{"gene":"CELF2","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1999,"finding":"ETR-3 (CELF2) binds to CUG repeat sequences (CUG)8 in vitro; both CUG-BP and ETR-3 bind to ETR-3 mRNA via its own CUG repeats, suggesting autoregulatory RNA binding. ETR-3 is highly expressed in heart tissue.","method":"RNA binding assays with recombinant protein; RT-PCR tissue distribution analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct in vitro binding demonstrated, multiple tissues examined, single lab","pmids":["9887331"],"is_preprint":false},{"year":2001,"finding":"CUGBP2 (CELF2) is a component of the apolipoprotein B mRNA editing holoenzyme: it co-fractionates with ACF, co-immunoprecipitates with ACF, and co-localizes with ACF in the nucleus. CUGBP2 binds an AU-rich sequence upstream of the edited cytidine in apoB RNA. Recombinant CUGBP2 dose-dependently inhibits C-to-U RNA editing in a reconstituted system, and antisense knockdown of CUGBP2 increases endogenous apoB RNA editing.","method":"Co-immunoprecipitation; immunodepletion; co-localization by immunofluorescence; reconstituted in vitro editing assay with recombinant protein; antisense knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstituted in vitro assay with recombinant protein plus co-IP and knockdown, multiple orthogonal methods in one study","pmids":["11577082"],"is_preprint":false},{"year":2002,"finding":"ETR-3 (CELF2) binds UG/G motifs within conserved muscle-specific intronic elements (MSEs) flanking cardiac troponin T (cTNT) exon 5 and directly activates exon inclusion in vitro. ETR-3 binding and splicing activation are antagonized by PTB. Dominant-negative mutants demonstrate that endogenous CELF (including ETR-3) and PTB activities are required for MSE-dependent activation in muscle and repression in non-muscle cells, respectively.","method":"In vitro splicing assay; dominant-negative mutant cotransfection; RNA binding assays; minigene reporter","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro splicing reconstitution plus in vivo dominant-negative genetics, multiple orthogonal methods","pmids":["11931771"],"is_preprint":false},{"year":2003,"finding":"CUGBP2 (CELF2) binds two AU-rich sequences (AREs) in the first 60 nucleotides of the COX-2 3'UTR, stabilizes COX-2 mRNA, but simultaneously inhibits its translation. CUGBP2 is rapidly induced by ionizing radiation and translocates from nucleus to cytoplasm. Antisense suppression of CUGBP2 confers radioprotection through a COX-2-dependent prostaglandin pathway.","method":"UV cross-linking and nitrocellulose filter binding to demonstrate RNA binding; chimeric luciferase-COX-2 3'UTR reporter assay for mRNA stability and translation; antisense knockdown with phenotypic readout; immunofluorescence for localization","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro binding assays, reporter assay, antisense knockdown with in vivo phenotype, multiple orthogonal methods in single study","pmids":["12535526"],"is_preprint":false},{"year":2004,"finding":"ETR-3 (CELF2) contains a strong nuclear localization signal (NLS) overlapping the C-terminal RRM3 domain that can confer nuclear localization on a normally cytoplasmic pyruvate kinase chimera. The divergent domain contains both nuclear localization and CRM1-dependent nuclear export activities. The C-terminus and a region within the divergent domain are important for splicing activity. Cytoplasmic localization signals also reside in the first two RRMs.","method":"GFP fusion protein live imaging; deletion mutants and domain swapping; leptomycin B treatment; cotransfection with cTNT minigene for splicing activity","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiments with multiple deletion mutants, functional splicing validation, CRM1 dependency established by inhibitor, multiple orthogonal methods","pmids":["15226369"],"is_preprint":false},{"year":2004,"finding":"For ETR-3 (CELF2), either RRM1 or RRM2 alone are sufficient to bind MSE RNA; non-overlapping N-terminal (RRM1+RRM2) and C-terminal (RRM3 plus divergent domain segments) regions can each independently activate MSE-dependent exon inclusion in vivo, demonstrating functional redundancy between termini.","method":"Comparative deletion analysis; in vivo splicing cotransfection assay with cTNT minigene; RNA binding assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo splicing assays with multiple deletion mutants, single lab","pmids":["14973222"],"is_preprint":false},{"year":2005,"finding":"ETR-3 (CELF2) preferentially binds UG-rich sequences, particularly UG repeats and UGUU motifs, as determined by SELEX. These binding motifs restore ETR-3 responsiveness to a non-responsive splicing reporter in vivo. ETR-3 regulates CFTR and MTMR1 splicing in a manner dependent on identified SELEX binding sites.","method":"SELEX (5 rounds); minigene splicing assay; site-directed mutagenesis of SELEX motif","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — SELEX to define binding preference, validated with minigene mutagenesis and in vivo splicing assay, multiple orthogonal methods","pmids":["15657417"],"is_preprint":false},{"year":2006,"finding":"ETR-3 (CELF2) promotes exclusion of Tau exon 2 in cellular models with DM1-like splicing patterns, as demonstrated by ectopic expression. ETR-3 selectively represses Tau exon 2 inclusion.","method":"Ectopic expression in cellular models; RT-PCR splicing analysis","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single overexpression experiment, replicated across multiple transcripts and models","pmids":["16862542"],"is_preprint":false},{"year":2006,"finding":"CUGBP2 (CELF2) and HuR heterodimerize in vitro via GST pull-down and yeast 2-hybrid, and co-localize in the nucleus. Both proteins bind COX-2 ARE with similar affinities, but CUGBP2 competitively inhibits HuR binding. HuR enhances translation of chimeric COX-2 3'UTR mRNA, while CUGBP2 inhibits it. After irradiation, COX-2 mRNA binding switches from HuR to CUGBP2, coupled with increased translational silencing.","method":"GST pull-down; yeast 2-hybrid; nitrocellulose filter binding; UV cross-linking; immunocytochemistry; heterokaryon assay for nucleocytoplasmic shuttling; chimeric luciferase mRNA reporter assay","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal protein-protein and protein-RNA interaction methods, functional translation assay, mechanistic competition demonstrated","pmids":["17383427"],"is_preprint":false},{"year":2008,"finding":"CUGBP2 (CELF2) binds Mcl-1 3'UTR both in vitro and in cells (RIP). CUGBP2 stabilizes Mcl-1 mRNA and a luciferase-Mcl-1 3'UTR reporter, but inhibits translation of the Mcl-1 mRNA. Stable CUGBP2 expression drives cells to apoptosis during G2/M phase; decreased Bcl-2 and Mcl-1 protein (but not mRNA) levels confirm translational inhibition as the mechanism.","method":"RNA immunoprecipitation (RIP); in vitro RNA binding; luciferase reporter assay; Western blot; flow cytometry; stable overexpression cell line","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — RIP plus in vitro binding plus reporter assay, multiple orthogonal methods demonstrating both mRNA stabilization and translational inhibition","pmids":["18292181"],"is_preprint":false},{"year":2008,"finding":"CUGBP2 (CELF2) splice variants differ in subcellular localization: variant 1 is predominantly nuclear and inhibits COX-2 mRNA translation and induces apoptosis/mitotic catastrophe; variants 2 and 3 (with additional N-terminal residues) are predominantly cytoplasmic, bind COX-2 mRNA but do not inhibit its translation, and do not induce apoptosis or G2/M arrest.","method":"Immunocytochemistry; luciferase reporter assay; Western blot; flow cytometry; overexpression of splice variants in HCT116 cells","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization imaging plus functional reporter assay, single lab","pmids":["18258790"],"is_preprint":false},{"year":2009,"finding":"CUGBP2 (CELF2) regulates branchpoint formation during alternative splicing of the NMDA R1 NI exon: chemical modification footprinting maps CUGBP2 contact sites to GU-rich motifs at the perimeter of branch sites. This perimeter-binding model explains target exon specificity. CUGBP2 also autoregulates its own splicing via direct interaction with functionally significant RNA motifs surrounding branch sites upstream of CUGBP2 exon 6.","method":"Chemical modification footprinting; in vitro splicing assay; identification of novel target exons with similar branch-site perimeter motif configurations","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with footprinting to map precise binding sites and mechanistic role in branchpoint formation, single lab with multiple validated targets","pmids":["19680430"],"is_preprint":false},{"year":2010,"finding":"ETR-3 (CELF2), but not CUG-BP1, strongly stimulates CFTR exon 9 skipping. Both proteins bind the polymorphic UG(m)U(n) sequence with similar and higher affinity than TDP-43. The divergent domain of ETR-3 is critical for exon 9 skipping activity, as demonstrated by deletion and domain-swapping experiments. The mechanism involves functional antagonism between U2AF65 and ETR-3 binding to the polypyrimidine stretch.","method":"Minigene splicing assay; deletion and domain-swapping mutants; RNA binding assays; competition binding with U2AF65","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — domain-swapping mutagenesis plus in vivo splicing assay plus RNA binding, multiple orthogonal methods identifying divergent domain as the specificity determinant","pmids":["20631008"],"is_preprint":false},{"year":2011,"finding":"CELF2 overexpression reduces inclusion of Tau exon 10 (promotes skipping) in cellular models. Increased CELF2 expression was observed specifically in the brain of DM1 patients with exon 10 mis-splicing. This effect is independent of MBNL1 loss-of-function and CELF1 gain-of-function.","method":"Ectopic overexpression and siRNA knockdown of splicing factors; RT-PCR splicing analysis; patient brain tissue analysis","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — overexpression and siRNA in cell models with correlation in patient tissue, single lab","pmids":["21439371"],"is_preprint":false},{"year":2011,"finding":"CELF2 controls signal-induced and developmental alternative splicing of LEF1 exon 6 in T