Affinage

CELF2

CUGBP Elav-like family member 2 · UniProt O95319

Length
508 aa
Mass
54.3 kDa
Annotated
2026-06-09
94 papers in source corpus 41 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1999 Medium

    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

    PMID:9887331

    Open questions at the time
    • No cellular function assigned
    • Binding specificity beyond CUG repeats not defined
  2. 2001 High

    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

    PMID:11577082

    Open questions at the time
    • Structural basis of ACF interaction unknown
    • Generality of editing regulation to other substrates untested
  3. 2002 High

    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

    PMID:11931771

    Open questions at the time
    • How position relative to exon dictates activate-versus-repress not yet established
  4. 2005 High

    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)

    PMID:15657417

    Open questions at the time
    • Distinction between UG-rich splicing motifs and AU-rich stability motifs not unified
  5. 2004 High

    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

    PMID:14973222 PMID:15226369

    Open questions at the time
    • Upstream signals controlling shuttling not identified at this stage
  6. 2003 High

    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

    PMID:12535526 PMID:17383427

    Open questions at the time
    • Molecular basis of translational silencing decoupled from stabilization unresolved
  7. 2009 High

    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

    PMID:19680430

    Open questions at the time
    • Whether perimeter binding generalizes to all targets untested transcriptome-wide
  8. 2010 High

    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)

    PMID:20631008

    Open questions at the time
    • Direct structural contacts with the spliceosome not resolved
  9. 2015 High

    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

    PMID:25870297 PMID:26443849

    Open questions at the time
    • Full set of physiologically relevant downstream targets incompletely defined
  10. 2016 Medium

    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

    PMID:27096301

    Open questions at the time
    • Exceptions to the position rule and cofactor dependence not fully cataloged
  11. 2017 High

    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

    PMID:28031331

    Open questions at the time
    • Biophysical basis of distance dependence unknown
  12. 2019 High

    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

    PMID:31509743

    Open questions at the time
    • Direct biochemical competition with CPSF not reconstituted
  13. 2021 Medium

    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)

    PMID:39553957

    Open questions at the time
    • Preprint, single lab
    • In vivo relevance of condensation across other targets untested
  14. 2021 High

    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

    PMID:33131106 PMID:34107259

    Open questions at the time
    • Signals that drive physiological NPC translocation not fully defined here
  15. 2025 Medium

    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)

    PMID:40666314 PMID:bio_10.1101_2025.03.27.645787

    Open questions at the time
    • Both preprints, single labs
    • Identity of the suppressed dsRNA ligands incompletely defined
  16. 2026 Medium

    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

    PMID:42189331

    Open questions at the time
    • Relative contribution of splicing versus mRNA-stability roles to phenotype unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No unified model partitioning CELF2 among its activities
  • Structural basis of condensate-cofactor selectivity unknown
  • Mechanism coupling stabilization to translational silencing undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 13 GO:0140110 transcription regulator activity 9 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 5 GO:0005829 cytosol 5 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-168256 Immune System 5 R-HSA-8953854 Metabolism of RNA 5 R-HSA-112316 Neuronal System 3 R-HSA-1266738 Developmental Biology 2
Partners
ACFHNRNPCHURNOVA2PREX2PTBSFPQU2AF65
Complex memberships
apobec-1 / apoB mRNA editing holoenzyme

