site that enhances JNK pathway activity (c-Jun phosphorylation, TNF-α upregulation), creating a positive feedback loop; ~25% of T-cell receptor-mediated alternative splicing events are JNK- and CELF2-dependent.\",\n      \"method\": \"JNK inhibitor, CELF2 knockdown, minigene reporters, CELF2 binding site analysis, c-Jun phosphorylation assay, RNA-seq\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis plus binding site analysis plus transcriptome-wide analysis establishes JNK-CELF2 feedback axis\",\n      \"pmids\": [\"26443849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CLIP-Seq in human T cells demonstrates that CELF2 binding position relative to an exon predicts its effect on splicing: binding upstream promotes exon skipping while binding downstream promotes inclusion; this position-dependence is generalizable across cellular contexts (heart, brain, T cells).\",\n      \"method\": \"CLIP-Seq, comparison with known functional splicing targets, bioinformatic positional analysis\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide CLIP-Seq with functional validation across multiple targets establishes general position-dependence rule\",\n      \"pmids\": [\"27096301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CELF2 and hnRNP C directly bind a cis-acting intronic element 340-440 nt upstream of TRAF3 exon 8 and together mediate activation-dependent exon skipping in T cells; CELF2 expression level is the decisive factor while hnRNP C is necessary but not sufficient; CELF2-mediated TRAF3 exon 8 skipping activates non-canonical NF-κB signaling.\",\n      \"method\": \"siRNA screen, cross-link immunoprecipitation (CLIP), mutational analysis of cis element, minigene with distance-alteration, correlation analysis across model systems\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — CLIP plus mutagenesis identifies binding site with distance-dependence, epistasis placing CELF2 upstream of NF-κB\",\n      \"pmids\": [\"28031331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CELF2 controls alternative polyadenylation (APA) of its own mRNA and broadly in T cells by competing with core enhancers of the polyadenylation machinery for RNA binding; CELF2 binding overlaps with APA enhancers transcriptome-wide, and ~half of T-cell signaling-induced APA events are CELF2-dependent.\",\n      \"method\": \"CELF2 knockdown, 3'READS APA profiling, CELF2 CLIP-Seq overlap analysis, competition assay with polyadenylation factors\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — CLIP-seq plus transcriptome-wide APA profiling plus functional competition mechanism\",\n      \"pmids\": [\"31509743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CELF2 restoration in breast cancer cells with CELF2 promoter hypermethylation has growth-inhibitory effects and restores normal alternative splicing patterns of ULK1 and CARD10; epigenetic silencing via promoter hypermethylation is a mechanism of CELF2 loss in cancer.\",\n      \"method\": \"Promoter methylation analysis, CELF2 restoration by demethylation/transfection, RNA splicing analysis of downstream targets, cell growth assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — loss-of-function with defined splicing phenotype, epigenetic mechanism identified, single study\",\n      \"pmids\": [\"31409895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CELF2 interacts with PREX2 protein and reduces PREX2-PTEN association, thereby upregulating PTEN phosphatase activity; CELF2 overexpression represses Akt phosphorylation and cell proliferation only in the presence of PTEN.\",\n      \"method\": \"Co-immunoprecipitation, PTEN phosphatase activity assay, CELF2/PREX2 interaction pulldown, Akt phosphorylation assay, PTEN-null cell controls, patient-derived xenograft (PDX) ex vivo\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP plus functional epistasis (PTEN-dependent effect) plus in vivo PDX, single lab\",\n      \"pmids\": [\"31241130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CELF2 regulates CD44 alternative splicing (CD44s to CD44v conversion) in pancreatic cancer, and this is regulated upstream by ALKBH5-mediated m6A modification leading to CELF2 mRNA degradation via YTHDF2; CELF2-mediated CD44 splicing affects endoplasmic reticulum-associated degradation (ERAD) pathway activity.\",\n      \"method\": \"m6A modification assay, ALKBH5/YTHDF2 knockdown, CELF2 splicing reporter, RNA-seq of CD44 splicing, ERAD pathway inhibitor rescue\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — m6A writer/reader identified, splicing target shown, pathway placement via inhibitor, single lab\",\n      \"pmids\": [\"35941702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CELF2 increases mRNA stability of Beclin-1, ATG5, and ATG12 (autophagy components) and promotes autophagic flux in colorectal cancer cells; CELF2 knockdown abrogates IR-induced autophagy both in vitro and in vivo.