cells: CELF2 expression increases upon T-cell signaling and CELF2 binds two intronic sequences flanking the regulated exon to promote exon 6 inclusion. Knockdown of CELF2 reduces exon 6 inclusion, which in turn reduces TCR-alpha mRNA expression.","method":"RNA binding assays; CELF2 knockdown; minigene reporter; RT-PCR","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding demonstrated plus functional knockdown with downstream consequence, single lab","pmids":["21444716"],"is_preprint":false},{"year":2012,"finding":"miR-196a silences CELF2 expression; CELF2 directly acts on AR mRNA to enhance its stability, thereby promoting AR-polyQ protein expression that drives SBMA pathology. AAV-mediated delivery of miR-196a ameliorates SBMA phenotypes in a mouse model.","method":"miRNA overexpression via AAV vector; mRNA stability assay; Western blot; mouse model phenotyping","journal":"Nature medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model rescue plus direct mRNA stability measurement, but CELF2-AR mRNA interaction not validated by RIP/pulldown in this abstract","pmids":["22660636"],"is_preprint":false},{"year":2012,"finding":"Alternative splicing of CUGBP2 (CELF2) exon 14 produces an isoform (R3δ) that lacks the first half of RRM3. NMR spectrometry and molecular dynamics simulation show R3δ has a flexible, non-canonical third RRM structure. R3δ and full-length CUGBP2 have similar effects on ACTN1 SM exon inclusion but opposite effects on insulin receptor exon 11 skipping, demonstrating that structural changes in RRM3 alter splicing target specificity.","method":"NMR spectrometry; molecular dynamics simulation; minigene splicing assay; overexpression of isoforms","journal":"BMC biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — NMR structural analysis plus functional splicing assays, single lab","pmids":["22433174"],"is_preprint":false},{"year":2013,"finding":"In cardiac H9c2 cells, CUGBP2 (CELF2) controls subcellular trafficking of COX-2 mRNA to cytoplasmic stress granules in response to a pro-inflammatory stimulus; gene silencing of CUGBP2 disrupts this stress granule trafficking, revealing a role for CUGBP2 in RNA stress granule dynamics.","method":"Gene silencing; fluorescence microscopy of stress granules; cell biological assays","journal":"Cell biology international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, fluorescence microscopy with gene silencing, limited mechanistic depth in abstract","pmids":["23661609"],"is_preprint":false},{"year":2015,"finding":"CELF2 expression is induced by T-cell receptor signaling via NF-κB-dependent transcription (within 6 h) followed by increased stability of CELF2 mRNA correlating with a change in CELF2 3'UTR length via alternative polyadenylation. Increased CELF2 drives dozens of downstream alternative splicing events during T-cell activation and development.","method":"NF-κB inhibitor; promoter-reporter assays; mRNA stability assay (actinomycin D chase); 3'UTR APA analysis; splicing-sensitive arrays; siRNA knockdown","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (transcriptional reporter, mRNA stability, APA, splicing arrays), replicated in cultured T cells and human thymus","pmids":["25870297"],"is_preprint":false},{"year":2015,"finding":"JNK signaling induces CELF2 expression upon T-cell activation; CELF2 then binds flanking intronic sequences to repress MKK7 exon 2 inclusion, generating an isoform that restores a JNK-docking site and enhances JNK signaling (c-Jun phosphorylation, TNF-α upregulation). This creates a positive feedback loop: JNK promotes its own signaling via CELF2-dependent MKK7 splicing.","method":"JNK inhibitor; siRNA knockdown of CELF2; minigene reporter; RNA binding assay; phosphorylation assays; splicing-sensitive RT-PCR; RNA-seq","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (JNK inhibitor + CELF2 KD), RNA binding, reporter assay, functional signaling readout, multiple orthogonal methods","pmids":["26443849"],"is_preprint":false},{"year":2016,"finding":"CLIP-Seq analysis of CELF2 binding in T cells reveals a generalizable position-dependent activity rule: CELF2 binding downstream of an exon promotes skipping while binding upstream promotes inclusion, consistent with prior mechanistic studies and sufficient to explain CELF2's bidirectional splicing activity across T-cell targets.","method":"CLIP-Seq; comparison with functional splicing data from same cell line","journal":"RNA biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CLIP-Seq plus functional validation by comparison with known targets, single lab","pmids":["27096301"],"is_preprint":false},{"year":2017,"finding":"CELF2 and hnRNP C directly bind a cis-regulatory element 340–440 nt upstream of TRAF3 exon 8 (identified by siRNA screen + CLIP) and together mediate activation-dependent exon skipping in T cells. CELF2 expression level correlates with TRAF3 skipping; hnRNP C is necessary but not sufficient, while CELF2 is the decisive factor. Activity depends on precise distance of the intronic silencer from the regulated exon.","method":"siRNA screen; cross-link immunoprecipitation (CLIP); mutational analysis of cis-element; minigene reporter; RT-PCR correlation across model systems","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — CLIP plus mutagenesis plus siRNA screen, multiple orthogonal methods identifying both cis- and trans-acting elements","pmids":["28031331"],"is_preprint":false},{"year":2019,"finding":"CELF2 controls alternative polyadenylation (APA) of its own mRNA and of ~50% of T-cell signaling-induced APA events by competing with core polyadenylation enhancers (e.g., CPSF) for binding to RNA near polyadenylation sites. CELF2 binding overlaps transcriptome-wide with APA enhancer sites.","method":"CELF2 CLIP-Seq overlaid with APA enhancer maps; APA-seq; CELF2 knockdown; competition binding assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — CLIP-Seq plus APA-seq plus KD with functional APA readout, multiple orthogonal methods","pmids":["31509743"],"is_preprint":false},{"year":2019,"finding":"CELF2 (CELF2/CUGBP2) increases the stability of Beclin-1, ATG5, and ATG12 mRNAs by binding to them, thereby increasing autophagic flux. Silencing CELF2 abrogates ionizing radiation-induced autophagy in colorectal cancer cells and in xenograft models.","method":"RNA immunoprecipitation; mRNA stability assay; Western blot; autophagic vacuole analysis; electron microscopy; xenograft knockdown","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus mRNA stability assay plus functional autophagy readout, single lab","pmids":["31020708"],"is_preprint":false},{"year":2019,"finding":"CELF2 interacts with PREX2 protein (by co-immunoprecipitation), reducing the association of PREX2 with PTEN, thereby relieving PREX2-mediated inhibition of PTEN phosphatase activity. CELF2 overexpression represses Akt phosphorylation and cell proliferation in a PTEN-dependent manner.","method":"Co-immunoprecipitation; PTEN phosphatase activity assay; Western blot for p-Akt; PTEN-null cell controls; patient-derived xenograft","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus enzymatic assay plus genetic PTEN-dependency control, single lab","pmids":["31241130"],"is_preprint":false},{"year":2019,"finding":"CELF2 promoter is targeted by hypermethylation-associated transcriptional silencing in human breast cancer. Restoration of CELF2 expression has growth-inhibitory effects and corrects aberrant alternative splicing of ULK1 and CARD10.","method":"Methylation analysis; CELF2 re-expression; splicing analysis; growth assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epigenetic mechanism validated with re-expression rescue and splicing readout, single lab","pmids":["31409895"],"is_preprint":false},{"year":2020,"finding":"CELF2 regulates species-specific alternative splicing of TREM2 exon 3: overexpression of CELF2 promotes exon 3 skipping and reduces full-length TREM2 protein (via NMD). A CELF-responsive sequence was mapped to intron 3 of human TREM2 using chimeric human/mouse minigenes. This regulation is shared between humans and monkeys but not mice.","method":"Overexpression of CELF1/CELF2; chimeric minigene analysis; Western blot for full-length TREM2; panel of RNA-binding proteins","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — minigene chimera mutagenesis plus protein-level readout, single lab","pmids":["33093587"],"is_preprint":false},{"year":2020,"finding":"hnRNP C and CELF2 reciprocally regulate each other's expression: loss of hnRNP C reduces CELF2 mRNA transcription, while loss of CELF2 decreases hnRNP C translation efficiency. This cross-regulation fine-tunes splicing patterns of many downstream target genes.","method":"siRNA knockdown of each factor; mRNA and protein level measurements; translation efficiency assay; splicing-sensitive analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal knockdown with defined transcriptional and translational readouts, single lab, two orthogonal mechanistic levels","pmids":["32338744"],"is_preprint":false},{"year":2020,"finding":"CELF2 binds AU/U-rich elements (AREs) in the FAM198B 3'UTR to stabilize FAM198B mRNA. FAM198B knockdown reverses CELF2-mediated suppression of ovarian cancer cell proliferation and migration; the CELF2/FAM198B axis represses MAPK/ERK signaling.","method":"RNA binding assay (RIP); mRNA stability assay; FAM198B knockdown rescue experiments; Western blot for ERK signaling","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus functional rescue experiment plus signaling readout, single lab","pmids":["33335801"],"is_preprint":false},{"year":2020,"finding":"In self-renewing neural stem/progenitor cells (NPCs), CELF2 resides in the cytoplasm and represses mRNAs encoding cell fate regulators. Translocation of CELF2 into the nucleus releases these mRNAs for translation, triggering NPC differentiation. De novo missense variants in CELF2 disrupt nucleocytoplasmic transport, causing cortical malformations in humans and perturbing NPC fate decisions in mice.","method":"Live cell imaging; subcellular fractionation; iPSC-derived NPCs; mouse genetic model; RNA-seq; de novo variant functional characterization","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiments in NPCs, mouse genetic model, human variant functional validation, multiple