{"gene":"RBM4","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1996,"finding":"Drosophila LARK (RBM4 ortholog) encodes an RRM-class RNA-binding protein with two RRM domains and a retroviral-type zinc finger (RTZF), and acts as a negative regulator (repressor) of the eclosion output pathway; gene dosage experiments showed decreased LARK causes early eclosion and increased LARK causes late eclosion, consistent with a repressor function.","method":"Genetic analysis, gene dosage experiments, sequence/domain analysis","journal":"Journal of neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with clear phenotypic readout, replicated by dosage series, single lab","pmids":["9120432"],"is_preprint":false},{"year":2000,"finding":"Drosophila LARK protein exhibits circadian changes in abundance in CCAP peptidergic neurons and is present in the cytoplasm of these cells (unlike its nuclear distribution in most cell types), suggesting cell-type-specific cytoplasmic RNA-binding functions linked to circadian regulation of ecdysis.","method":"Immunocytochemistry, protein blotting, subcellular fractionation/localization","journal":"Journal of neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence tied to circadian behavior, single lab","pmids":["10992253"],"is_preprint":false},{"year":2001,"finding":"Site-directed mutagenesis of Drosophila LARK demonstrated that RRM1, RRM2, and the RTZF zinc finger are each required for wild-type in vivo function; RRM1 and RRM2 are essential for viability, while RRM2 and RTZF act together for developmental and morphological functions.","method":"Site-directed mutagenesis, in vivo genetic analysis","journal":"Genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of each structural domain with clear in vivo phenotypic readouts, multiple domain mutations tested","pmids":["11560900"],"is_preprint":false},{"year":2005,"finding":"RBM4 directly influences alpha-tropomyosin exon selection by binding to intronic pyrimidine-rich/CU-rich elements and antagonizing PTB-mediated exon exclusion; RBM4 activates skeletal muscle-specific exon inclusion by competing with PTB for a CU-rich element.","method":"Differential display, minigene splicing assays, co-immunoprecipitation, RNA-binding assays, overexpression/knockdown","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — minigene functional assays with mutagenesis of cis-elements, direct RNA-binding demonstrated, overexpression and knockdown both performed","pmids":["16260624"],"is_preprint":false},{"year":2006,"finding":"RBM4 stimulates tau exon 10 inclusion by binding to a putative intronic splicing enhancer in intron 10; mutations in the RNA-binding domain of RBM4 abolish this splicing stimulatory activity.","method":"Expression cloning, tau minigene transfection, RBM4 overexpression/knockdown, RNA-binding domain mutagenesis, immunohistology","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — minigene assay with domain mutagenesis, loss-of-function and gain-of-function, intronic enhancer mapped","pmids":["16777844"],"is_preprint":false},{"year":2006,"finding":"RBM4 (shown to be identical to LARK) localizes to nuclear speckles and nucleoli; the C-terminus is required for targeting to speckles; upon transcription inhibition, RBM4 redistributes to perinucleolar clusters, a behavior distinct from other splicing factors.","method":"Immunofluorescence imaging, C-terminal deletion/mutation constructs, transcription inhibitor treatment","journal":"DNA and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional domain mapping, single lab, multiple constructs tested","pmids":["16907643"],"is_preprint":false},{"year":2006,"finding":"WT1(+KTS) isoform physically interacts with RBM4, colocalizes in nuclear speckles, cosediments with supraspliceosomes, and abrogates RBM4-mediated alternative splicing regulation in a dose-dependent, cell-specific manner; WT1(-KTS) does not interact with RBM4.","method":"Co-immunoprecipitation, glycerol gradient sedimentation, immunofluorescence colocalization, minigene splicing reporter assays, overexpression","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, colocalization, functional splicing assay, single lab","pmids":["16934801"],"is_preprint":false},{"year":2007,"finding":"Cell stress (arsenite) induces phosphorylation of RBM4 at serine 309 via the MKK(3/6)-p38 signaling pathway, drives cytoplasmic accumulation and targeting to stress granules, suppresses cap-dependent translation in a cis-element-dependent manner, and activates IRES-mediated translation by promoting association of eIF4A with IRES-containing mRNAs; a nonphosphorylatable S309 mutant fails to activate IRES-mediated translation.","method":"Phospho-specific analysis, p38 pathway inhibition, stress granule imaging, cap-dependent/IRES reporter assays, Co-IP (RBM4-eIF4A), S309A mutant, polysome profiling","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (phospho-mutant, IRES reporter, Co-IP, pathway inhibition, localization) in single rigorous study","pmids":["17284590"],"is_preprint":false},{"year":2007,"finding":"Mouse LARK (mLARK/RBM4) directly binds a cis-element in the 3' UTR of mPer1 mRNA and activates mPER1 protein expression through translational regulation; mLARK knockdown shortens circadian period and overexpression lengthens it in cycling cells.","method":"RNA pulldown/direct binding assay, siRNA knockdown, overexpression, circadian period measurement in cycling cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding to 3'UTR demonstrated, both loss- and gain-of-function with quantitative period phenotype, multiple orthogonal methods","pmids":["17264215"],"is_preprint":false},{"year":2008,"finding":"Drosophila FMRP (dFMRP) physically interacts with LARK, the two proteins are present in a complex in vivo, LARK promotes stability of dFMRP, and genetic interactions demonstrate they function together to regulate eye development and circadian behavior.","method":"Co-immunoprecipitation, in vivo