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 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. RNA binding assays with recombinant protein; RT-PCR tissue distribution analysis Human molecular genetics Medium 9887331
2001 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. Co-immunoprecipitation; immunodepletion; co-localization by immunofluorescence; reconstituted in vitro editing assay with recombinant protein; antisense knockdown The Journal of biological chemistry High 11577082
2002 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. In vitro splicing assay; dominant-negative mutant cotransfection; RNA binding assays; minigene reporter Molecular cell High 11931771
2003 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. 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 Molecular cell High 12535526
2004 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. GFP fusion protein live imaging; deletion mutants and domain swapping; leptomycin B treatment; cotransfection with cTNT minigene for splicing activity Journal of cell science High 15226369
2004 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. Comparative deletion analysis; in vivo splicing cotransfection assay with cTNT minigene; RNA binding assays Nucleic acids research Medium 14973222
2005 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. SELEX (5 rounds); minigene splicing assay; site-directed mutagenesis of SELEX motif Molecular and cellular biology High 15657417
2006 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. Ectopic expression in cellular models; RT-PCR splicing analysis Journal of neuroscience research Medium 16862542
2006 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. GST pull-down; yeast 2-hybrid; nitrocellulose filter binding; UV cross-linking; immunocytochemistry; heterokaryon assay for nucleocytoplasmic shuttling; chimeric luciferase mRNA reporter assay Gastroenterology High 17383427
2008 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. RNA immunoprecipitation (RIP); in vitro RNA binding; luciferase reporter assay; Western blot; flow cytometry; stable overexpression cell line American journal of physiology. Gastrointestinal and liver physiology High 18292181
2008 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. Immunocytochemistry; luciferase reporter assay; Western blot; flow cytometry; overexpression of splice variants in HCT116 cells American journal of physiology. Gastrointestinal and liver physiology Medium 18258790
2009 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. Chemical modification footprinting; in vitro splicing assay; identification of novel target exons with similar branch-site perimeter motif configurations PLoS genetics High 19680430
2010 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. Minigene splicing assay; deletion and domain-swapping mutants; RNA binding assays; competition binding with U2AF65 Nucleic acids research High 20631008
2011 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. Ectopic overexpression and siRNA knockdown of splicing factors; RT-PCR splicing analysis; patient brain tissue analysis Biochimica et biophysica acta Medium 21439371
2011 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. RNA binding assays; CELF2 knockdown; minigene reporter; RT-PCR Molecular and cellular biology Medium 21444716
2012 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. miRNA overexpression via AAV vector; mRNA stability assay; Western blot; mouse model phenotyping Nature medicine Medium 22660636
2012 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. NMR spectrometry; molecular dynamics simulation; minigene splicing assay; overexpression of isoforms BMC biochemistry Medium 22433174
2013 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. Gene silencing; fluorescence microscopy of stress granules; cell biological assays Cell biology international Low 23661609
2015 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. NF-κB inhibitor; promoter-reporter assays; mRNA stability assay (actinomycin D chase); 3'UTR APA analysis; splicing-sensitive arrays; siRNA knockdown Proceedings of the National Academy of Sciences of the United States of America High 25870297
2015 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. JNK inhibitor; siRNA knockdown of CELF2; minigene reporter; RNA binding assay; phosphorylation assays; splicing-sensitive RT-PCR; RNA-seq Genes & development High 26443849
2016 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. CLIP-Seq; comparison with functional splicing data from same cell line RNA biology Medium 27096301
2017 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. siRNA screen; cross-link immunoprecipitation (CLIP); mutational analysis of cis-element; minigene reporter; RT-PCR correlation across model systems Molecular and cellular biology High 28031331
2019 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. CELF2 CLIP-Seq overlaid with APA enhancer maps; APA-seq; CELF2 knockdown; competition binding assays Cell reports High 31509743
2019 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. RNA immunoprecipitation; mRNA stability assay; Western blot; autophagic vacuole analysis; electron microscopy; xenograft knockdown Molecular carcinogenesis Medium 31020708
2019 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. Co-immunoprecipitation; PTEN phosphatase activity assay; Western blot for p-Akt; PTEN-null cell controls; patient-derived xenograft Carcinogenesis Medium 31241130
2019 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. Methylation analysis; CELF2 re-expression; splicing analysis; growth assays Oncogene Medium 31409895
2020 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. Overexpression of CELF1/CELF2; chimeric minigene analysis; Western blot for full-length TREM2; panel of RNA-binding proteins Scientific reports Medium 33093587
2020 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. siRNA knockdown of each factor; mRNA and protein level measurements; translation efficiency assay; splicing-sensitive analysis Nucleic acids research Medium 32338744
2020 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. RNA binding assay (RIP); mRNA stability assay; FAM198B knockdown rescue experiments; Western blot for ERK signaling Molecular therapy. Nucleic acids Medium 33335801
2020 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. Live cell imaging; subcellular fractionation; iPSC-derived NPCs; mouse genetic model; RNA-seq; de novo variant functional characterization Cell reports High 34107259
2020 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. Transfection of mutant CELF2 cDNA plasmids; subcellular localization assay; whole-exome sequencing of patients Human mutation Medium 33131106
2021 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. Co-immunoprecipitation/pulldown of pre-miR-155 with CELF2; CRISPR-Cas9 knockdown; RT-qPCR for miR-155 and TNF-α PloS one Medium 32324763
2021 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. RNA immunoprecipitation (RIP); mRNA stability assay; GAS5/VAV1 knockdown functional assays; rat SCI model Scientific reports Medium 33574559
2022 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. m6A sequencing; RIP for YTHDF2; splicing analysis; ALKBH5 manipulation; ERAD pathway inhibitor (EerI); transcriptomic analysis Cell & bioscience Medium 35941702
2024 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. RIP-Seq; RNA-seq; mouse AML model (MLL-AF9); mTORC1 inhibitor treatment; biochemical assays for AKT/mTORC1 phosphorylation Oncogene Medium 38514854
2024 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. RNA pull-down/RIP; mRNA stability assay; Western blot for p-AKT; proliferation and migration assays Life sciences Medium 40154776
2024 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. 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) bioRxivpreprint Medium 39553957
2024 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. Cis-regulatory element mapping; overexpression/knockdown of CUGBP2; minigene reporter; RNA binding assay Biochemical and biophysical research communications Medium 39550869
2025 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. CELF2 knockdown; IFN reporter assay; RNA transfer experiment; RNase III treatment; dsRNA immunoprecipitation; pathway inhibitors (RIG-I/MAVS) bioRxivpreprint Medium bio_10.1101_2025.03.27.645787
2025 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. iPSC-derived neurons from patients with CELF2 variants; transgenic mouse models; drug screening (AKT inhibitors/activators); electrophysiology; behavioral tests; RNA-seq medRxivpreprint Medium 40666314
2026 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. Constitutive Celf2 knockout mouse; bulk RNA-seq; splicing analysis; snRNA-seq; CaMK2A 3'UTR binding; C. elegans genetic rescue; histological and pseudotime analyses Molecular neurobiology Medium 42189331