orthogonal methods","pmids":["34107259"],"is_preprint":false},{"year":2020,"finding":"De novo CELF2 variants clustering in the C-terminal 20 amino acids (which include the nuclear localization signal overlapping RRM3) cause extranuclear mislocalization of CELF2 protein in transfected cells, establishing that these variants disrupt NLS function.","method":"Transfection of mutant CELF2 cDNA plasmids; subcellular localization assay; whole-exome sequencing of patients","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment with mutant protein, replicated across multiple variants","pmids":["33131106"],"is_preprint":false},{"year":2021,"finding":"CELF2 associates with pre-miR-155 in IL-10-treated macrophages (CRISPR-Cas9 KO of CELF2 impairs IL-10's ability to inhibit miR-155 expression and TNF-α expression), indicating CELF2 is required for IL-10-mediated inhibition of pre-miR-155 maturation.","method":"Co-immunoprecipitation/pulldown of pre-miR-155 with CELF2; CRISPR-Cas9 knockdown; RT-qPCR for miR-155 and TNF-α","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with functional miRNA and cytokine readouts plus RNA binding data, single lab","pmids":["32324763"],"is_preprint":false},{"year":2021,"finding":"In spinal cord injury models, GAS5 lncRNA recruits CELF2 protein to the coding region of VAV1 mRNA, resulting in increased VAV1 mRNA stability and expression. GAS5/CELF2-mediated VAV1 stabilization promotes oxidative stress and cell injury.","method":"RNA immunoprecipitation (RIP); mRNA stability assay; GAS5/VAV1 knockdown functional assays; rat SCI model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP demonstrates CELF2 binding to VAV1 mRNA in context of GAS5, functional rescue experiments, single lab","pmids":["33574559"],"is_preprint":false},{"year":2022,"finding":"N6-methyladenosine (m6A) modification of CELF2 mRNA is mediated by ALKBH5 demethylase; when m6A is present (ALKBH5 depleted), YTHDF2 binds CELF2 mRNA and promotes its degradation. CELF2 then regulates alternative splicing of CD44 (promoting CD44s over CD44V), affecting the ERAD signaling pathway.","method":"m6A sequencing; RIP for YTHDF2; splicing analysis; ALKBH5 manipulation; ERAD pathway inhibitor (EerI); transcriptomic analysis","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A writer/reader identified biochemically with functional splicing and signaling readout, single lab","pmids":["35941702"],"is_preprint":false},{"year":2024,"finding":"CELF2 deficiency in hematopoietic cells stabilizes FAT10 mRNA and promotes FAT10 translation, thereby activating AKT phosphorylation and mTORC1 signaling. This was established by gene expression profiling integrated with RIP-Seq (showing CELF2 binding to FAT10 mRNA), and combination therapy with mTORC1 inhibitor plus EPZ-5676 reduced leukemia burden in CELF2-deficient AML mice.","method":"RIP-Seq; RNA-seq; mouse AML model (MLL-AF9); mTORC1 inhibitor treatment; biochemical assays for AKT/mTORC1 phosphorylation","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP-Seq plus mouse model with targeted therapy, single lab","pmids":["38514854"],"is_preprint":false},{"year":2024,"finding":"CELF2 binds AU-rich motifs in the 3'UTR of CXCL5 mRNA, reducing CXCL5 mRNA stability, thereby inhibiting CXCL5/CXCR2/AKT signaling and suppressing bladder cancer cell proliferation and migration.","method":"RNA pull-down/RIP; mRNA stability assay; Western blot for p-AKT; proliferation and migration assays","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA binding plus mRNA stability assay plus signaling readout, single lab","pmids":["40154776"],"is_preprint":false},{"year":2024,"finding":"CELF2 promotes tau exon 10 inclusion (increasing 4R:3R ratio) in the mouse brain. The hinge domain of CELF2 contains an intrinsically disordered region (IDR) that drives CELF2 condensation in the nucleus and is required for splicing activity. The IDR can be functionally substituted by IDRs from FUS or TAF15. CELF2 co-condenses with NOVA2 and SFPQ, which cooperate with CELF2 to regulate tau exon 10 splicing. A conserved negatively charged residue D388 in the IDR is critical for condensate formation, NOVA2/SFPQ interactions, and tau exon 10 splicing function. Specific binding to the intron adjacent to tau exon 10 was demonstrated by TurboID proximity proteomics.","method":"Mouse brain CELF2 knockout; TurboID proximity labeling; in vitro condensation assay; IDR substitution mutants; D388 mutagenesis; co-immunoprecipitation of NOVA2/SFPQ; splicing analysis (4R:3R ratio)","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — reconstitution-level mechanistic study (condensation assay, mutagenesis, IDR swaps) but preprint, single lab","pmids":["39553957"],"is_preprint":true},{"year":2024,"finding":"CELF2 regulates alternative splicing of STAT3 pre-mRNA by binding UG-rich elements in intron 22, modulating the balance between STAT3α and STAT3β isoforms. Loss/gain-of-function experiments with CUGBP2/ETR-3 established it as a trans-acting splicing factor for STAT3.","method":"Cis-regulatory element mapping; overexpression/knockdown of CUGBP2; minigene reporter; RNA binding assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cis-element mapping plus functional splicing assay with gain/loss of function, single lab","pmids":["39550869"],"is_preprint":false},{"year":2025,"finding":"CELF2 depletion in macrophages leads to spontaneous type I interferon (IFN) and IFN-stimulated gene signature, dependent on the RIG-I–MAVS pathway. RNA from CELF2-depleted macrophages is sufficient to induce IFN in naïve cells; this immunostimulatory activity is double-stranded RNA (sensitive to RNase III). Immunoprecipitation of dsRNA from CELF2-depleted cells identifies specific immunostimulatory RNAs. Thus CELF2 suppresses endogenous dsRNA ligands that would otherwise activate RIG-I.","method":"CELF2 knockdown; IFN reporter assay; RNA transfer experiment; RNase III treatment; dsRNA immunoprecipitation; pathway inhibitors (RIG-I/MAVS)","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CELF2 KD with pathway-specific rescue, RNA transfer functional test, dsRNA biochemical validation, preprint, single lab","pmids":["bio_10.1101_2025.03.27.645787"],"is_preprint":true},{"year":2025,"finding":"CELF2 undergoes activity-dependent nucleocytoplasmic shuttling in excitatory neurons; cytoplasmic retention of CELF2 (due to disease variants) causes neuronal hyperexcitability and learning/memory deficits. AKT signaling was identified as a key regulator of CELF2 shuttling. In the cytoplasm, CELF2 regulates mRNAs critical for synaptic function and neuronal excitability.","method":"iPSC-derived neurons from patients with CELF2 variants; transgenic mouse models; drug screening (AKT inhibitors/activators); electrophysiology; behavioral tests; RNA-seq","journal":"medRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — iPSC neurons plus transgenic mice plus drug rescue, multiple models, preprint","pmids":["40666314"],"is_preprint":true},{"year":2026,"finding":"CELF2 is required for normal neuronal maturation and cortical architecture: CELF2 knockout causes neonatal lethality with impaired neuronal maturation and disrupted cortical organization. CELF2 binds the Camk2a 3'UTR to regulate Camk2a mRNA levels; loss of CELF2 markedly reduces CaMK2A transcript and protein. Expression of human CAMK2A partially rescues synaptic puncta deficits in C. elegans unc-75 (CELF ortholog) mutants. CELF2 loss reduces exon inclusion in multiple neurodevelopmental transcripts (RNA splicing) and selectively depletes upper layer II/III excitatory neurons.","method":"Constitutive Celf2 knockout mouse; bulk RNA-seq; splicing analysis; snRNA-seq; CaMK2A 3'UTR binding; C. elegans genetic rescue; histological and pseudotime analyses","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse model plus cross-species genetic rescue plus 3'UTR binding, multiple orthogonal approaches, single lab","pmids":["42189331"],"is_preprint":false}],"current_model":"CELF2 (ETR-3/CUGBP2) is a nucleocytoplasmic shuttling RNA-binding protein that recognizes UG-rich and AU-rich sequences via its three RRM domains; in the nucleus it regulates alternative splicing (activating or repressing exon inclusion depending on its binding position relative to the regulated exon, through mechanisms including branch-site occlusion and condensate formation via an IDR in its hinge domain with co-factors NOVA2/SFPQ), and in the cytoplasm it simultaneously stabilizes target mRNAs (COX-2, Mcl-1, FAM198B, CXCL5, Camk2a, autophagy mRNAs) while inhibiting their translation; it also controls alternative polyadenylation by competing with core polyadenylation enhancers, participates in apoB mRNA C-to-U editing as a regulatory subunit of the apobec-1 holoenzyme, suppresses endogenous dsRNA ligands to prevent RIG-I-mediated interferon induction, and its subcellular localization—regulated by NLS signals in RRM3, CRM1-dependent nuclear export, AKT signaling, and signal-induced transcriptional/mRNA stability changes downstream of NF-κB and JNK—determines whether it promotes stem cell self-renewal or differentiation in neural progenitors and T cells."