complex analysis, genetic epistasis, protein stability assay","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical interaction (Co-IP) plus genetic epistasis, single lab","pmids":["18842880"],"is_preprint":false},{"year":2009,"finding":"RBM4 and CoAA counter-regulate tau exon 10 splicing and undergo trans-splicing during stem/progenitor cell neural differentiation; CoAA and RBM4 splice variants generated by trans-splicing affect each other's splicing activities and lineage-specific gene expression.","method":"Trans-splicing variant identification, overexpression, minigene reporter assays, embryoid body formation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional trans-splicing validated with splicing reporters and cellular differentiation assay, single lab","pmids":["19416963"],"is_preprint":false},{"year":2011,"finding":"RBM4 down-regulates PTB and nPTB expression during myogenesis by activating exon skipping of their transcripts, coupling to nonsense-mediated mRNA decay; RBM4 and PTB target a common set of transcripts for muscle cell-specific alternative splicing, with RBM4 promoting muscle-specific isoforms and PTB acting oppositely, establishing a hierarchical splicing cascade.","method":"Alternative splicing analysis, NMD assays, overexpression/knockdown, isoform-specific RT-PCR, minigene assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — mechanistic cascade demonstrated with multiple methods (AS-NMD, minigene, KO/OE), clearly defined epistatic relationship","pmids":["21518792"],"is_preprint":false},{"year":2012,"finding":"RBM4 knockout mice exhibit hyperglycemia, reduced insulin, and reduced pancreatic islet size; RBM4 promotes insulin gene expression and pancreas cell differentiation by altering isoform balance of transcription factors Isl1 and Pax4 via alternative splicing, and overexpression of RBM4 is sufficient to convert AR42J acinar cells into insulin-producing cells.","method":"Gene knockout (mouse), pancreas histology, glucose/insulin measurement, overexpression in AR42J cells, minigene/RT-PCR splicing analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO phenotype plus cell-based reconstitution showing isoform-specific mechanism, multiple orthogonal methods","pmids":["23129807"],"is_preprint":false},{"year":2013,"finding":"TLR4-induced miR-146a promotes cytoplasmic accumulation of RBM4 by preventing phosphorylation of RBM4 at serine-309 by p38 MAPK; cytoplasmic RBM4 then interacts with Ago2, forming a translation-repressor complex that inhibits TNFα and IL-6 cytokine synthesis in endotoxin-adapted monocytes.","method":"miR-146a antagomirs, phosphatase inhibitor (okadaic acid), Co-IP (RBM4-Ago2), subcellular fractionation, cytokine measurement","journal":"Immunology and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, subcellular localization, functional cytokine output, multiple perturbations, single lab","pmids":["23897118"],"is_preprint":false},{"year":2013,"finding":"RBM4 homologs from multiple species can be phosphorylated by SR protein kinases; the C-terminal domain of RBM4 influences subnuclear localization and functional divergence between homologs, while the N-terminal RNA-binding domain has a dominant role in determining splicing outcome.","method":"In vitro kinase assay, chimeric construct analysis, immunofluorescence, minigene splicing reporter assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus chimeric domain swap with functional splicing readout, single lab","pmids":["23527094"],"is_preprint":false},{"year":2014,"finding":"RBM4 suppresses cancer cell proliferation and migration by regulating cancer-related alternative splicing; specifically, RBM4 regulates Bcl-x splicing to induce apoptosis (coexpression of Bcl-xL partially reverses RBM4-mediated tumor suppression), and RBM4 antagonizes SRSF1 to inhibit mTOR activation.","method":"Overexpression/knockdown, splicing reporter assays, apoptosis assays, migration assays, xenograft models, epistasis by Bcl-xL coexpression","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cancer cell lines, genetic epistasis (Bcl-xL rescue), mTOR pathway analysis, in vivo xenograft, multiple orthogonal methods","pmids":["25203323"],"is_preprint":false},{"year":2014,"finding":"Elevated SRPK1 causes cytoplasmic accumulation of RBM4 in breast cancer cells; RBM4 binds CU-rich elements within MCL-1 exon 2 and downstream intron to facilitate exon exclusion, generating the pro-apoptotic MCL-1S isoform; SRPK1-RBM4 network modulates apoptotic sensitivity through IR-B and MCL-1S splicing.","method":"Overexpression/siRNA knockdown, RNA-immunoprecipitation, minigene splicing assays, Co-IP, subcellular fractionation","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct RNA binding mapped to CU-rich elements, minigene functional validation, subcellular localization linked to mechanism, multiple methods","pmids":["25140042"],"is_preprint":false},{"year":2014,"finding":"Drosophila LARK directly regulates translation of dbt (DOUBLETIME/CKIδ/ε) transcripts in clock cells; LARK promotes translation of dbt-RC and light-induced dbt-RE transcripts, and altered LARK abundance affects circadian period length in a dbt allele-dependent manner; LARK delays nuclear degradation of PER, consistent with DBT regulation.","method":"Translational reporter assays, genetic epistasis with dbt alleles, circadian period measurement, in vivo translation analysis","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional translational reporter plus allele-specific epistasis, single lab","pmids":["25211129"],"is_preprint":false},{"year":2015,"finding":"During brown adipocyte differentiation, RBM4 enhances skipping of the MEF2Cγ exon; the resulting MEF2Cγ- isoform in turn induces transcriptional activity of the RBM4 promoter, establishing a positive feed-forward circuit; this network induces miR-1 expression to promote brown adipogenesis.","method":"Overexpression, splicing reporter assays, promoter-luciferase