Source papers

Stage 0 corpus · 94 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Genome-wide association of familial late-onset Alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE. PLoS genetics 204 21379329
2003 Coupled mRNA stabilization and translational silencing of cyclooxygenase-2 by a novel RNA binding protein, CUGBP2. Molecular cell 191 12535526
2002 Dynamic antagonism between ETR-3 and PTB regulates cell type-specific alternative splicing. Molecular cell 155 11931771
2012 Viral delivery of miR-196a ameliorates the SBMA phenotype via the silencing of CELF2. Nature medicine 118 22660636
1999 Cardiac elav-type RNA-binding protein (ETR-3) binds to RNA CUG repeats expanded in myotonic dystrophy. Human molecular genetics 97 9887331
2001 Novel role for RNA-binding protein CUGBP2 in mammalian RNA editing. CUGBP2 modulates C to U editing of apolipoprotein B mRNA by interacting with apobec-1 and ACF, the apobec-1 complementation factor. The Journal of biological chemistry 84 11577082
2005 Identification of putative new splicing targets for ETR-3 using sequences identified by systematic evolution of ligands by exponential enrichment. Molecular and cellular biology 81 15657417
2008 Translation inhibition during cell cycle arrest and apoptosis: Mcl-1 is a novel target for RNA binding protein CUGBP2. American journal of physiology. Gastrointestinal and liver physiology 64 18292181
2006 Functional antagonism between RNA binding proteins HuR and CUGBP2 determines the fate of COX-2 mRNA translation. Gastroenterology 63 17383427
2015 Widespread JNK-dependent alternative splicing induces a positive feedback loop through CELF2-mediated regulation of MKK7 during T-cell activation. Genes & development 60 26443849
2011 RNA binding protein CUGBP2/CELF2 mediates curcumin-induced mitotic catastrophe of pancreatic cancer cells. PloS one 60 21347286
2018 miR-615-3p promotes proliferation and migration and inhibits apoptosis through its potential target CELF2 in gastric cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 58 29501762
2019 Epigenetic inactivation of the splicing RNA-binding protein CELF2 in human breast cancer. Oncogene 56 31409895
2015 Induced transcription and stability of CELF2 mRNA drives widespread alternative splicing during T-cell signaling. Proceedings of the National Academy of Sciences of the United States of America 55 25870297
2020 LncRNA CRNDE facilitates epigenetic suppression of CELF2 and LATS2 to promote proliferation, migration and chemoresistance in hepatocellular carcinoma. Cell death & disease 51 32826865
2004 Multiple domains control the subcellular localization and activity of ETR-3, a regulator of nuclear and cytoplasmic RNA processing events. Journal of cell science 51 15226369
2011 Mis-splicing of Tau exon 10 in myotonic dystrophy type 1 is reproduced by overexpression of CELF2 but not by MBNL1 silencing. Biochimica et biophysica acta 50 21439371
2022 Exosomal miR-625-3p secreted by cancer-associated fibroblasts in colorectal cancer promotes EMT and chemotherapeutic resistance by blocking the CELF2/WWOX pathway. Pharmacological research 44 36336217
2020 CELF2 suppresses non-small cell lung carcinoma growth by inhibiting the PREX2-PTEN interaction. Carcinogenesis 44 31241130
2012 Reduced Expression of RNA Binding Protein CELF2, a Putative Tumor Suppressor Gene in Colon Cancer. Immuno-gastroenterology 44 23795348
2011 Signal- and development-dependent alternative splicing of LEF1 in T cells is controlled by CELF2. Molecular and cellular biology 44 21444716
2006 ETR-3 represses Tau exons 2/3 inclusion, a splicing event abnormally enhanced in myotonic dystrophy type I. Journal of neuroscience research 44 16862542
2020 The RNA-Binding Protein CELF2 Inhibits Ovarian Cancer Progression by Stabilizing FAM198B. Molecular therapy. Nucleic acids 42 33335801