},"narrative":{"mechanistic_narrative":"CELF2 (ETR-3/CUGBP2) is a nucleocytoplasmic shuttling RNA-binding protein that governs gene expression at the levels of alternative splicing, mRNA stability/translation, and polyadenylation through recognition of UG-rich and AU-rich elements via its three RRM domains [PMID:9887331, PMID:15657417]. In the nucleus, CELF2 acts as a position-dependent splicing regulator: binding upstream of a regulated exon promotes inclusion while binding downstream promotes skipping, a rule that explains its bidirectional activity across diverse targets including cardiac troponin T, CFTR, NMDA R1, Tau, LEF1, MKK7, TRAF3, TREM2, and STAT3 [PMID:11931771, PMID:15657417, PMID:19680430, PMID:20631008, PMID:21444716, PMID:26443849, PMID:27096301, PMID:28031331]. Mechanistically it operates through branch-site perimeter occupancy, functional antagonism with U2AF65 and PTB, and condensate formation driven by an intrinsically disordered region in its hinge domain that recruits co-factors NOVA2 and SFPQ [PMID:11931771, PMID:19680430, PMID:20631008, PMID:39553957]. In the cytoplasm CELF2 binds AU-rich elements to control mRNA fate, frequently uncoupling stability from translation—it stabilizes yet translationally silences COX-2 and Mcl-1 mRNAs, switching binding with HuR after irradiation [PMID:12535526, PMID:17383427, PMID:18292181]—while in other contexts it stabilizes (FAM198B, autophagy mRNAs, Camk2a) or destabilizes (CXCL5) target transcripts to tune proliferation, autophagy, and neuronal signaling [PMID:31020708, PMID:33335801, PMID:40154776, PMID:42189331]. CELF2 additionally controls alternative polyadenylation by competing with core polyadenylation enhancers, serves as a regulatory subunit of the apoB mRNA C-to-U editing holoenzyme, and suppresses endogenous double-stranded RNA ligands that would otherwise trigger RIG-I-dependent interferon induction [PMID:11577082, PMID:31509743, PMID:bio_10.1101_2025.03.27.645787]. Its subcellular partitioning is the master switch over its activity: an NLS overlapping RRM3, CRM1-dependent export, and AKT signaling direct shuttling, and de novo variants disrupting the C-terminal NLS cause extranuclear mislocalization, cortical malformations, and neuronal hyperexcitability with learning and memory deficits in humans [PMID:15226369, PMID:34107259, PMID:33131106, PMID:40666314]. Consistent with this, CELF2 is required for neuronal maturation and cortical architecture, with knockout causing neonatal lethality [PMID:42189331].","teleology":[{"year":1999,"claim":"Establishing that CELF2 is a sequence-specific RNA-binding protein answered the foundational question of its molecular activity and hinted at autoregulation.","evidence":"in vitro RNA binding assays with recombinant protein and RT-PCR tissue profiling","pmids":["9887331"],"confidence":"Medium","gaps":["No cellular function assigned","Binding specificity beyond CUG repeats not defined"]},{"year":2001,"claim":"Identifying CELF2 as a regulatory subunit of the apoB editing holoenzyme showed it acts beyond splicing, modulating C-to-U RNA editing.","evidence":"co-IP, immunodepletion, reconstituted in vitro editing assay, and antisense knockdown","pmids":["11577082"],"confidence":"High","gaps":["Structural basis of ACF interaction unknown","Generality of editing regulation to other substrates untested"]},{"year":2002,"claim":"Demonstrating direct activation of cTNT exon 5 inclusion antagonized by PTB defined CELF2 as a genuine alternative splicing regulator with combinatorial control.","evidence":"in vitro splicing reconstitution, dominant-negative genetics, minigene reporters","pmids":["11931771"],"confidence":"High","gaps":["How position relative to exon dictates activate-versus-repress not yet established"]},{"year":2005,"claim":"SELEX defined UG-rich/UGUU binding preference and mapped functional binding sites, providing the cis-code for target prediction.","evidence":"SELEX with minigene splicing validation and motif mutagenesis (CFTR, MTMR1)","pmids":["15657417"],"confidence":"High","gaps":["Distinction between UG-rich splicing motifs and AU-rich stability motifs not unified"]},{"year":2004,"claim":"Mapping an NLS overlapping RRM3 plus CRM1-dependent export and redundant RRM activities explained how localization and modular domains control splicing function.","evidence":"GFP fusion imaging, deletion/domain swaps, leptomycin B, cTNT minigene assays","pmids":["15226369","14973222"],"confidence":"High","gaps":["Upstream signals controlling shuttling not identified at this stage"]},{"year":2003,"claim":"Showing CELF2 stabilizes COX-2 mRNA while silencing its translation, with radiation-induced nuclear-to-cytoplasmic relocation, revealed its dual cytoplasmic post-transcriptional role.","evidence":"UV cross-linking, luciferase-3'UTR reporters, antisense knockdown with radioprotection phenotype","pmids":["12535526","17383427"],"confidence":"High","gaps":["Molecular basis of translational silencing decoupled from stabilization unresolved"]},{"year":2009,"claim":"Branch-site perimeter footprinting provided a mechanistic explanation for target exon specificity and confirmed CELF2 autoregulates its own splicing.","evidence":"chemical modification footprinting and in vitro splicing on NMDA R1 and CUGBP2 exon 6","pmids":["19680430"],"confidence":"High","gaps":["Whether perimeter binding generalizes to all targets untested transcriptome-wide"]},{"year":2010,"claim":"Pinpointing the divergent domain as the specificity determinant and U2AF65 competition clarified how CELF2 represses exon inclusion.","evidence":"domain-swapping mutagenesis, minigene splicing, U2AF65 competition binding (CFTR exon 9)","pmids":["20631008"],"confidence":"High","gaps":["Direct structural contacts with the spliceosome not resolved"]},{"year":2015,"claim":"Linking TCR signaling to CELF2 induction via NF-kB transcription and APA-mediated mRNA stabilization, plus a JNK/MKK7 feedback loop, embedded CELF2 in signal-responsive splicing programs.","evidence":"NF-kB and JNK inhibitors, promoter reporters, mRNA stability and APA analysis, splicing arrays, minigene reporters in T cells","pmids":["25870297","26443849"],"confidence":"High","gaps":["Full set of physiologically relevant downstream targets incompletely defined"]},{"year":2016,"claim":"Transcriptome-wide CLIP established the generalizable position-dependent rule that resolved CELF2's bidirectional splicing behavior.","evidence":"CLIP-Seq integrated with functional splicing data in T cells","pmids":["27096301"],"confidence":"Medium","gaps":["Exceptions to the position rule and cofactor dependence not fully cataloged"]},{"year":2017,"claim":"Showing CELF2 and hnRNP C jointly act on a distance-sensitive intronic silencer at TRAF3 defined combinatorial, geometry-dependent splicing control.","evidence":"siRNA screen, CLIP, cis-element mutagenesis, minigene reporters","pmids":["28031331"],"confidence":"High","gaps":["Biophysical basis of distance dependence unknown"]},{"year":2019,"claim":"Demonstrating CELF2 competes with CPSF-type polyadenylation enhancers extended its regulatory reach to alternative polyadenylation transcriptome-wide.","evidence":"CLIP-Seq overlaid with APA enhancer maps, APA-seq, knockdown","pmids":["31509743"],"confidence":"High","gaps":["Direct biochemical competition with CPSF not reconstituted"]},{"year":2021,"claim":"Identifying the IDR-driven nuclear condensation with NOVA2/SFPQ and a critical D388 residue revealed a phase-separation mechanism underlying splicing activity (e.g., tau exon 10).","evidence":"TurboID proximity proteomics, in vitro condensation, IDR-swap and D388 mutagenesis, NOVA2/SFPQ co-IP, mouse brain knockout (preprint)","pmids":["39553957"],"confidence":"Medium","gaps":["Preprint, single lab","In vivo relevance of condensation across other targets untested"]},{"year":2021,"claim":"Linking CELF2 localization to cell-fate decisions in neural progenitors and disease showed that nucleocytoplasmic partitioning is the functional switch, with NLS variants causing human cortical malformation.","evidence":"iPSC-derived NPCs, mouse genetic model, RNA-seq, de novo variant transfection/localization assays","pmids":["34107259","33131106"],"confidence":"High","gaps":["Signals that drive physiological NPC translocation not fully defined here"]},{"year":2025,"claim":"Implicating AKT signaling in activity-dependent neuronal shuttling and showing CELF2 suppresses endogenous dsRNA RIG-I ligands extended the localization-switch and immune-surveillance models.","evidence":"iPSC neurons, transgenic mice, AKT inhibitor/activator screen, electrophysiology (preprint); CELF2 knockdown, RNA transfer, RNase III, dsRNA IP, RIG-I/MAVS inhibitors (preprint)","pmids":["40666314","bio_10.1101_2025.03.27.645787"],"confidence":"Medium","gaps":["Both preprints, single labs","Identity of the suppressed dsRNA ligands incompletely defined"]},{"year":2026,"claim":"Demonstrating that CELF2 is required for neuronal maturation and cortical architecture, acting partly through Camk2a mRNA regulation, established its organismal necessity.","evidence":"constitutive Celf2 knockout mouse, RNA-seq, snRNA-seq, Camk2a 3'UTR binding, C. elegans unc-75 cross-species rescue","pmids":["42189331"],"confidence":"Medium","gaps":["Relative contribution of splicing versus mRNA-stability roles to phenotype unresolved"]},{"year":null,"claim":"How CELF2 integrates its multiple molecular activities (splicing, APA, mRNA stability/translation, editing, dsRNA suppression) into a single coherent decision per cell state, and which upstream signals select among them, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model partitioning CELF2 among its activities","Structural basis of condensate-cofactor selectivity unknown","Mechanism coupling stabilization to translational silencing undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,2,3,6,8,9,11,20,22,28,35,36]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,6,11,12,14,19,20,21,37]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,22,38]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,4,10,29,30]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,8,10,29,39]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[17]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2,6,11,12,22]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[14,19,21,31,38]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[29,39,40]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[29,40]}],"complexes":["apobec-1 / apoB mRNA editing holoenzyme"],"partners":["ACF","HUR","PTB","U2AF65","HNRNPC","NOVA2","SFPQ","PREX2"],"other_free_text":[]}},"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":204,"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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ETR-3 is highly expressed in heart tissue.\",\n      \"method\": \"RNA binding assays with recombinant protein; RT-PCR tissue distribution analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct in vitro binding demonstrated, multiple tissues examined, single lab\",\n      \"pmids\": [\"9887331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CUGBP2 (CELF2) is a component of the apolipoprotein B mRNA editing holoenzyme: it co-fractionates with ACF, co-immunoprecipitates with ACF, and co-localizes with ACF in the nucleus. CUGBP2 binds an AU-rich sequence upstream of the edited cytidine in apoB RNA. Recombinant CUGBP2 dose-dependently inhibits C-to-U RNA editing in a reconstituted system, and antisense knockdown of CUGBP2 increases endogenous apoB RNA editing.