\",\n      \"method\": \"RNA stability assay, immunoblotting, immunofluorescence, autophagic vacuole and electron microscopy analysis, siRNA knockdown, xenograft model\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — RNA stability assay plus multiple functional autophagy readouts plus in vivo validation, single lab\",\n      \"pmids\": [\"31020708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CELF2 increases stability of FAM198B mRNA by binding AU/U-rich elements in the FAM198B 3'UTR; CELF2-mediated FAM198B stabilization suppresses ovarian cancer progression via inhibiting MAPK/ERK signaling.\",\n      \"method\": \"RNA immunoprecipitation, 3'UTR reporter assay, mRNA stability assay, CELF2 knockdown/overexpression, FAM198B rescue experiment\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — RIP plus stability assay plus functional rescue, single lab\",\n      \"pmids\": [\"33335801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CELF2 regulates TREM2 exon 3 alternative splicing; only CELF2 (not CELF1) reduces full-length TREM2 protein by promoting exon 3 skipping; a CELF-responsive sequence was mapped to intron 3 of human TREM2 using chimeric human-mouse minigenes.\",\n      \"method\": \"CELF1/CELF2 overexpression, siRNA knockdown, chimeric human/mouse TREM2 minigenes, Western blot for full-length TREM2\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — minigene mapping of responsive sequence plus protein level functional consequence\",\n      \"pmids\": [\"33093587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"hnRNP C and CELF2 reciprocally regulate each other's expression: loss of hnRNP C reduces CELF2 transcription, while loss of CELF2 decreases hnRNP C translation efficiency; this cross-regulation fine-tunes downstream splicing patterns.\",\n      \"method\": \"siRNA knockdown of each RBP, transcription assay, polysome fractionation/translation efficiency measurement, downstream splicing RNA-seq\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reciprocal knockdown with mechanistically distinct readouts (transcription vs translation), single lab\",\n      \"pmids\": [\"32338744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"De novo CELF2 variants clustering in the C-terminal 20 amino acids (overlapping the nuclear localization signal) cause extranuclear mislocalization of CELF2 in transfected cells, demonstrating that the C-terminus is required for nuclear localization.\",\n      \"method\": \"Exome sequencing, expression of mutant CELF2 constructs in cells, immunofluorescence localization\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct localization experiment with mutant constructs, consistent with earlier domain studies\",\n      \"pmids\": [\"33131106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CELF2 undergoes nucleocytoplasmic shuttling that is functionally linked to neural stem cell fate: in self-renewing NPCs CELF2 resides in the cytoplasm where it represses mRNAs encoding cell-fate regulators; translocation to the nucleus releases these mRNAs for translation and triggers NPC differentiation; de novo missense variants disrupting this shuttling cause cortical malformations.\",\n      \"method\": \"De novo variant identification, transgenic mouse NPC analysis, subcellular fractionation, CELF2 localization imaging, translational reporter assays, patient cortical malformation phenotype\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — subcellular localization directly linked to functional fate outcome in multiple systems (patient variants, mouse model, in vitro NPCs)\",\n      \"pmids\": [\"34107259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In IL-10-treated macrophages, CELF2 association with pre-miR-155 increases; CRISPR-Cas9 knockdown of CELF2 impairs IL-10's ability to inhibit miR-155 expression and TNF-α expression, placing CELF2 in the IL-10 signaling pathway controlling pre-miR-155 maturation.\",\n      \"method\": \"RNA immunoprecipitation, CRISPR-Cas9 CELF2 knockdown, miR-155 and TNF-α expression assay, IL-10 treatment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — RIP plus CRISPR KD with defined molecular phenotype, single lab\",\n      \"pmids\": [\"32324763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CELF2 deficiency in hematopoietic cells stabilizes FAT10 mRNA (shown by RIP-Seq) and promotes FAT10 translation, increasing AKT phosphorylation and mTORC1 signaling; loss of Celf2 in mice accelerates AML development in MLL-AF9 models.