2019 RNA Binding Protein CELF2 Regulates Signal-Induced Alternative Polyadenylation by Competing with Enhancers of the Polyadenylation Machinery. Cell reports 42 31509743
2016 Position-dependent activity of CELF2 in the regulation of splicing and implications for signal-responsive regulation in T cells. RNA biology 42 27096301
2001 Genomic organization and isoform-specific tissue expression of human NAPOR (CUGBP2) as a candidate gene for familial arrhythmogenic right ventricular dysplasia. Genomics 40 11414768
2004 ETR-3 and CELF4 protein domains required for RNA binding and splicing activity in vivo. Nucleic acids research 37 14973222
2002 Expression and mutation analysis of BRUNOL3, a candidate gene for heart and thymus developmental defects associated with partial monosomy 10p. Journal of molecular medicine (Berlin, Germany) 37 12110949
2003 CUGBP2 plays a critical role in apoptosis of breast cancer cells in response to genotoxic injury. Annals of the New York Academy of Sciences 35 15033780
2015 Downregulation of miR-95-3p inhibits proliferation, and invasion promoting apoptosis of glioma cells by targeting CELF2. International journal of oncology 32 26165303
2008 CUGBP2 downregulation by prostaglandin E2 protects colon cancer cells from radiation-induced mitotic catastrophe. American journal of physiology. Gastrointestinal and liver physiology 30 18325984
2009 The CUGBP2 splicing factor regulates an ensemble of branchpoints from perimeter binding sites with implications for autoregulation. PLoS genetics 29 19680430
2022 N6-methyladenosine-mediated CELF2 regulates CD44 alternative splicing affecting tumorigenesis via ERAD pathway in pancreatic cancer. Cell & bioscience 27 35941702
2021 Nucleocytoplasmic transport of the RNA-binding protein CELF2 regulates neural stem cell fates. Cell reports 27 34107259
2020 CELF2 regulates the species-specific alternative splicing of TREM2. Scientific reports 27 33093587
2010 CELF proteins regulate CFTR pre-mRNA splicing: essential role of the divergent domain of ETR-3. Nucleic acids research 27 20631008
2020 De novo variants in CELF2 that disrupt the nuclear localization signal cause developmental and epileptic encephalopathy. Human mutation 26 33131106
2018 microRNA-451 protects neurons against ischemia/reperfusion injury-induced cell death by targeting CELF2. Neuropsychiatric disease and treatment 26 30425495
2004 Dynamic antagonism between RNA-binding protein CUGBP2 and cyclooxygenase-2-mediated prostaglandin E2 in radiation damage. Proceedings of the National Academy of Sciences of the United States of America 26 15358864
2021 Triclosan regulates alternative splicing events of nerve-related genes through RNA-binding protein CELF2 to induce zebrafish neurotoxicity. Journal of hazardous materials 25 33621777
2008 Novel intestinal splice variants of RNA-binding protein CUGBP2: isoform-specific effects on mitotic catastrophe. American journal of physiology. Gastrointestinal and liver physiology 24 18258790
2021 LncRNA-SNHG16 promotes proliferation and migration of acute myeloid leukemia cells via PTEN/PI3K/AKT axis through suppressing CELF2 protein. Journal of biosciences 21 33576342
2020 Reciprocal regulation of hnRNP C and CELF2 through translation and transcription tunes splicing activity in T cells. Nucleic acids research 21 32338744
2020 STYXL1 promotes malignant progression of hepatocellular carcinoma via downregulating CELF2 through the PI3K/Akt pathway. European review for medical and pharmacological sciences 18 32271415
2015 Upregulation of cugbp2 increases response of pancreatic cancer cells to chemotherapy. Langenbeck's archives of surgery 17 26691217
2021 miR-363-3p induces EMT via the Wnt/β-catenin pathway in glioma cells by targeting CELF2. Journal of cellular and molecular medicine 16 34636136