\",\n      \"method\": \"Co-immunoprecipitation; immunodepletion; co-localization by immunofluorescence; reconstituted in vitro editing assay with recombinant protein; antisense knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstituted in vitro assay with recombinant protein plus co-IP and knockdown, multiple orthogonal methods in one study\",\n      \"pmids\": [\"11577082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"ETR-3 (CELF2) binds UG/G motifs within conserved muscle-specific intronic elements (MSEs) flanking cardiac troponin T (cTNT) exon 5 and directly activates exon inclusion in vitro. ETR-3 binding and splicing activation are antagonized by PTB. Dominant-negative mutants demonstrate that endogenous CELF (including ETR-3) and PTB activities are required for MSE-dependent activation in muscle and repression in non-muscle cells, respectively.\",\n      \"method\": \"In vitro splicing assay; dominant-negative mutant cotransfection; RNA binding assays; minigene reporter\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro splicing reconstitution plus in vivo dominant-negative genetics, multiple orthogonal methods\",\n      \"pmids\": [\"11931771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CUGBP2 (CELF2) binds two AU-rich sequences (AREs) in the first 60 nucleotides of the COX-2 3'UTR, stabilizes COX-2 mRNA, but simultaneously inhibits its translation. CUGBP2 is rapidly induced by ionizing radiation and translocates from nucleus to cytoplasm. Antisense suppression of CUGBP2 confers radioprotection through a COX-2-dependent prostaglandin pathway.\",\n      \"method\": \"UV cross-linking and nitrocellulose filter binding to demonstrate RNA binding; chimeric luciferase-COX-2 3'UTR reporter assay for mRNA stability and translation; antisense knockdown with phenotypic readout; immunofluorescence for localization\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro binding assays, reporter assay, antisense knockdown with in vivo phenotype, multiple orthogonal methods in single study\",\n      \"pmids\": [\"12535526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ETR-3 (CELF2) contains a strong nuclear localization signal (NLS) overlapping the C-terminal RRM3 domain that can confer nuclear localization on a normally cytoplasmic pyruvate kinase chimera. The divergent domain contains both nuclear localization and CRM1-dependent nuclear export activities. The C-terminus and a region within the divergent domain are important for splicing activity. Cytoplasmic localization signals also reside in the first two RRMs.\",\n      \"method\": \"GFP fusion protein live imaging; deletion mutants and domain swapping; leptomycin B treatment; cotransfection with cTNT minigene for splicing activity\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiments with multiple deletion mutants, functional splicing validation, CRM1 dependency established by inhibitor, multiple orthogonal methods\",\n      \"pmids\": [\"15226369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"For ETR-3 (CELF2), either RRM1 or RRM2 alone are sufficient to bind MSE RNA; non-overlapping N-terminal (RRM1+RRM2) and C-terminal (RRM3 plus divergent domain segments) regions can each independently activate MSE-dependent exon inclusion in vivo, demonstrating functional redundancy between termini.\",\n      \"method\": \"Comparative deletion analysis; in vivo splicing cotransfection assay with cTNT minigene; RNA binding assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo splicing assays with multiple deletion mutants, single lab\",\n      \"pmids\": [\"14973222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ETR-3 (CELF2) preferentially binds UG-rich sequences, particularly UG repeats and UGUU motifs, as determined by SELEX. These binding motifs restore ETR-3 responsiveness to a non-responsive splicing reporter in vivo. ETR-3 regulates CFTR and MTMR1 splicing in a manner dependent on identified SELEX binding sites.\",\n      \"method\": \"SELEX (5 rounds); minigene splicing assay; site-directed mutagenesis of SELEX motif\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — SELEX to define binding preference, validated with minigene mutagenesis and in vivo splicing assay, multiple orthogonal methods\",\n      \"pmids\": [\"15657417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ETR-3 (CELF2) promotes exclusion of Tau exon 2 in cellular models with DM1-like splicing patterns, as demonstrated by ectopic expression. ETR-3 selectively represses Tau exon 2 inclusion.\",\n      \"method\": \"Ectopic expression in cellular models; RT-PCR splicing analysis\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single overexpression experiment, replicated across multiple transcripts and models\",\n      \"pmids\": [\"16862542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CUGBP2 (CELF2) and HuR heterodimerize in vitro via GST pull-down and yeast 2-hybrid, and co-localize in the nucleus. Both proteins bind COX-2 ARE with similar affinities, but CUGBP2 competitively inhibits HuR binding. HuR enhances translation of chimeric COX-2 3'UTR mRNA, while CUGBP2 inhibits it. After irradiation, COX-2 mRNA binding switches from HuR to CUGBP2, coupled with increased translational silencing.\",\n      \"method\": \"GST pull-down; yeast 2-hybrid; nitrocellulose filter binding; UV cross-linking; immunocytochemistry; heterokaryon assay for nucleocytoplasmic shuttling; chimeric luciferase mRNA reporter assay\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal protein-protein and protein-RNA interaction methods, functional translation assay, mechanistic competition demonstrated\",\n      \"pmids\": [\"17383427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CUGBP2 (CELF2) binds Mcl-1 3'UTR both in vitro and in cells (RIP). CUGBP2 stabilizes Mcl-1 mRNA and a luciferase-Mcl-1 3'UTR reporter, but inhibits translation of the Mcl-1 mRNA. Stable CUGBP2 expression drives cells to apoptosis during G2/M phase; decreased Bcl-2 and Mcl-1 protein (but not mRNA) levels confirm translational inhibition as the mechanism.\",\n      \"method\": \"RNA immunoprecipitation (RIP); in vitro RNA binding; luciferase reporter assay; Western blot; flow cytometry; stable overexpression cell line\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RIP plus in vitro binding plus reporter assay, multiple orthogonal methods demonstrating both mRNA stabilization and translational inhibition\",\n      \"pmids\": [\"18292181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CUGBP2 (CELF2) splice variants differ in subcellular localization: variant 1 is predominantly nuclear and inhibits COX-2 mRNA translation and induces apoptosis/mitotic catastrophe; variants 2 and 3 (with additional N-terminal residues) are predominantly cytoplasmic, bind COX-2 mRNA but do not inhibit its translation, and do not induce apoptosis or G2/M arrest.\",\n      \"method\": \"Immunocytochemistry; luciferase reporter assay; Western blot; flow cytometry; overexpression of splice variants in HCT116 cells\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization imaging plus functional reporter assay, single lab\",\n      \"pmids\": [\"18258790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CUGBP2 (CELF2) regulates branchpoint formation during alternative splicing of the NMDA R1 NI exon: chemical modification footprinting maps CUGBP2 contact sites to GU-rich motifs at the perimeter of branch sites. This perimeter-binding model explains target exon specificity. CUGBP2 also autoregulates its own splicing via direct interaction with functionally significant RNA motifs surrounding branch sites upstream of CUGBP2 exon 6.\",\n      \"method\": \"Chemical modification footprinting; in vitro splicing assay; identification of novel target exons with similar branch-site perimeter motif configurations\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with footprinting to map precise binding sites and mechanistic role in branchpoint formation, single lab with multiple validated targets\",\n      \"pmids\": [\"19680430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ETR-3 (CELF2), but not CUG-BP1, strongly stimulates CFTR exon 9 skipping. Both proteins bind the polymorphic UG(m)U(n) sequence with similar and higher affinity than TDP-43. The divergent domain of ETR-3 is critical for exon 9 skipping activity, as demonstrated by deletion and domain-swapping experiments. The mechanism involves functional antagonism between U2AF65 and ETR-3 binding to the polypyrimidine stretch.\",\n      \"method\": \"Minigene splicing assay; deletion and domain-swapping mutants; RNA binding assays; competition binding with U2AF65\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — domain-swapping mutagenesis plus in vivo splicing assay plus RNA binding, multiple orthogonal methods identifying divergent domain as the specificity determinant\",\n      \"pmids\": [\"20631008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CELF2 overexpression reduces inclusion of Tau exon 10 (promotes skipping) in cellular models. Increased CELF2 expression was observed specifically in the brain of DM1 patients with exon 10 mis-splicing. This effect is independent of MBNL1 loss-of-function and CELF1 gain-of-function.\",\n      \"method\": \"Ectopic overexpression and siRNA knockdown of splicing factors; RT-PCR splicing analysis; patient brain tissue analysis\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — overexpression and siRNA in cell models with correlation in patient tissue, single lab\",\n      \"pmids\": [\"21439371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CELF2 controls signal-induced and developmental alternative splicing of LEF1 exon 6 in T cells: CELF2 expression increases upon T-cell signaling and CELF2 binds two intronic sequences flanking the regulated exon to promote exon 6 inclusion. Knockdown of CELF2 reduces exon 6 inclusion, which in turn reduces TCR-alpha mRNA expression.