reporter, differentiation assays in C3H10T1/2 cells","journal":"RNA biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — splicing and promoter reporter assays with functional differentiation readout, single lab","pmids":["25826570"],"is_preprint":false},{"year":2016,"finding":"RBM4 directly regulates alternative splicing of pyruvate kinase M (PKM), promoting the PKM2-to-PKM1 isoform switch during neuronal differentiation; RBM4 antagonizes PTB in PKM splicing; overexpression of RBM4 or PKM1 increases mitochondrial respiration capacity and promotes neuronal differentiation of mesenchymal stem cells.","method":"RBM4 knockout mouse, PKM minigene assay, siRNA knockdown, overexpression, mitochondrial respiration (Seahorse), splicing RT-PCR","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — minigene functional assay, in vivo KO, mitochondrial function measurement, PKM1 overexpression rescue, multiple orthogonal methods","pmids":["27821480"],"is_preprint":false},{"year":2016,"finding":"RBM4 modulates Numb isoform expression by promoting exon 3 inclusion and exon 9 exclusion; RBM4-depleted embryonic mouse brain shows aberrant Numb splicing; the RBM4-induced Numb isoform (with exon 3, without exon 9) restores Mash1 expression and neuronal differentiation; this Numb isoform also rescues neurite outgrowth defects in RBM4-depleted neurons.","method":"RBM4 knockout mouse, splicing minigene reporter, siRNA knockdown, overexpression, in utero electroporation, neurite outgrowth assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO, minigene, rescue by specific isoform, multiple orthogonal methods","pmids":["27009199"],"is_preprint":false},{"year":2016,"finding":"RBM4a ablation increases PTBP1, PTBP2, and Nova1 proteins; elevated RBM4a reduces PTBP1/2 via AS-coupled NMD; RBM4a indirectly shortens Nova1 transcript half-life through PTBP2 regulation; RBM4a counteracts PTBP2's effects on FGFR2 and PKM splicing during brown adipogenesis.","method":"RNA-sequencing, RT-PCR, overexpression/knockout, NMD assays, transcript stability assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq plus functional AS-NMD validation, multiple targets analyzed, single lab","pmids":["26857472"],"is_preprint":false},{"year":2016,"finding":"RBM4a ablation enhances Nova1 exon 4-excluded isoform; Nova1 isoforms differentially repress brown adipocyte development; overexpression of Nova1 reduces SRSF6 by enhancing intron 2-retained SRSF6 transcripts (AS-NMD); SRSF6 positively affects brown adipocyte development, establishing an RBM4a-Nova1-SRSF6 splicing cascade.","method":"RNA-sequencing, KO mouse, overexpression/knockdown, RT-PCR, differentiation assays","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq with functional validation in KO cells, cascade confirmed by overexpression, single lab","pmids":["27535496"],"is_preprint":false},{"year":2017,"finding":"RBM4 reprograms splicing profile of SRSF3; upregulated SRSF3 modulates MAP4K4 exon 16 utilization in a sequence-dependent manner; alternatively spliced MAP4K4 variants exhibit differential phosphorylation of JNK1 and modulate E-cadherin, N-cadherin, vimentin expression, controlling migration/invasion of colorectal cancer cells.","method":"RNA-sequencing, RT-PCR, overexpression/knockdown, minigene assays, JNK phosphorylation assay, migration/invasion assays","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cascade validated by splicing reporter and downstream signaling/phenotypic assays, single lab","pmids":["29138007"],"is_preprint":false},{"year":2018,"finding":"RBM4 promotes inclusion of Dab1 exons 7/8 and directly counteracts PTBP1-mediated exon skipping; Rbm4a knockout brain shows altered Dab1 isoform ratios and delayed cortical neuronal migration; full-length Dab1 (but not exon 7/8-truncated Dab1) rescues neuronal migration defects in RBM4-depleted neurons.","method":"RBM4 knockout mouse, RNA immunoprecipitation with high-throughput sequencing (RIP-seq), in utero electroporation, splicing minigene, overexpression/knockdown, migration assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — RIP-seq identifies target, in vivo KO plus in utero electroporation, isoform-specific rescue experiment, multiple orthogonal methods","pmids":["29581187"],"is_preprint":false},{"year":2018,"finding":"RBM4a enhances production of PRDM16-ex16 transcripts (encoding PRDM16S isoform) by simultaneously interacting with exonic and intronic CU elements; the PRDM16S isoform more strongly enhances RBM4a and PGC-1α promoter activity and BAT-related gene programs than PRDM16L.","method":"RNA-sequencing, RT-PCR, overexpression, RNA-immunoprecipitation, promoter reporter assay","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA binding to CU elements shown by RIP, functional promoter reporter, single lab","pmids":["30327195"],"is_preprint":false},{"year":2019,"finding":"LARK/RBM4 is a G-quadruplex (G4)-binding protein; RBM4 from multiple species (including human) binds G4 structures in promoters of target genes; upon binding, RBM4 facilitates G4 formation and stability, enhancing transcription of target genes.","method":"EMSA, G4 pull-down, reporter assays, immunofluorescence (G4 visualization in vivo), overexpression/knockdown","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — EMSA demonstrates direct binding, reporter assays show functional consequence, single lab","pmids":["31165881"],"is_preprint":false},{"year":2019,"finding":"SRSF1 and RBM4 antagonistically regulate HIF-1α exon 14 utilization in a CU element-dependent manner: SRSF1 facilitates HIF-1α-ex14 (short isoform), while RBM4 enhances HIF-1α+ex14 (long isoform) production.","method":"Transcriptome analysis, splicing reporter assay, overexpression/knockdown, CU-element mutant reporters","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — splicing reporter with CU-element mutagenesis, overexpression/knockdown, single lab","pmids":["31491447"],"is_preprint":false},{"year":2020,"finding":"RBM4 directly