\",\n      \"method\": \"RIP-Seq, gene expression profiling, mTORC1 signaling assay, Celf2 conditional KO mice, MLL-AF9 AML model, rapamycin/EPZ-5676 combination treatment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RIP-Seq identifies direct mRNA target, in vivo mouse model with defined signaling pathway, pharmacological rescue\",\n      \"pmids\": [\"38514854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CELF2 undergoes activity-dependent nucleocytoplasmic shuttling in excitatory neurons; cytoplasmic retention of CELF2 (caused by disease-associated variants) causes neuronal hyperexcitability and learning/memory deficits; cytoplasmic CELF2 regulates mRNAs critical for synaptic function; AKT signaling regulates CELF2 shuttling.\",\n      \"method\": \"iPSC-derived neurons from probands, transgenic mouse models, neuronal excitability recordings, drug screening identifying AKT as regulator, subcellular fractionation\",\n      \"journal\": \"medRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple model systems (iPSC neurons + transgenic mice) with functional readouts, but preprint\",\n      \"pmids\": [\"40666314\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CELF2 hinge domain contains an intrinsically disordered region (IDR) that mediates CELF2 condensate formation; condensation is required for tau exon 10 splicing regulation; CELF2 co-condenses with NOVA2 and SFPQ to cooperatively regulate tau exon 10 inclusion; a conserved negatively charged residue D388 in the IDR is critical for condensate formation, protein-protein interactions, and splicing function.\",\n      \"method\": \"TurboID proximity labeling, IDR deletion/swap (with FUS/TAF15 IDRs), D388 mutagenesis, tau exon 10 splicing assay, CELF2 KO mouse brain, live-cell imaging of condensates\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis plus IDR swap plus in vivo KO, strong mechanistic data but preprint status\",\n      \"pmids\": [\"39553957\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CELF2 binds AU-rich motifs in the CXCL5 3'UTR, reducing CXCL5 mRNA stability and thereby suppressing CXCL5/CXCR2/AKT signaling and bladder cancer cell proliferation and migration.\",\n      \"method\": \"RNA binding assay (RNA pulldown), mRNA stability assay, CELF2 overexpression/knockdown, AKT phosphorylation assay, cell functional assays, in vivo xenograft\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — RNA pulldown plus stability assay plus pathway analysis, single lab\",\n      \"pmids\": [\"40154776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CELF2 suppresses immunostimulatory endogenous double-stranded RNA ligands in macrophages; CELF2 depletion leads to spontaneous IFN and ISG induction dependent on RIG-I-MAVS pathway; RNA from CELF2-depleted cells can transfer IFN-inducing activity to naïve cells.\",\n      \"method\": \"CELF2 knockdown in macrophages, IFN/ISG expression assay, RIG-I/MAVS pathway inhibition, RNA transfer experiment, RNase III treatment, dsRNA immunoprecipitation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods establishing novel innate immune function, but preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CELF2 regulates STAT3 alternative splicing by binding UG-rich elements in intron 22 of STAT3 pre-mRNA, modulating the balance between STAT3α and STAT3β isoforms.\",\n      \"method\": \"Minigene splicing assay, cis-element identification by deletion, CELF2 overexpression, RNA binding to intron 22\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — minigene plus binding site identification, single study\",\n      \"pmids\": [\"39550869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CUGBP2/CELF2 variant 1 (but not variants 2 or 3) is predominantly nuclear and inhibits translation of COX-2 mRNA; variants 2 and 3 (with additional N-terminal sequences from alternative promoters) are predominantly cytoplasmic and do not induce G2/M arrest or apoptosis, demonstrating isoform-specific subcellular localization and function.\",\n      \"method\": \"Identification of splice variants, subcellular localization by immunocytochemistry, COX-2 3'UTR luciferase reporter, cell cycle analysis, apoptosis assays\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — isoform-specific localization linked to distinct functional phenotypes, single lab\",\n      \"pmids\": [\"18258790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CUGBP2/CELF2 controls trafficking of COX-2 mRNA to cytoplasmic stress granules in cardiac H9c2 cells in response to pro-inflammatory stimuli; gene silencing experiments demonstrate this is a mechanism for maintaining homeostasis.\",\n      \"method\": \"Gene silencing, fluorescence microscopy, stress granule co-localization\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, co-localization without deep mechanistic follow-up\",\n      \"pmids\": [\"23661609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In spinal cord injury, GAS5 lncRNA recruits CELF2 to the coding region of VAV1 mRNA, increasing VAV1 mRNA stability and expression; GAS5 knockdown reduces CELF2-mediated VAV1 mRNA stabilization and alleviates oxidative stress and cell injury.