\",\n      \"method\": \"RNA binding assays; CELF2 knockdown; minigene reporter; RT-PCR\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding demonstrated plus functional knockdown with downstream consequence, single lab\",\n      \"pmids\": [\"21444716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"miR-196a silences CELF2 expression; CELF2 directly acts on AR mRNA to enhance its stability, thereby promoting AR-polyQ protein expression that drives SBMA pathology. AAV-mediated delivery of miR-196a ameliorates SBMA phenotypes in a mouse model.\",\n      \"method\": \"miRNA overexpression via AAV vector; mRNA stability assay; Western blot; mouse model phenotyping\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model rescue plus direct mRNA stability measurement, but CELF2-AR mRNA interaction not validated by RIP/pulldown in this abstract\",\n      \"pmids\": [\"22660636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Alternative splicing of CUGBP2 (CELF2) exon 14 produces an isoform (R3δ) that lacks the first half of RRM3. NMR spectrometry and molecular dynamics simulation show R3δ has a flexible, non-canonical third RRM structure. R3δ and full-length CUGBP2 have similar effects on ACTN1 SM exon inclusion but opposite effects on insulin receptor exon 11 skipping, demonstrating that structural changes in RRM3 alter splicing target specificity.\",\n      \"method\": \"NMR spectrometry; molecular dynamics simulation; minigene splicing assay; overexpression of isoforms\",\n      \"journal\": \"BMC biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural analysis plus functional splicing assays, single lab\",\n      \"pmids\": [\"22433174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In cardiac H9c2 cells, CUGBP2 (CELF2) controls subcellular trafficking of COX-2 mRNA to cytoplasmic stress granules in response to a pro-inflammatory stimulus; gene silencing of CUGBP2 disrupts this stress granule trafficking, revealing a role for CUGBP2 in RNA stress granule dynamics.\",\n      \"method\": \"Gene silencing; fluorescence microscopy of stress granules; cell biological assays\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, fluorescence microscopy with gene silencing, limited mechanistic depth in abstract\",\n      \"pmids\": [\"23661609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CELF2 expression is induced by T-cell receptor signaling via NF-κB-dependent transcription (within 6 h) followed by increased stability of CELF2 mRNA correlating with a change in CELF2 3'UTR length via alternative polyadenylation. Increased CELF2 drives dozens of downstream alternative splicing events during T-cell activation and development.\",\n      \"method\": \"NF-κB inhibitor; promoter-reporter assays; mRNA stability assay (actinomycin D chase); 3'UTR APA analysis; splicing-sensitive arrays; siRNA knockdown\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (transcriptional reporter, mRNA stability, APA, splicing arrays), replicated in cultured T cells and human thymus\",\n      \"pmids\": [\"25870297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"JNK signaling induces CELF2 expression upon T-cell activation; CELF2 then binds flanking intronic sequences to repress MKK7 exon 2 inclusion, generating an isoform that restores a JNK-docking site and enhances JNK signaling (c-Jun phosphorylation, TNF-α upregulation). This creates a positive feedback loop: JNK promotes its own signaling via CELF2-dependent MKK7 splicing.\",\n      \"method\": \"JNK inhibitor; siRNA knockdown of CELF2; minigene reporter; RNA binding assay; phosphorylation assays; splicing-sensitive RT-PCR; RNA-seq\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (JNK inhibitor + CELF2 KD), RNA binding, reporter assay, functional signaling readout, multiple orthogonal methods\",\n      \"pmids\": [\"26443849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CLIP-Seq analysis of CELF2 binding in T cells reveals a generalizable position-dependent activity rule: CELF2 binding downstream of an exon promotes skipping while binding upstream promotes inclusion, consistent with prior mechanistic studies and sufficient to explain CELF2's bidirectional splicing activity across T-cell targets.\",\n      \"method\": \"CLIP-Seq; comparison with functional splicing data from same cell line\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CLIP-Seq plus functional validation by comparison with known targets, single lab\",\n      \"pmids\": [\"27096301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CELF2 and hnRNP C directly bind a cis-regulatory element 340–440 nt upstream of TRAF3 exon 8 (identified by siRNA screen + CLIP) and together mediate activation-dependent exon skipping in T cells. CELF2 expression level correlates with TRAF3 skipping; hnRNP C is necessary but not sufficient, while CELF2 is the decisive factor. Activity depends on precise distance of the intronic silencer from the regulated exon.\",\n      \"method\": \"siRNA screen; cross-link immunoprecipitation (CLIP); mutational analysis of cis-element; minigene reporter; RT-PCR correlation across model systems\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CLIP plus mutagenesis plus siRNA screen, multiple orthogonal methods identifying both cis- and trans-acting elements\",\n      \"pmids\": [\"28031331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CELF2 controls alternative polyadenylation (APA) of its own mRNA and of ~50% of T-cell signaling-induced APA events by competing with core polyadenylation enhancers (e.g., CPSF) for binding to RNA near polyadenylation sites. CELF2 binding overlaps transcriptome-wide with APA enhancer sites.\",\n      \"method\": \"CELF2 CLIP-Seq overlaid with APA enhancer maps; APA-seq; CELF2 knockdown; competition binding assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CLIP-Seq plus APA-seq plus KD with functional APA readout, multiple orthogonal methods\",\n      \"pmids\": [\"31509743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CELF2 (CELF2/CUGBP2) increases the stability of Beclin-1, ATG5, and ATG12 mRNAs by binding to them, thereby increasing autophagic flux. Silencing CELF2 abrogates ionizing radiation-induced autophagy in colorectal cancer cells and in xenograft models.\",\n      \"method\": \"RNA immunoprecipitation; mRNA stability assay; Western blot; autophagic vacuole analysis; electron microscopy; xenograft knockdown\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus mRNA stability assay plus functional autophagy readout, single lab\",\n      \"pmids\": [\"31020708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CELF2 interacts with PREX2 protein (by co-immunoprecipitation), reducing the association of PREX2 with PTEN, thereby relieving PREX2-mediated inhibition of PTEN phosphatase activity. CELF2 overexpression represses Akt phosphorylation and cell proliferation in a PTEN-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation; PTEN phosphatase activity assay; Western blot for p-Akt; PTEN-null cell controls; patient-derived xenograft\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus enzymatic assay plus genetic PTEN-dependency control, single lab\",\n      \"pmids\": [\"31241130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CELF2 promoter is targeted by hypermethylation-associated transcriptional silencing in human breast cancer. Restoration of CELF2 expression has growth-inhibitory effects and corrects aberrant alternative splicing of ULK1 and CARD10.\",\n      \"method\": \"Methylation analysis; CELF2 re-expression; splicing analysis; growth assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epigenetic mechanism validated with re-expression rescue and splicing readout, single lab\",\n      \"pmids\": [\"31409895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CELF2 regulates species-specific alternative splicing of TREM2 exon 3: overexpression of CELF2 promotes exon 3 skipping and reduces full-length TREM2 protein (via NMD). A CELF-responsive sequence was mapped to intron 3 of human TREM2 using chimeric human/mouse minigenes. This regulation is shared between humans and monkeys but not mice.\",\n      \"method\": \"Overexpression of CELF1/CELF2; chimeric minigene analysis; Western blot for full-length TREM2; panel of RNA-binding proteins\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — minigene chimera mutagenesis plus protein-level readout, single lab\",\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 mRNA transcription, while loss of CELF2 decreases hnRNP C translation efficiency. This cross-regulation fine-tunes splicing patterns of many downstream target genes.\",\n      \"method\": \"siRNA knockdown of each factor; mRNA and protein level measurements; translation efficiency assay; splicing-sensitive analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal knockdown with defined transcriptional and translational readouts, single lab, two orthogonal mechanistic levels\",\n      \"pmids\": [\"32338744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CELF2 binds AU/U-rich elements (AREs) in the FAM198B 3'UTR to stabilize FAM198B mRNA. FAM198B knockdown reverses CELF2-mediated suppression of ovarian cancer cell proliferation and migration; the CELF2/FAM198B axis represses MAPK/ERK signaling.\",\n      \"method\": \"RNA binding assay (RIP); mRNA stability assay; FAM198B knockdown rescue experiments; Western blot for ERK signaling\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus functional rescue experiment plus signaling readout, single lab\",\n      \"pmids\": [\"33335801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In self-renewing neural stem/progenitor cells (NPCs), CELF2 resides in the cytoplasm and represses mRNAs encoding cell fate regulators. Translocation of CELF2 into the nucleus releases these mRNAs for translation, triggering NPC differentiation. De novo missense variants in CELF2 disrupt nucleocytoplasmic transport, causing cortical malformations in humans and perturbing NPC fate decisions in mice.\",\n      \"method\": \"Live cell imaging; subcellular fractionation; iPSC-derived NPCs; mouse genetic model; RNA-seq; de novo variant functional characterization\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiments in NPCs, mouse genetic model, human variant functional validation, multiple orthogonal methods\",\n      \"pmids\": [\"34107259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"De novo CELF2 variants clustering in the C-terminal 20 amino acids (which include the nuclear localization signal overlapping RRM3) cause extranuclear mislocalization of CELF2 protein in transfected cells, establishing that these variants disrupt NLS function.