binds HERV-K and HERV-H endogenous retroviral transcripts at CGG consensus elements; loss of RBM4 elevates HERV-K/-H transcript levels and HERV-K envelope protein expression; a conserved CGG-containing LTR element mediates RBM4 regulation of HERV-K.","method":"PAR-CLIP (photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation), siRNA knockdown, luciferase reporter assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — PAR-CLIP directly maps binding sites, reporter assay validates functional element, loss-of-function phenotype, multiple orthogonal methods","pmids":["33020268"],"is_preprint":false},{"year":2020,"finding":"RBM4 suppresses IFN-γ-induced M1 macrophage polarization by inhibiting glycolysis; RBM4 knockdown promotes STAT1 activation by increasing STAT1 mRNA stability; RBM4 interacts with YTHDF2 to degrade m6A-modified STAT1 mRNA, thereby reducing glycolysis-related gene transcription and M1 polarization.","method":"RNA-sequencing, protein immunoprecipitation with mass spectrometry, extracellular acidification rate (Seahorse), Co-IP (RBM4-YTHDF2), mRNA stability assay, overexpression/knockdown","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifies YTHDF2 interaction, mRNA stability assay, metabolic measurement, single lab with multiple orthogonal methods","pmids":["32248017"],"is_preprint":false},{"year":2020,"finding":"Drosophila Lark/RBM4 is induced by enteric infection; overexpression of lark promotes intron retention preferentially at the 5' end of transcripts, mimicking infection-induced splicing changes; Lark binding motif is enriched in retained intron sequences; lark overexpression and knockdown alter survival upon infection.","method":"Genome-wide splicing analysis across 38 inbred lines, overexpression/knockdown with survival assay, motif enrichment analysis","journal":"Genome biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systems splicing analysis plus overexpression/KD functional validation, single lab","pmids":["31948480"],"is_preprint":false},{"year":2022,"finding":"Nuclear AURKA promotes oncogenic splicing of RBM4 (from full-length RBM4-FL to short RBM4-S isoform) in a kinase-independent manner by disrupting SRSF3 binding to YTHDC1 and recruiting hnRNP K to YTHDC1, resulting in m6A-YTHDC1-hnRNP K-dependent exon skipping; RBM4-S abolishes RBM4-FL-mediated inhibition of SRSF1-mTORC1 signaling.","method":"Co-IP, nuclear fractionation, splicing reporter assays, overexpression/knockdown, kinase-dead AURKA mutant, mTORC1 pathway analysis","journal":"Signal transduction and targeted therapy","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic dissection with kinase-dead mutant, multiple protein interactions (Co-IP), splicing reporters, pathway analysis, multiple orthogonal methods","pmids":["35361747"],"is_preprint":false},{"year":2022,"finding":"RBM4 promotes VEGFA mRNA translation by directly binding the G4 structure within the IRES-A element of the VEGFA 5'UTR; disruption of the G4 structure reduces IRES activity; G4 stabilizer increases IRES activity; RBM4 knockdown reduces and overexpression increases IRES-mediated translation.","method":"EMSA, dicistronic reporter assay, G4 structure mutation, G4 stabilizer (PDS) treatment, siRNA knockdown, overexpression","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct binding by EMSA, functional reporter with G4 mutation, pharmacological G4 stabilization, single lab","pmids":["35054929"],"is_preprint":false},{"year":2023,"finding":"RBM4 competitively binds LKB1 to disrupt the LKB1/STRAD/MO25 heterotrimeric complex, recruits E3 ligase TRIM26 to LKB1, promotes LKB1 ubiquitination and nuclear degradation, and thereby suppresses LKB1-AMPK-mTOR signaling to allow bypass of senescence and promote glutamine-dependent proliferation in ESCC cells.","method":"Co-IP, ubiquitination assay, overexpression/knockdown, AMPK-mTOR pathway analysis, ESCC cell and xenograft models","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrates complex disruption, ubiquitination assay, pathway analysis, single lab with multiple methods","pmids":["37080995"],"is_preprint":false},{"year":2023,"finding":"RBM4 depletion reduces miR-1244 levels by promoting degradation of primary miR-1244 transcripts (pri-miR1244), leading to increased SERPINE1 expression and induction of cellular senescence; either SERPINE1 inhibitor or miR-1244 mimics attenuate RBM4 depletion-induced senescence.","method":"siRNA knockdown, miR-1244 mimic/antagomir, luciferase 3'UTR reporter, pri-miRNA stability assay, senescence assays (SA-β-gal, p21/p27), SERPINE1 inhibitor","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pri-miRNA stability assay, 3'UTR reporter, multiple perturbation rescue experiments, single lab","pmids":["36639375"],"is_preprint":false},{"year":2023,"finding":"RBM4 promotes expression of BDNF and full-length TrkB; constitutive knockout of both Rbm4 homologs reduces BDNF levels and causes cerebellar foliation defects and delayed motor learning; prenatal supplementation with TrkB agonist 7,8-dihydroxyflavone rescues cerebellar malformation and motor learning in Rbm4 double KO mice.","method":"Rbm4 double knockout mouse, cerebellar histology, BDNF/TrkB expression analysis, TrkB agonist supplementation, motor learning behavioral assay","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo double KO with rescue by downstream pathway agonist, multiple phenotypic readouts, mechanistic link to BDNF-TrkB established","pmids":["37670183"],"is_preprint":false},{"year":2023,"finding":"In cardiomyocytes, Ang II-induced m6A methylation of RBM4 mRNA enhances YTHDF1-mediated translation of RBM4; elevated RBM4 localizes in the nucleus and down-regulates PTBP1 expression to prevent cardiomyocyte hypertrophy.","method":"Overexpression/knockdown, m6A MeRIP, YTHDF1 interaction assay, subcellular fractionation, cardiomyocyte hypertrophy assay","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A MeRIP confirms methylation, YTHDF1 