\",\n      \"method\": \"RIP assay, mRNA stability assay, GAS5/CELF2 knockdown, OGD cell model, SCI rat model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — RIP identifies interaction, functional consequence shown but single lab\",\n      \"pmids\": [\"33574559\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CELF2 (CUGBP2/ETR-3) is a nucleocytoplasmic RNA-binding protein that recognizes UG-rich and AU-rich sequence motifs through its three RRM domains; it regulates alternative splicing (by binding intronic elements in a position-dependent manner to activate or repress exon inclusion, mechanistically by blocking branchpoint formation or competing with other splicing factors such as PTB and U2AF65), mRNA stability (stabilizing transcripts including COX-2, Mcl-1, AR, and autophagy factors by binding their 3'UTRs), mRNA translation (inhibiting translation of stabilized targets such as COX-2 and Mcl-1 while competing with activators like HuR), alternative polyadenylation (by competing with polyadenylation machinery enhancers), and miRNA processing (regulating pre-miR-155 maturation and strand selection); its activity and localization are regulated by signal-dependent nucleocytoplasmic shuttling (controlled by an NLS in RRM3, CRM1-dependent nuclear export, and AKT signaling), alternative splicing of its own transcript, NF-κB- and JNK-dependent transcriptional induction, and epigenetic promoter methylation, with cytoplasmic CELF2 repressing mRNA translation in neural progenitors and nuclear CELF2 activating splicing programs in T cells and neurons.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CELF2 is a multifunctional RNA-binding protein that coordinates post-transcriptional gene regulation through alternative splicing, mRNA stability control, translational repression, and alternative polyadenylation across diverse cell types including T cells, neurons, and macrophages. Its three RRM domains recognize UG-rich and AU-rich RNA elements, and it regulates alternative splicing in a position-dependent manner—binding upstream of an exon promotes skipping while binding downstream promotes inclusion—mechanistically by blocking branchpoint formation or competing with U2AF65 and PTB [PMID:27096301, PMID:19680430, PMID:11931771, PMID:20631008]. In the cytoplasm, CELF2 binds 3′UTR AU-rich elements to stabilize target mRNAs (COX-2, Mcl-1, AR, autophagy factors) while simultaneously inhibiting their translation, competing with the translational activator HuR [PMID:12535526, PMID:18292181, PMID:17383427]. Signal-dependent nucleocytoplasmic shuttling—controlled by an NLS in RRM3, CRM1-dependent export, and AKT signaling—serves as a functional switch: cytoplasmic CELF2 represses translation to maintain neural progenitor self-renewal, while nuclear translocation releases targets and activates splicing programs during T-cell activation and neuronal differentiation, and de novo variants disrupting this shuttling cause cortical malformations [PMID:34107259, PMID:15226369, PMID:25870297].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing CELF2 as a CUG-repeat-binding RNA-binding protein with high cardiac expression and potential autoregulatory capacity answered the initial question of whether CELF family members beyond CUG-BP1 existed with tissue-specific expression.\",\n      \"evidence\": \"RNA binding assays and tissue distribution analysis of ETR-3/CELF2\",\n      \"pmids\": [\"9887331\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional consequence of CUG-repeat binding demonstrated\", \"Autoregulation inferred from binding but not tested functionally\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Discovery that CELF2 is a component of the apoB mRNA editing holoenzyme and dose-dependently inhibits C-to-U editing revealed an unexpected role in RNA editing beyond splicing regulation.\",\n      \"evidence\": \"Co-fractionation, co-immunoprecipitation with ACF/apobec-1, and reconstituted editing assay\",\n      \"pmids\": [\"11577082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CELF2 regulates editing of other transcripts beyond apoB is unknown\", \"Structural basis of editing inhibition not determined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrating that CELF2 directly activates exon inclusion via intronic UG-rich muscle-specific elements in competition with PTB established the paradigm that CELF2 and PTB antagonistically regulate tissue-specific splicing.