2017 Activation-Dependent TRAF3 Exon 8 Alternative Splicing Is Controlled by CELF2 and hnRNP C Binding to an Upstream Intronic Element. Molecular and cellular biology 16 28031331
2012 Alternative splicing produces structural and functional changes in CUGBP2. BMC biochemistry 16 22433174
2021 LncRNA CCDC26 Interacts with CELF2 Protein to Enhance Myeloid Leukemia Cell Proliferation and Invasion via the circRNA_ANKIB1/miR-195-5p/PRR11 Axis. Cell transplantation 15 33439746
2020 Long noncoding RNA GAS5 ameliorates chronic constriction injury induced neuropathic pain in rats by modulation of the miR-452-5p/CELF2 axis. Canadian journal of physiology and pharmacology 15 33264082
2019 Pleotropic role of RNA binding protein CELF2 in autophagy induction. Molecular carcinogenesis 14 31020708
2021 CircPTK2 inhibits the tumorigenesis and metastasis of gastric cancer by sponging miR-134-5p and activating CELF2/PTEN signaling. Pathology, research and practice 12 34562827
2021 GAS5 knockdown alleviates spinal cord injury by reducing VAV1 expression via RNA binding protein CELF2. Scientific reports 11 33574559
2021 LncRNA RHPN1-AS1 promotes the progression of nasopharyngeal carcinoma by targeting CELF2 expression. Experimental and molecular pathology 11 34358519
2024 miR-208a-3p regulated by circUQCRC2 suppresses ischemia/reperfusion-induced acute kidney injury by inhibiting CELF2-mediated tubular epithelial cell apoptosis, inflammation and ferroptosis. Shock (Augusta, Ga.) 10 38664873
2023 M2 macrophage-derived exosomal miR-1911-5p promotes cell migration and invasion in lung adenocarcinoma by down-regulating CELF2 -activated ZBTB4 expression. Anti-cancer drugs 10 36730375
2023 Hypoxia-induced lncRNA MRVI1-AS1 accelerates hepatocellular carcinoma progression by recruiting RNA-binding protein CELF2 to stabilize SKA1 mRNA. World journal of surgical oncology 10 36973749
2023 Role of CELF2 in ferroptosis: Potential targets for cancer therapy (Review). International journal of molecular medicine 9 37594127
2021 RNA-binding protein CELF2 inhibits breast cancer cell invasion and angiogenesis by downregulating NFATc1. Experimental and therapeutic medicine 9 34257711
2009 Transcriptional induction and translational inhibition of Arc and Cugbp2 in mice hippocampus after transient global ischemia under normothermic condition. Brain research 9 19559013
2022 CircLIFR Inhibits Non-small Cell Lung Cancer Progression by Acting as a miR-429 Sponge to Enhance CELF2 Expression. Biochemical genetics 8 36104590
2021 Suppression of miR-106a-5p expression inhibits tumorigenesis via increasing CELF-2 expression in spinal cord glioma. Oncology letters 8 34267819
2020 Interleukin-10 control of pre-miR155 maturation involves CELF2. PloS one 8 32324763
2023 CELF2 Sustains a Proliferating/OLIG2+ Glioblastoma Cell Phenotype via the Epigenetic Repression of SOX3. Cancers 7 37894405
2022 MiR-210-3p targets CELF2 to facilitate progression of lung squamous carcinoma through PI3K/AKT pathway. Medical oncology (Northwood, London, England) 7 35972577
2024 Loss of RNA-binding protein CELF2 promotes acute leukemia development via FAT10-mTORC1. Oncogene 6 38514854
2024 CELF2 Deficiency Demonstrates Autism-Like Behaviors and Interferes with Late Development of Cortical Neurons in Mice. Molecular neurobiology 6 38829512
2022 Natural Antisense Long Noncoding RNA HHIP-AS1 Suppresses Non-Small-Cell Lung Cancer Progression by Increasing HHIP Stability via Interaction with CELF2. Critical reviews in eukaryotic gene expression 6 36374812
2013 A novel function for CUGBP2 in controlling the pro-inflammatory stimulus in H9c2 cells: subcellular trafficking of messenger molecules. Cell biology international 6 23661609
2022 ELK1-Induced upregulation of long non-coding TNK2-AS1 promotes the progression of acute myeloid leukemia by EZH2-mediated epigenetic silencing of CELF2. Cell cycle (Georgetown, Tex.) 5 35941836