interaction shown, functional hypertrophy assay, single lab","pmids":["39118568"],"is_preprint":false},{"year":2023,"finding":"The m6A demethylase FTO stabilizes RBM4 mRNA by reducing its m6A methylation; FTO knockdown increases m6A on RBM4 mRNA and destabilizes it, reducing RBM4 expression; RBM4 in turn promotes RUNX2 exon 5 inclusion; overexpression of RBM4 in Fto-knockout cells restores RUNX2 exon 5 inclusion and odontoblast differentiation capacity.","method":"m6A MeRIP, mRNA stability assay, RBM4 overexpression/KO, splicing RT-PCR, mineralization assay, Fto knockout mouse","journal":"International endodontic journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A MeRIP, stability assay, in vivo KO, rescue by RBM4 overexpression, single lab","pmids":["37698901"],"is_preprint":false},{"year":2023,"finding":"AMG232 upregulates p53 which transcriptionally activates RBM4; RBM4 directly binds VEGFR2 mRNA and shortens its half-life, promoting its degradation and inhibiting glioma endothelial cell angiogenesis; both p53 silencing and RBM4 silencing reverse AMG232's anti-angiogenic effects.","method":"In vitro/in vivo angiogenesis assays, siRNA knockdown, p53-RBM4 promoter-reporter, mRNA half-life assay, RNA binding assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mRNA stability assay, promoter reporter, in vivo xenograft, rescue experiments, single lab","pmids":["36601864"],"is_preprint":false},{"year":2024,"finding":"RBM4 recognizes CU-rich sequences in intron 8 of TFEB, increasing production of the TFEB-L spliceosome which promotes autophagy; RBM4 overexpression increases autophagy and promotes differentiation of AML cells.","method":"Splicing reporter assay, CU-rich motif analysis, overexpression, autophagy assay, differentiation assay in THP-1/K562 cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct CU-rich motif identified, splicing reporter, functional autophagy/differentiation readout, single lab","pmids":["39214303"],"is_preprint":false},{"year":2024,"finding":"RBM4 promotes excision of Hsf1 intron 6; Rbm4 knockout induces intron 6 retention in Hsf1, downregulating HSF1 protein and its downstream target BDNF; NMDAR signaling promotes RBM4 nuclear translocation and RBM4-mediated intron excision via a CU-rich motif; RBM4 and PTB proteins play antagonistic roles in Hsf1 intron excision; ectopic HSF1 restores cerebellar foliation and motor learning in Rbm4-knockout mice.","method":"Rbm4 knockout mouse, splicing analysis, NMDAR signaling perturbation, CU-rich motif mutagenesis, HSF1 rescue experiment, cerebellar foliation/motor learning assay","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO, motif mutagenesis, NMDAR-RBM4 axis, downstream rescue by HSF1 overexpression, multiple orthogonal methods","pmids":["39738787"],"is_preprint":false}],"current_model":"RBM4 is a multifunctional RNA-binding protein containing two RRM domains and a CCHC-type zinc finger that (1) regulates alternative pre-mRNA splicing by binding CU-rich/pyrimidine-rich intronic and exonic elements, antagonizing PTB/SRSF1 activity to promote tissue-specific isoforms during muscle, neuronal, pancreatic, and adipocyte differentiation; (2) controls translation by switching between suppression of cap-dependent translation and activation of IRES-mediated translation in response to stress, a switch dependent on p38-mediated phosphorylation at serine 309; (3) shuttles between nucleus and cytoplasm under stress or oncogenic signals (e.g., SRPK1, miR-146a, AURKA-YTHDC1), altering its function in splicing versus translational control; (4) promotes posttranscriptional repression of ERV transcripts and VEGFR2 mRNA by binding and destabilizing them; and (5) interacts with partners including PTB, SRSF1, WT1(+KTS), eIF4A, Ago2, YTHDF2, TRIM26, and LKB1 to mediate its diverse roles in cancer suppression, innate immunity, circadian rhythms, and organogenesis."},"narrative":{"mechanistic_narrative":"RBM4 (the vertebrate ortholog of Drosophila LARK) is a multifunctional RNA-binding protein that controls cell-type-specific gene expression through both alternative pre-mRNA splicing and translational regulation [PMID:9120432, PMID:16260624, PMID:17284590]. As a splicing regulator it binds intronic and exonic CU-rich/pyrimidine-rich elements and acts antagonistically to PTB-family proteins, promoting tissue-specific exon usage in targets including alpha-tropomyosin, tau, Numb, Dab1, and PKM during muscle, neuronal, and other differentiation programs [PMID:16260624, PMID:16777844, PMID:21518792, PMID:27821480, PMID:27009199, PMID:29581187]. RBM4 establishes hierarchical splicing cascades by downregulating PTBP1/PTBP2 and Nova1 through alternative-splicing-coupled nonsense-mediated decay, thereby reinforcing differentiation-specific isoform landscapes [PMID:21518792, PMID:26857472, PMID:27535496]. Beyond splicing, cell stress drives p38 MAPK-mediated phosphorylation of RBM4 at serine 309, triggering cytoplasmic relocalization to stress granules, suppression of cap-dependent translation, and activation of IRES-mediated translation via association with eIF4A [PMID:17284590]; this nucleocytoplasmic switch is further tuned in circadian, immune, and oncogenic contexts (e.g., translational control of Per1, miR-146a/Ago2-dependent cytokine repression, SRPK1- and AURKA-driven relocalization) [PMID:17264215, PMID:23897118, PMID:25140042, PMID:35361747]. RBM4 also binds and stabilizes G-quadruplex structures to regulate transcription and IRES-driven VEGFA translation [PMID:31165881, PMID:35054929], and it post-transcriptionally represses targets such as endogenous retroviral transcripts and VEGFR2 mRNA [PMID:33020268, PMID:36601864]. Functionally, RBM4 acts as a tumor suppressor by antagonizing SRSF1-mTOR signaling and shifting Bcl-x and MCL-1 splicing toward pro-apoptotic isoforms [PMID:25203323, PMID:25140042], and it is required in vivo for pancreatic islet function, cortical neuronal migration, and cerebellar development