\",\n      \"evidence\": \"In vitro splicing reconstitution with cTNT minigene plus dominant-negative mutants\",\n      \"pmids\": [\"11931771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance in cardiac tissue not yet shown\", \"Direct physical competition between CELF2 and PTB on the same RNA not resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"The discovery that CELF2 simultaneously stabilizes COX-2 mRNA yet inhibits its translation established the dual mRNA stability/translational repression paradigm central to CELF2 cytoplasmic function.\",\n      \"evidence\": \"UV cross-linking, luciferase-COX-2 3′UTR reporter, antisense knockdown, in vivo radiation model\",\n      \"pmids\": [\"12535526\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of translational inhibition not elucidated\", \"Whether this dual activity applies to other targets was untested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Mapping the NLS to RRM3, CRM1-dependent nuclear export to the divergent domain, and cytoplasmic retention signals to RRM1/2 resolved how CELF2 achieves regulated nucleocytoplasmic distribution and linked domain architecture to splicing function.\",\n      \"evidence\": \"GFP fusion localization, systematic deletion analysis, leptomycin B treatment, cotransfection splicing assay\",\n      \"pmids\": [\"15226369\", \"14973222\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal-dependent regulation of shuttling not identified\", \"Which upstream kinases or pathways control localization was unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"SELEX identification of UG-rich motifs as the CELF2 RNA binding consensus, validated by mutagenesis of CFTR and MTMR1 reporters, provided the sequence rules enabling transcriptome-wide target prediction.\",\n      \"evidence\": \"SELEX, minigene splicing reporters, site-directed mutagenesis\",\n      \"pmids\": [\"15657417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Context-dependent binding preferences (structural RNA features) not addressed\", \"Affinity measurements for different motif variants not determined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating that CELF2 and HuR compete for COX-2 ARE binding with opposite translational outcomes, and that radiation shifts occupancy from HuR to CELF2, established a signal-responsive competitive binding model for translational control.\",\n      \"evidence\": \"Nitrocellulose filter binding, GST pulldown, yeast two-hybrid, heterokaryon shuttling assay, luciferase reporter\",\n      \"pmids\": [\"17383427\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CELF2-HuR competition operates on other shared mRNA targets was untested\", \"The signal transduction pathway mediating the switch was not identified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extension of the dual stabilize-but-repress-translation mechanism to Mcl-1 mRNA, with consequent apoptosis during G2-M, generalized the paradigm beyond COX-2 and linked it to cell fate decisions.\",\n      \"evidence\": \"RNA immunoprecipitation, Mcl-1 3′UTR reporter, flow cytometry in stable CELF2-expressing cells\",\n      \"pmids\": [\"18292181\", \"18258790\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of translational repression still unresolved\", \"Whether CELF2 recruits specific deadenylation or ribosome-stalling factors unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Chemical footprinting revealed that CELF2 binds GU-rich motifs at the perimeter of branchpoint sequences to block spliceosome assembly, providing the first direct mechanistic explanation for CELF2-mediated exon silencing and demonstrating autoregulation of its own exon 6.\",\n      \"evidence\": \"Chemical modification RNA footprinting, in vitro splicing with NMDA R1 NI exon and CELF2 exon 6\",\n      \"pmids\": [\"19680430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether branchpoint blocking applies to all CELF2-silenced exons or only a subset is unknown\", \"Structural basis of branchpoint occlusion not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Domain-swap experiments showing that the divergent domain unique to CELF2 (not shared with CUG-BP1) is required for CFTR exon 9 skipping via competition with U2AF65 established paralog-specific functional determinants within the CELF family.\",\n      \"evidence\": \"Minigene splicing assays, ETR-3/CUG-BP1 domain swapping, U2AF65 competition\",\n      \"pmids\": [\"20631008\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of divergent domain function not determined\", \"Whether the divergent domain mediates all paralog-specific effects is untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification that CELF2 stabilizes AR mRNA and that miR-196a-mediated CELF2 silencing ameliorates SBMA phenotypes in mice placed CELF2 in a disease-relevant mRNA stability pathway and demonstrated therapeutic potential of targeting CELF2 indirectly.