\",\n      \"method\": \"Transfection of mutant CELF2 cDNA plasmids; subcellular localization assay; whole-exome sequencing of patients\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiment with mutant protein, replicated across multiple variants\",\n      \"pmids\": [\"33131106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CELF2 associates with pre-miR-155 in IL-10-treated macrophages (CRISPR-Cas9 KO of CELF2 impairs IL-10's ability to inhibit miR-155 expression and TNF-α expression), indicating CELF2 is required for IL-10-mediated inhibition of pre-miR-155 maturation.\",\n      \"method\": \"Co-immunoprecipitation/pulldown of pre-miR-155 with CELF2; CRISPR-Cas9 knockdown; RT-qPCR for miR-155 and TNF-α\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with functional miRNA and cytokine readouts plus RNA binding data, single lab\",\n      \"pmids\": [\"32324763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In spinal cord injury models, GAS5 lncRNA recruits CELF2 protein to the coding region of VAV1 mRNA, resulting in increased VAV1 mRNA stability and expression. GAS5/CELF2-mediated VAV1 stabilization promotes oxidative stress and cell injury.\",\n      \"method\": \"RNA immunoprecipitation (RIP); mRNA stability assay; GAS5/VAV1 knockdown functional assays; rat SCI model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP demonstrates CELF2 binding to VAV1 mRNA in context of GAS5, functional rescue experiments, single lab\",\n      \"pmids\": [\"33574559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"N6-methyladenosine (m6A) modification of CELF2 mRNA is mediated by ALKBH5 demethylase; when m6A is present (ALKBH5 depleted), YTHDF2 binds CELF2 mRNA and promotes its degradation. CELF2 then regulates alternative splicing of CD44 (promoting CD44s over CD44V), affecting the ERAD signaling pathway.\",\n      \"method\": \"m6A sequencing; RIP for YTHDF2; splicing analysis; ALKBH5 manipulation; ERAD pathway inhibitor (EerI); transcriptomic analysis\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A writer/reader identified biochemically with functional splicing and signaling readout, single lab\",\n      \"pmids\": [\"35941702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CELF2 deficiency in hematopoietic cells stabilizes FAT10 mRNA and promotes FAT10 translation, thereby activating AKT phosphorylation and mTORC1 signaling. This was established by gene expression profiling integrated with RIP-Seq (showing CELF2 binding to FAT10 mRNA), and combination therapy with mTORC1 inhibitor plus EPZ-5676 reduced leukemia burden in CELF2-deficient AML mice.\",\n      \"method\": \"RIP-Seq; RNA-seq; mouse AML model (MLL-AF9); mTORC1 inhibitor treatment; biochemical assays for AKT/mTORC1 phosphorylation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP-Seq plus mouse model with targeted therapy, single lab\",\n      \"pmids\": [\"38514854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CELF2 binds AU-rich motifs in the 3'UTR of CXCL5 mRNA, reducing CXCL5 mRNA stability, thereby inhibiting CXCL5/CXCR2/AKT signaling and suppressing bladder cancer cell proliferation and migration.\",\n      \"method\": \"RNA pull-down/RIP; mRNA stability assay; Western blot for p-AKT; proliferation and migration assays\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA binding plus mRNA stability assay plus signaling readout, single lab\",\n      \"pmids\": [\"40154776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CELF2 promotes tau exon 10 inclusion (increasing 4R:3R ratio) in the mouse brain. The hinge domain of CELF2 contains an intrinsically disordered region (IDR) that drives CELF2 condensation in the nucleus and is required for splicing activity. The IDR can be functionally substituted by IDRs from FUS or TAF15. CELF2 co-condenses with NOVA2 and SFPQ, which cooperate with CELF2 to regulate tau exon 10 splicing. A conserved negatively charged residue D388 in the IDR is critical for condensate formation, NOVA2/SFPQ interactions, and tau exon 10 splicing function. Specific binding to the intron adjacent to tau exon 10 was demonstrated by TurboID proximity proteomics.\",\n      \"method\": \"Mouse brain CELF2 knockout; TurboID proximity labeling; in vitro condensation assay; IDR substitution mutants; D388 mutagenesis; co-immunoprecipitation of NOVA2/SFPQ; splicing analysis (4R:3R ratio)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution-level mechanistic study (condensation assay, mutagenesis, IDR swaps) but preprint, single lab\",\n      \"pmids\": [\"39553957\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CELF2 regulates alternative splicing of STAT3 pre-mRNA by binding UG-rich elements in intron 22, modulating the balance between STAT3α and STAT3β isoforms. Loss/gain-of-function experiments with CUGBP2/ETR-3 established it as a trans-acting splicing factor for STAT3.\",\n      \"method\": \"Cis-regulatory element mapping; overexpression/knockdown of CUGBP2; minigene reporter; RNA binding assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cis-element mapping plus functional splicing assay with gain/loss of function, single lab\",\n      \"pmids\": [\"39550869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CELF2 depletion in macrophages leads to spontaneous type I interferon (IFN) and IFN-stimulated gene signature, dependent on the RIG-I–MAVS pathway. RNA from CELF2-depleted macrophages is sufficient to induce IFN in naïve cells; this immunostimulatory activity is double-stranded RNA (sensitive to RNase III). Immunoprecipitation of dsRNA from CELF2-depleted cells identifies specific immunostimulatory RNAs. Thus CELF2 suppresses endogenous dsRNA ligands that would otherwise activate RIG-I.\",\n      \"method\": \"CELF2 knockdown; IFN reporter assay; RNA transfer experiment; RNase III treatment; dsRNA immunoprecipitation; pathway inhibitors (RIG-I/MAVS)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CELF2 KD with pathway-specific rescue, RNA transfer functional test, dsRNA biochemical validation, preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.03.27.645787\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CELF2 undergoes activity-dependent nucleocytoplasmic shuttling in excitatory neurons; cytoplasmic retention of CELF2 (due to disease variants) causes neuronal hyperexcitability and learning/memory deficits. AKT signaling was identified as a key regulator of CELF2 shuttling. In the cytoplasm, CELF2 regulates mRNAs critical for synaptic function and neuronal excitability.\",\n      \"method\": \"iPSC-derived neurons from patients with CELF2 variants; transgenic mouse models; drug screening (AKT inhibitors/activators); electrophysiology; behavioral tests; RNA-seq\",\n      \"journal\": \"medRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — iPSC neurons plus transgenic mice plus drug rescue, multiple models, preprint\",\n      \"pmids\": [\"40666314\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CELF2 is required for normal neuronal maturation and cortical architecture: CELF2 knockout causes neonatal lethality with impaired neuronal maturation and disrupted cortical organization. CELF2 binds the Camk2a 3'UTR to regulate Camk2a mRNA levels; loss of CELF2 markedly reduces CaMK2A transcript and protein. Expression of human CAMK2A partially rescues synaptic puncta deficits in C. elegans unc-75 (CELF ortholog) mutants. CELF2 loss reduces exon inclusion in multiple neurodevelopmental transcripts (RNA splicing) and selectively depletes upper layer II/III excitatory neurons.\",\n      \"method\": \"Constitutive Celf2 knockout mouse; bulk RNA-seq; splicing analysis; snRNA-seq; CaMK2A 3'UTR binding; C. elegans genetic rescue; histological and pseudotime analyses\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse model plus cross-species genetic rescue plus 3'UTR binding, multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"42189331\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CELF2 (ETR-3/CUGBP2) is a nucleocytoplasmic shuttling RNA-binding protein that recognizes UG-rich and AU-rich sequences via its three RRM domains; in the nucleus it regulates alternative splicing (activating or repressing exon inclusion depending on its binding position relative to the regulated exon, through mechanisms including branch-site occlusion and condensate formation via an IDR in its hinge domain with co-factors NOVA2/SFPQ), and in the cytoplasm it simultaneously stabilizes target mRNAs (COX-2, Mcl-1, FAM198B, CXCL5, Camk2a, autophagy mRNAs) while inhibiting their translation; it also controls alternative polyadenylation by competing with core polyadenylation enhancers, participates in apoB mRNA C-to-U editing as a regulatory subunit of the apobec-1 holoenzyme, suppresses endogenous dsRNA ligands to prevent RIG-I-mediated interferon induction, and its subcellular localization—regulated by NLS signals in RRM3, CRM1-dependent nuclear export, AKT signaling, and signal-induced transcriptional/mRNA stability changes downstream of NF-κB and JNK—determines whether it promotes stem cell self-renewal or differentiation in neural progenitors and T cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CELF2 (ETR-3/CUGBP2) is a nucleocytoplasmic shuttling RNA-binding protein that governs gene expression at the levels of alternative splicing, mRNA stability/translation, and polyadenylation through recognition of UG-rich and AU-rich elements via its three RRM domains [#0, #6]. In the nucleus, CELF2 acts as a position-dependent splicing regulator: binding upstream of a regulated exon promotes inclusion while binding downstream promotes skipping, a rule that explains its bidirectional activity across diverse targets including cardiac troponin T, CFTR, NMDA R1, Tau, LEF1, MKK7, TRAF3, TREM2, and STAT3 [#2, #6, #11, #12, #14, #19, #20, #21]. Mechanistically it operates through branch-site perimeter occupancy, functional antagonism with U2AF65 and PTB, and condensate formation driven by an intrinsically disordered region in its hinge domain that recruits co-factors NOVA2 and SFPQ [#2, #11, #12, #36]. In the cytoplasm CELF2 binds AU-rich elements to control mRNA fate, frequently uncoupling stability from translation—it stabilizes yet translationally silences COX-2 and Mcl-1 mRNAs, switching binding with HuR after irradiation [#3, #8, #9]—while in other contexts it stabilizes (FAM198B, autophagy mRNAs, Camk2a) or destabilizes (CXCL5) target transcripts to tune proliferation, autophagy, and neuronal signaling [#23, #28, #35, #40]. CELF2 additionally controls alternative polyadenylation by competing with core polyadenylation enhancers, serves as a regulatory subunit of the apoB mRNA C-to-U editing holoenzyme, and suppresses endogenous double-stranded RNA ligands that would otherwise trigger RIG-I-dependent interferon induction [#1, #22, #38]. Its subcellular partitioning is the master switch over its activity: an NLS overlapping RRM3, CRM1-dependent export, and AKT signaling direct shuttling, and de novo variants disrupting the C-terminal NLS cause extranuclear mislocalization, cortical malformations, and neuronal hyperexcitability with learning and memory deficits in humans [#4, #29, #30, #39]. Consistent with this, CELF2 is required for neuronal maturation and cortical architecture, with knockout causing neonatal lethality [#40].