through control of insulin gene expression, neuronal isoform balance, and the BDNF-TrkB axis [PMID:23129807, PMID:27009199, PMID:29581187, PMID:37670183, PMID:39738787].","teleology":[{"year":1996,"claim":"Established that the RBM4 ortholog LARK is an RRM/zinc-finger RNA-binding protein acting as a repressor in a behavioral output pathway, framing RBM4 as a post-transcriptional regulator rather than a structural protein.","evidence":"Genetic dosage series and domain analysis in Drosophila","pmids":["9120432"],"confidence":"Medium","gaps":["No molecular RNA targets identified","Repressor mechanism not defined at the biochemical level"]},{"year":2000,"claim":"Showed that LARK abundance cycles and that it can localize to the cytoplasm in specific neurons, the first hint that subcellular distribution gates its function and links it to circadian regulation.","evidence":"Immunocytochemistry and fractionation in Drosophila neurons","pmids":["10992253"],"confidence":"Medium","gaps":["Cytoplasmic RNA targets unknown","Mechanism coupling localization to circadian output undefined"]},{"year":2001,"claim":"Demonstrated that both RRM domains and the zinc finger are individually required in vivo, establishing the structural basis of RNA recognition and function.","evidence":"Site-directed mutagenesis with in vivo phenotypic readout in Drosophila","pmids":["11560900"],"confidence":"High","gaps":["Specific RNA contacts of each domain not mapped","No biochemical binding affinities determined"]},{"year":2005,"claim":"Defined RBM4's first mechanistic splicing role: binding CU-rich intronic elements to antagonize PTB and activate muscle-specific exon inclusion, establishing the RBM4-versus-PTB antagonism paradigm.","evidence":"Minigene splicing assays, RNA-binding, and Co-IP with cis-element mutagenesis","pmids":["16260624"],"confidence":"High","gaps":["Whether antagonism is competitive binding or downstream effect not fully resolved","Genome-wide target scope unknown at this stage"]},{"year":2006,"claim":"Extended splicing activation to tau exon 10 via an intronic enhancer and tied function to the RNA-binding domain, while localization and partner studies (WT1+KTS) placed RBM4 in nuclear speckles within the spliceosomal machinery.","evidence":"Tau minigene assays with domain mutagenesis; Co-IP, gradient sedimentation, and immunofluorescence","pmids":["16777844","16907643","16934801"],"confidence":"High","gaps":["How WT1(+KTS) abrogates RBM4 splicing activity mechanistically unclear","Speckle-targeting signal in C-terminus not defined at residue level"]},{"year":2007,"claim":"Resolved RBM4's translational arm: stress-induced p38/S309 phosphorylation relocalizes RBM4 to the cytoplasm to suppress cap-dependent and activate IRES-mediated translation, and in parallel RBM4 was shown to translationally activate Per1 to set circadian period.","evidence":"Phospho-mutant (S309A), IRES reporters, polysome profiling, eIF4A Co-IP; RNA pulldown and circadian period measurement","pmids":["17284590","17264215"],"confidence":"High","gaps":["Full set of stress-regulated IRES mRNAs unknown","How eIF4A recruitment is selectively directed to IRES mRNAs unresolved"]},{"year":2008,"claim":"Identified a stabilizing protein partner (FMRP) and genetic cofunction in circadian and developmental contexts, linking RBM4 to a broader RNP regulatory network.","evidence":"Co-IP, in vivo complex analysis, and genetic epistasis in Drosophila","pmids":["18842880"],"confidence":"Medium","gaps":["Direct vs indirect interaction not established","Functional consequence on shared mRNA targets not defined"]},{"year":2011,"claim":"Established a hierarchical splicing cascade in myogenesis whereby RBM4 downregulates PTB/nPTB via AS-coupled NMD, showing RBM4 reshapes the splicing regulatory environment rather than acting only on individual exons.","evidence":"AS-NMD assays, minigene reporters, and gain/loss-of-function during myogenesis","pmids":["21518792"],"confidence":"High","gaps":["Genome-wide overlap of RBM4 and PTB targets incompletely mapped","Quantitative contribution of direct splicing vs PTB suppression not separated"]},{"year":2012,"claim":"Provided the first in vivo loss-of-function phenotype, showing RBM4 is required for pancreatic islet development and insulin expression through isoform control of Isl1 and Pax4.","evidence":"Rbm4 knockout mice plus AR42J reprogramming and minigene splicing analysis","pmids":["23129807"],"confidence":"High","gaps":["Direct RBM4 binding sites on Isl1/Pax4 not mapped","Relationship of splicing role to translational role in islets unclear"]},{"year":2013,"claim":"Showed RBM4's cytoplasmic, kinase-gated state extends to innate immunity, where miR-146a blocks S309 phosphorylation to retain RBM4 in the cytoplasm where it forms an Ago2 repressor complex limiting cytokine synthesis; phosphorylation by SR kinases and domain-dependent localization were also characterized.","evidence":"Antagomirs, phosphatase inhibition, Ago2 Co-IP, fractionation; in vitro kinase assays and chimeric construct analysis","pmids":["23897118","23527094"],"confidence":"Medium","gaps":["mRNA targets of the RBM4-Ago2 repressor complex not enumerated","Which SR kinase acts physiologically in each context unresolved"]},{"year":2014,"claim":"Defined RBM4 as a tumor suppressor by antagonizing SRSF1-mTOR signaling and shifting Bcl-x/MCL-1 splicing toward pro-apoptotic isoforms, with SRPK1-driven cytoplasmic relocalization modulating this output.","evidence":"Splicing/apoptosis/migration assays, Bcl-xL epistasis rescue, xenografts; RIP and minigene mapping of MCL-1 CU elements","pmids":["25203323","25140042"],"confidence":"High","gaps":["Mechanism by which RBM4 antagonizes SRSF1 at shared elements not fully defined","Contribution of nuclear vs cytoplasmic RBM4 to tumor suppression not dissected"]},{"year":2016,"claim":"Mapped RBM4-driven differentiation programs in detail: control of PKM, Numb, and an RBM4-Nova1-SRSF6 cascade governing