\",\n      \"evidence\": \"AAV-mediated miR-196a delivery in SBMA mice, CELF2 gain/loss-of-function, AR mRNA stability assay\",\n      \"pmids\": [\"22660636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CELF2-AR mRNA interaction is direct (specific binding site) was not mapped\", \"Contribution of CELF2 to AR mRNA stability in normal physiology unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"NMR characterization of a CELF2 splice isoform (R3δ) lacking part of RRM3 revealed an unstructured, flexible third RRM with target-specific functional consequences (opposite effects on insulin receptor vs. ACTN1 splicing), demonstrating that alternative splicing of CELF2 itself tunes its regulatory output.\",\n      \"evidence\": \"NMR spectroscopy, molecular dynamics, minigene splicing assays for ACTN1 and insulin receptor\",\n      \"pmids\": [\"22433174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which isoform predominates in specific tissues/developmental stages was not determined\", \"Crystal structure of full-length CELF2 remains unavailable\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Establishing that TCR signaling induces CELF2 via NF-κB-dependent transcription followed by 3′UTR shortening-mediated mRNA stabilization, with CELF2 controlling dozens of downstream splicing events during T-cell activation and thymic development, defined CELF2 as a signal-responsive master splicing regulator in the immune system.\",\n      \"evidence\": \"T-cell stimulation with NF-κB inhibitor, transcription/stability assays, CELF2 knockdown with splicing RNA-seq, human thymus samples\",\n      \"pmids\": [\"25870297\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct NF-κB binding site in CELF2 promoter not mapped\", \"Full T-cell splicing network architecture downstream of CELF2 not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovery of a JNK→CELF2→MKK7 splicing→JNK positive feedback loop revealed that CELF2 amplifies T-cell activation signaling, with ~25% of TCR-mediated splicing events being JNK- and CELF2-dependent.\",\n      \"evidence\": \"JNK inhibitor, CELF2 knockdown, minigene reporters, c-Jun phosphorylation, RNA-seq\",\n      \"pmids\": [\"26443849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the feedback loop is terminated to prevent runaway signaling is unknown\", \"Whether similar feedback operates in non-immune contexts untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Genome-wide CLIP-Seq in T cells established the position-dependent splicing rule—upstream binding promotes skipping, downstream binding promotes inclusion—as a general principle across tissues (heart, brain, T cells), providing a predictive framework for CELF2 splicing regulation.\",\n      \"evidence\": \"CLIP-Seq in human T cells with bioinformatic positional analysis validated against known targets\",\n      \"pmids\": [\"27096301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Exceptions to the positional rule not systematically catalogued\", \"Whether position-dependence reflects distinct co-factor recruitment is unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of CELF2 and hnRNP C as co-regulators binding a defined intronic element upstream of TRAF3 exon 8 demonstrated combinatorial splicing control, with CELF2 expression level as the rate-limiting factor controlling non-canonical NF-κB activation.\",\n      \"evidence\": \"siRNA screen, CLIP, cis-element mutagenesis with distance alteration, minigene reporters\",\n      \"pmids\": [\"28031331\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CELF2-hnRNP C co-regulation extends beyond TRAF3 is partially addressed but incomplete\", \"Structural basis of cooperative binding not determined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealing that CELF2 controls alternative polyadenylation by competing with polyadenylation machinery enhancers for RNA binding expanded CELF2's regulatory repertoire beyond splicing and translation to 3′ end processing, with ~half of T-cell signaling-induced APA events being CELF2-dependent.\",\n      \"evidence\": \"CELF2 knockdown, 3′READS APA profiling, CLIP-Seq overlap analysis, competition assay\",\n      \"pmids\": [\"31509743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which specific polyadenylation factors CELF2 competes with directly was not fully resolved\", \"Functional consequences of individual APA events not characterized\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Multiple studies expanded CELF2's mRNA stability targets (autophagy factors Beclin-1/ATG5/ATG12, FAM198B, CXCL5) and identified upstream regulation of CELF2 itself by m6A modification (ALKBH5/YTHDF2 axis), reciprocal regulation with hnRNP C, and promoter hypermethylation in cancer, building a picture of CELF2 as a broadly acting mRNA stability regulator under multilayered control.