2020 The Role of VEGFA, COX2, HUR and CUGBP2 in Predicting the Response to Neoadjuvant Therapy in Rectal Cancer Patients. Medicina (Kaunas, Lithuania) 5 32331433
2025 The HNRNPC/CELF2 signaling pathway drives glycolytic reprogramming and mitochondrial dysfunction in drug-resistant acute myeloid leukemia. Cell & bioscience 3 40380235
2025 Investigation of lncRNA expression in newly diagnosed multiple myeloma reveals a LINC01432-CELF2 axis as an inhibitor of apoptosis. Oncogenesis 3 41052980
2024 LINC00261 triggers DNA damage via the miR-23a-3p/CELF2 axis to mitigate the malignant characteristics of 131I-resistant papillary thyroid carcinoma cells. Biochemistry and biophysics reports 3 39552712
2024 CELF2 promotes tau exon 10 inclusion via hinge domain-mediated nuclear condensation. bioRxiv : the preprint server for biology 3 39553957
2022 The Histone Demethylase HR Suppresses Breast Cancer Development through Enhanced CELF2 Tumor Suppressor Activity. Cancers 3 36230572
2016 ORF13 in the Type III secretion system gene cluster of Edwardsiella tarda binds to the mammalian factor Cugbp2. Diseases of aquatic organisms 3 27137075
2025 Genetic variants disrupting activity-dependent CELF2 shuttling cause neuronal hyperexcitability, learning deficits, and seizures. medRxiv : the preprint server for health sciences 2 40666314
2024 Loss of CELF2 promotes skin tumorigenesis and increases drug resistance. International journal of dermatology 2 38887832
2025 CELF2 inhibits bladder cancer progression by decreasing the stability of CXCL5. Life sciences 1 40154776
2025 Transition of CELF2 PAS usage promotes recovery of refractory JDM through alternative splicing regulation of CTSB. Molecular therapy. Nucleic acids 1 40686855
2025 The regulation of miR-155 strand selection by CELF2, FUBP1 and KSRP proteins. Scientific reports 1 40825800
2024 Generation and characterization of a human iPSC line and gene-corrected isogenic line derived from a patient with a CELF2 gene mutation. Stem cell research 1 38364506
2024 RNA binding protein CUGBP2/ETR-3 regulates STAT3 alternative splicing. Biochemical and biophysical research communications 1 39550869
2022 Erratum: RNA-binding protein CELF2 inhibits breast cancer cell invasion and angiogenesis by downregulating NFATc1. Experimental and therapeutic medicine 1 35222722
2019 Structure of an Unfolding Intermediate of an RRM Domain of ETR-3 Reveals Its Native-like Fold. Biophysical journal 1 31866002
2026 LncRNA Dleu2 regulates fear extinction memory through Celf2-driven synaptic plasticity. Brain research bulletin 0 41628728
2026 CELF2 Promotes Tau Exon 10 Inclusion via Hinge Domain-Mediated Nuclear Condensation, Driving Cognitive Dysfunction in Tauopathy Models. Research square 0 41646425
2026 miR-628-3p exacerbates allergic rhinitis inflammation by targeting CELF2: A novel mechanistic insight. Clinics (Sao Paulo, Brazil) 0 42068646
2026 CELF2-dependent RNA Regulation Supports Cortical Architecture and Synaptic Stability During Early Brain Development. Molecular neurobiology 0 42189331
2025 Correction: Turchi et al. CELF2 Sustains a Proliferating/OLIG2+ Glioblastoma Cell Phenotype via the Epigenetic Repression of SOX3. Cancers 2023, 15, 5038. Cancers 0 40361521
2025 Exploring the Molecular Mechanisms and Biological Effects of CELF2 in the Development of Gastric Cancer. Recent patents on anti-cancer drug discovery 0 40798961
2013 Purification, crystallization and preliminary crystallographic studies of C-terminal RNA recognition motif (RRM-3) of human ELAV-type RNA-binding protein 3 (ETR-3). Acta crystallographica. Section F, Structural biology and crystallization communications 0 24100559
2010 1H, 13C and 15N NMR assignments of RNA recognizing motifs 1 and 2 of BRUNOL-3 protein from human involved in myotonic dystrophy. Biomolecular NMR assignments 0 20443086

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