neuronal differentiation and brown adipogenesis, establishing RBM4 as a master regulator of differentiation-coupled splicing networks.","evidence":"Rbm4 KO mice, minigenes, RNA-seq, AS-NMD assays, in utero electroporation, Seahorse respirometry, isoform-specific rescue","pmids":["27821480","27009199","26857472","27535496","25826570"],"confidence":"High","gaps":["Hierarchy among multiple downstream splicing factors not fully ordered","Direct vs cascade-mediated effects on individual targets sometimes inferred"]},{"year":2018,"claim":"Strengthened the in vivo neuronal role by showing RBM4 controls Dab1 isoforms required for cortical neuronal migration, with RIP-seq providing direct target evidence and isoform-specific rescue confirming causality.","evidence":"Rbm4 KO mice, RIP-seq, in utero electroporation, minigene, and isoform rescue; PRDM16 splicing characterization","pmids":["29581187","30327195"],"confidence":"High","gaps":["Full RIP-seq target set not exhaustively functionally validated","Interplay with translational regulation in migrating neurons unaddressed"]},{"year":2019,"claim":"Revealed a non-canonical activity in which RBM4 binds and stabilizes G-quadruplex structures to enhance transcription of target genes, and continued to define SRSF1-antagonistic splicing (HIF-1alpha).","evidence":"EMSA, G4 pull-down, reporters, in vivo G4 imaging; splicing reporters with CU-element mutagenesis","pmids":["31165881","31491447"],"confidence":"Medium","gaps":["Genome-wide G4 binding repertoire not defined","Mechanism linking G4 stabilization to transcriptional activation unresolved"]},{"year":2020,"claim":"Expanded RBM4 into mRNA-stability-based repression: PAR-CLIP defined direct binding to CGG elements in endogenous retroviral transcripts to silence them, and RBM4 was shown to recruit YTHDF2 to degrade m6A-modified STAT1 mRNA, restraining macrophage M1 polarization; Drosophila Lark also linked to infection-induced intron retention.","evidence":"PAR-CLIP, knockdown, reporters; RNA-seq, MS, Co-IP (YTHDF2), mRNA stability assays; genome-wide splicing analysis","pmids":["33020268","32248017","31948480"],"confidence":"High","gaps":["How RBM4 selects CGG vs CU-rich elements mechanistically unclear","Relationship between m6A-reader recruitment and direct binding not unified"]},{"year":2022,"claim":"Identified an oncogenic regulatory switch on RBM4 itself: nuclear AURKA reprograms m6A-YTHDC1-hnRNP K-dependent splicing of RBM4 to a short isoform that loses SRSF1-mTORC1 inhibition, and RBM4 was shown to drive VEGFA IRES translation via 5'UTR G4 binding.","evidence":"Co-IP, fractionation, kinase-dead AURKA mutant, splicing/mTORC1 analysis; EMSA, dicistronic reporters, G4 mutation and stabilizer","pmids":["35361747","35054929"],"confidence":"High","gaps":["Physiological signals controlling RBM4 isoform choice beyond AURKA unknown","Generality of G4-IRES mechanism across mRNAs untested"]},{"year":2023,"claim":"Broadened RBM4 functions to direct protein-complex regulation and additional in vivo developmental roles: it disrupts the LKB1/STRAD/MO25 complex and recruits TRIM26 to degrade LKB1, controls senescence via pri-miR-1244/SERPINE1, represses VEGFR2 downstream of p53, and is itself regulated by m6A (FTO/YTHDF1) while being required for the BDNF-TrkB axis in cerebellar development.","evidence":"Co-IP, ubiquitination assays, ESCC xenografts; miRNA mimics and stability assays; MeRIP and m6A reader assays; Rbm4 double-KO mice with TrkB-agonist rescue","pmids":["37080995","36639375","36601864","37698901","37670183","39118568"],"confidence":"Medium","gaps":["Direct RBM4-LKB1 binding interface not structurally defined","Integration of RBM4's protein-degradation role with its RNA roles unclear"]},{"year":2024,"claim":"Connected RBM4's splicing activity to neuronal-activity signaling and stress programs in vivo, showing NMDAR-driven RBM4 nuclear translocation promotes Hsf1 intron excision (antagonizing PTB) to sustain HSF1-BDNF for cerebellar development, and that RBM4 promotes autophagy-favoring TFEB splicing in leukemia cells.","evidence":"Rbm4 KO mice, CU-rich motif mutagenesis, NMDAR perturbation, HSF1 rescue, motor-learning assays; splicing/autophagy/differentiation assays in AML lines","pmids":["39738787","39214303"],"confidence":"High","gaps":["Signal transduction from NMDAR to RBM4 translocation incompletely mapped","Whether autophagy and developmental roles share common direct targets unknown"]},{"year":null,"claim":"How RBM4's multiple activities — CU-rich splicing antagonism of PTB/SRSF, G4 binding, mRNA destabilization, m6A-reader recruitment, and protein-complex disruption — are coordinated and selected within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking RNA-sequence preference (CU-rich vs CGG vs G4) to functional outcome","No structural model of RBM4-RNA or RBM4-protein interfaces","Determinants gating nuclear splicing vs cytoplasmic translational roles beyond S309 phosphorylation incompletely defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[3,4,16,24,28,32]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[3,11,19,24,40]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[7,8,32]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[26]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[33]}],"localization":[{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[5,6]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,7,13,16]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,36,40]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[3,4,11,19,24]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[7,8,32]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[12,20,24,35]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[15,16,31,33]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[13,28,29]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[8,17]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[15,31,33]}],"complexes":["stress granule","nuclear