\",\n      \"evidence\": \"RNA stability assays, RIP, 3′UTR reporters, CELF2 overexpression/knockdown, m6A modification assays, polysome fractionation, promoter methylation analysis across multiple cancer cell systems\",\n      \"pmids\": [\"31020708\", \"33335801\", \"35941702\", \"32338744\", \"31409895\", \"40154776\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Most mRNA stability targets characterized in single labs without independent replication\", \"Relative contributions of splicing vs. stability regulation in cancer phenotypes not disentangled\", \"Direct binding sites on most stability targets not mapped at nucleotide resolution\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Studies of CELF2 in miRNA biology and non-canonical protein interactions revealed that CELF2 regulates pre-miR-155 maturation downstream of IL-10 in macrophages and interacts with PREX2 to relieve PTEN inhibition, extending CELF2 function to innate immune regulation and signaling pathway modulation.\",\n      \"evidence\": \"RIP for pre-miR-155, CRISPR-Cas9 CELF2 knockdown in macrophages, co-IP of CELF2-PREX2, PTEN phosphatase activity assay in PTEN-null controls\",\n      \"pmids\": [\"32324763\", \"31241130\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CELF2 binding affects pre-miR-155 processing not determined\", \"CELF2-PREX2 interaction not independently confirmed\", \"Whether CELF2 broadly regulates miRNA biogenesis or is specific to miR-155 is unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linking CELF2 nucleocytoplasmic shuttling to neural progenitor fate decisions—cytoplasmic CELF2 represses translation to maintain self-renewal, nuclear translocation releases mRNAs for differentiation—and demonstrating that de novo variants disrupting shuttling cause cortical malformations established CELF2 as a critical regulator of brain development with direct disease relevance.\",\n      \"evidence\": \"De novo variant identification in patients, transgenic mouse NPC analysis, subcellular fractionation, translational reporter assays\",\n      \"pmids\": [\"34107259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the full set of mRNAs repressed by cytoplasmic CELF2 in NPCs not catalogued\", \"Whether cortical malformation phenotype is primarily due to splicing or translation defects is unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery that CELF2 loss stabilizes FAT10 mRNA and activates AKT/mTORC1 signaling to accelerate AML in mice established CELF2 as a tumor suppressor in hematopoietic malignancy through a defined mRNA target-signaling axis.\",\n      \"evidence\": \"RIP-Seq in hematopoietic cells, Celf2 conditional KO mice, MLL-AF9 AML model, rapamycin/EPZ-5676 rescue\",\n      \"pmids\": [\"38514854\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CELF2 destabilizes or translationally represses FAT10 mRNA not fully distinguished\", \"Contribution of other CELF2 targets to the AML phenotype not assessed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis of CELF2's dual stabilize-but-repress-translation mechanism; how condensate formation via the intrinsically disordered hinge region integrates with splicing regulation in vivo; the full scope of CELF2's role in suppressing immunostimulatory dsRNA; and the precise kinase cascades controlling signal-dependent nucleocytoplasmic shuttling across different cell types.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of full-length CELF2 or CELF2-RNA complex\", \"Condensate-dependent splicing regulation shown only in preprint, awaits peer review\", \"dsRNA suppression function shown only in preprint, awaits independent confirmation\", \"Complete upstream signaling pathway for CELF2 shuttling not mapped in any single system\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 2, 3, 5, 7, 8, 9, 16]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 8, 29]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 7, 8, 20, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 26, 27, 35]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 27, 35]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2, 5, 9, 10, 11, 14, 15, 16, 17, 18]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [14, 15, 17, 28]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 7, 8, 29]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [22]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [27]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [15, 20, 29]}\n    ],\n    \"complexes\": [\n      \"apoB mRNA editing holoenzyme\"\n    ],\n    \"partners\": [\n      \"PTB\",\n      \"HuR\",\n      \"hnRNP C\",\n      \"U2AF65\",\n      \"ACF\",\n      \"APOBEC1\",\n      \"PREX2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}