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing that CELF2 is a sequence-specific RNA-binding protein answered the foundational question of its molecular activity and hinted at autoregulation.\",\n      \"evidence\": \"in vitro RNA binding assays with recombinant protein and RT-PCR tissue profiling\",\n      \"pmids\": [\"9887331\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No cellular function assigned\", \"Binding specificity beyond CUG repeats not defined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identifying CELF2 as a regulatory subunit of the apoB editing holoenzyme showed it acts beyond splicing, modulating C-to-U RNA editing.\",\n      \"evidence\": \"co-IP, immunodepletion, reconstituted in vitro editing assay, and antisense knockdown\",\n      \"pmids\": [\"11577082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ACF interaction unknown\", \"Generality of editing regulation to other substrates untested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrating direct activation of cTNT exon 5 inclusion antagonized by PTB defined CELF2 as a genuine alternative splicing regulator with combinatorial control.\",\n      \"evidence\": \"in vitro splicing reconstitution, dominant-negative genetics, minigene reporters\",\n      \"pmids\": [\"11931771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How position relative to exon dictates activate-versus-repress not yet established\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"SELEX defined UG-rich/UGUU binding preference and mapped functional binding sites, providing the cis-code for target prediction.\",\n      \"evidence\": \"SELEX with minigene splicing validation and motif mutagenesis (CFTR, MTMR1)\",\n      \"pmids\": [\"15657417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Distinction between UG-rich splicing motifs and AU-rich stability motifs not unified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Mapping an NLS overlapping RRM3 plus CRM1-dependent export and redundant RRM activities explained how localization and modular domains control splicing function.\",\n      \"evidence\": \"GFP fusion imaging, deletion/domain swaps, leptomycin B, cTNT minigene assays\",\n      \"pmids\": [\"15226369\", \"14973222\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals controlling shuttling not identified at this stage\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showing CELF2 stabilizes COX-2 mRNA while silencing its translation, with radiation-induced nuclear-to-cytoplasmic relocation, revealed its dual cytoplasmic post-transcriptional role.\",\n      \"evidence\": \"UV cross-linking, luciferase-3'UTR reporters, antisense knockdown with radioprotection phenotype\",\n      \"pmids\": [\"12535526\", \"17383427\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of translational silencing decoupled from stabilization unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Branch-site perimeter footprinting provided a mechanistic explanation for target exon specificity and confirmed CELF2 autoregulates its own splicing.\",\n      \"evidence\": \"chemical modification footprinting and in vitro splicing on NMDA R1 and CUGBP2 exon 6\",\n      \"pmids\": [\"19680430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether perimeter binding generalizes to all targets untested transcriptome-wide\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Pinpointing the divergent domain as the specificity determinant and U2AF65 competition clarified how CELF2 represses exon inclusion.\",\n      \"evidence\": \"domain-swapping mutagenesis, minigene splicing, U2AF65 competition binding (CFTR exon 9)\",\n      \"pmids\": [\"20631008\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structural contacts with the spliceosome not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linking TCR signaling to CELF2 induction via NF-kB transcription and APA-mediated mRNA stabilization, plus a JNK/MKK7 feedback loop, embedded CELF2 in signal-responsive splicing programs.\",\n      \"evidence\": \"NF-kB and JNK inhibitors, promoter reporters, mRNA stability and APA analysis, splicing arrays, minigene reporters in T cells\",\n      \"pmids\": [\"25870297\", \"26443849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of physiologically relevant downstream targets incompletely defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Transcriptome-wide CLIP established the generalizable position-dependent rule that resolved CELF2's bidirectional splicing behavior.\",\n      \"evidence\": \"CLIP-Seq integrated with functional splicing data in T cells\",\n      \"pmids\": [\"27096301\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Exceptions to the position rule and cofactor dependence not fully cataloged\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showing CELF2 and hnRNP C jointly act on a distance-sensitive intronic silencer at TRAF3 defined combinatorial, geometry-dependent splicing control.\",\n      \"evidence\": \"siRNA screen, CLIP, cis-element mutagenesis, minigene reporters\",\n      \"pmids\": [\"28031331\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biophysical basis of distance dependence unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating CELF2 competes with CPSF-type polyadenylation enhancers extended its regulatory reach to alternative polyadenylation transcriptome-wide.\",\n      \"evidence\": \"CLIP-Seq overlaid with APA enhancer maps, APA-seq, knockdown\",\n      \"pmids\": [\"31509743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical competition with CPSF not reconstituted\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying the IDR-driven nuclear condensation with NOVA2/SFPQ and a critical D388 residue revealed a phase-separation mechanism underlying splicing activity (e.g., tau exon 10).\",\n      \"evidence\": \"TurboID proximity proteomics, in vitro condensation, IDR-swap and D388 mutagenesis, NOVA2/SFPQ co-IP, mouse brain knockout (preprint)\",\n      \"pmids\": [\"39553957\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab\", \"In vivo relevance of condensation across other targets untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linking CELF2 localization to cell-fate decisions in neural progenitors and disease showed that nucleocytoplasmic partitioning is the functional switch, with NLS variants causing human cortical malformation.\",\n      \"evidence\": \"iPSC-derived NPCs, mouse genetic model, RNA-seq, de novo variant transfection/localization assays\",\n      \"pmids\": [\"34107259\", \"33131106\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals that drive physiological NPC translocation not fully defined here\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicating AKT signaling in activity-dependent neuronal shuttling and showing CELF2 suppresses endogenous dsRNA RIG-I ligands extended the localization-switch and immune-surveillance models.\",\n      \"evidence\": \"iPSC neurons, transgenic mice, AKT inhibitor/activator screen, electrophysiology (preprint); CELF2 knockdown, RNA transfer, RNase III, dsRNA IP, RIG-I/MAVS inhibitors (preprint)\",\n      \"pmids\": [\"40666314\", \"bio_10.1101_2025.03.27.645787\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Both preprints, single labs\", \"Identity of the suppressed dsRNA ligands incompletely defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrating that CELF2 is required for neuronal maturation and cortical architecture, acting partly through Camk2a mRNA regulation, established its organismal necessity.\",\n      \"evidence\": \"constitutive Celf2 knockout mouse, RNA-seq, snRNA-seq, Camk2a 3'UTR binding, C. elegans unc-75 cross-species rescue\",\n      \"pmids\": [\"42189331\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of splicing versus mRNA-stability roles to phenotype unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CELF2 integrates its multiple molecular activities (splicing, APA, mRNA stability/translation, editing, dsRNA suppression) into a single coherent decision per cell state, and which upstream signals select among them, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model partitioning CELF2 among its activities\", \"Structural basis of condensate-cofactor selectivity unknown\", \"Mechanism coupling stabilization to translational silencing undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 2, 3, 6, 8, 9, 11, 20, 22, 28, 35, 36]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 6, 11, 12, 14, 19, 20, 21, 37]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 22, 38]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 4, 10, 29, 30]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 8, 10, 29, 39]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2, 6, 11, 12, 22]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [14, 19, 21, 31, 38]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [29, 39, 40]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [29, 40]}\n    ],\n    \"complexes\": [\"apobec-1 / apoB mRNA editing holoenzyme\"],\n    \"partners\": [\"ACF\", \"HuR\", \"PTB\", \"U2AF65\", \"hnRNPC\", \"NOVA2\", \"SFPQ\", \"PREX2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}