speckle"],"partners":["PTBP1","SRSF1","WT1","EIF4A","AGO2","YTHDF2","TRIM26","LKB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BWF3","full_name":"RNA-binding protein 4","aliases":["Lark homolog","hLark","RNA-binding motif protein 4","RNA-binding motif protein 4a"],"length_aa":364,"mass_kda":40.3,"function":"RNA-binding factor involved in multiple aspects of cellular processes like alternative splicing of pre-mRNA and translation regulation. Modulates alternative 5'-splice site and exon selection. Acts as a muscle cell differentiation-promoting factor. Activates exon skipping of the PTB pre-mRNA during muscle cell differentiation. Antagonizes the activity of the splicing factor PTBP1 to modulate muscle cell-specific exon selection of alpha tropomyosin. Binds to intronic pyrimidine-rich sequence of the TPM1 and MAPT pre-mRNAs. Required for the translational activation of PER1 mRNA in response to circadian clock. Binds directly to the 3'-UTR of the PER1 mRNA. Exerts a suppressive activity on Cap-dependent translation via binding to CU-rich responsive elements within the 3'UTR of mRNAs, a process increased under stress conditions or during myocytes differentiation. Recruits EIF4A1 to stimulate IRES-dependent translation initiation in respons to cellular stress. Associates to internal ribosome entry segment (IRES) in target mRNA species under stress conditions. Plays a role for miRNA-guided RNA cleavage and translation suppression by promoting association of AGO2-containing miRNPs with their cognate target mRNAs. Associates with miRNAs during muscle cell differentiation. Binds preferentially to 5'-CGCGCG[GCA]-3' motif in vitro","subcellular_location":"Nucleus; Nucleus, nucleolus; Nucleus speckle; Cytoplasm; Cytoplasmic granule","url":"https://www.uniprot.org/uniprotkb/Q9BWF3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RBM4","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":383,"dependency_fraction":0.018276762402088774},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000173933","cell_line_id":"CID001485","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"chromatin","grade":2},{"compartment":"cytoplasmic","grade":1}],"interactors":[{"gene":"RBM4;RBM4B","stoichiometry":10.0},{"gene":"SAE1","stoichiometry":0.2},{"gene":"GSPT1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001485","total_profiled":1310},"omim":[{"mim_id":"621045","title":"RNA-BINDING MOTIF PROTEIN 4B; RBM4B","url":"https://www.omim.org/entry/621045"},{"mim_id":"605895","title":"EUKARYOTIC TRANSLATION INITIATION FACTOR 4E FAMILY, MEMBER 2; EIF4E2","url":"https://www.omim.org/entry/605895"},{"mim_id":"603349","title":"ENDOTHELIAL PAS DOMAIN PROTEIN 1; EPAS1","url":"https://www.omim.org/entry/603349"},{"mim_id":"602571","title":"RNA-BINDING MOTIF PROTEIN 4; RBM4","url":"https://www.omim.org/entry/602571"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RBM4"},"hgnc":{"alias_symbol":["LARK","RBM4A","ZCRB3A","ZCCHC21"],"prev_symbol":[]},"alphafold":{"accession":"Q9BWF3","domains":[{"cath_id":"3.30.70.330","chopping":"1-68","consensus_level":"high","plddt":92.1869,"start":1,"end":68},{"cath_id":"3.30.70.330","chopping":"77-144","consensus_level":"high","plddt":91.1094,"start":77,"end":144}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BWF3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BWF3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BWF3-F1-predicted_aligned_error_v6.png","plddt_mean":64.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RBM4","jax_strain_url":"https://www.jax.org/strain/search?query=RBM4"},"sequence":{"accession":"Q9BWF3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BWF3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BWF3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BWF3"}},"corpus_meta":[{"pmid":"25203323","id":"PMC_25203323","title":"The splicing factor RBM4 controls apoptosis, proliferation, and migration to suppress tumor progression.","date":"2014","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/25203323","citation_count":185,"is_preprint":false},{"pmid":"17284590","id":"PMC_17284590","title":"Cell stress modulates the function of splicing regulatory protein RBM4 in translation control.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17284590","citation_count":87,"is_preprint":false},{"pmid":"17264215","id":"PMC_17264215","title":"LARK activates posttranscriptional expression of an essential mammalian clock protein, PERIOD1.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17264215","citation_count":87,"is_preprint":false},{"pmid":"32248017","id":"PMC_32248017","title":"RBM4 regulates M1 macrophages polarization through targeting STAT1-mediated glycolysis.","date":"2020","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32248017","citation_count":78,"is_preprint":false},{"pmid":"25140042","id":"PMC_25140042","title":"Elevated SRPK1 lessens apoptosis in breast cancer cells through RBM4-regulated splicing events.","date":"2014","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/25140042","citation_count":70,"is_preprint":false},{"pmid":"9120432","id":"PMC_9120432","title":"Regulation of a specific circadian clock output pathway by lark, a putative RNA-binding protein with repressor activity.","date":"1996","source":"Journal of neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/9120432","citation_count":70,"is_preprint":false},{"pmid":"21518792","id":"PMC_21518792","title":"RBM4 down-regulates PTB and antagonizes its activity in muscle cell-specific alternative splicing.","date":"2011","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21518792","citation_count":65,"is_preprint":false},{"pmid":"16260624","id":"PMC_16260624","title":"Exon selection in alpha-tropomyosin mRNA is regulated by the antagonistic action of RBM4 and PTB.","date":"2005","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16260624","citation_count":64,"is_preprint":false},{"pmid":"35361747","id":"PMC_35361747","title":"Nuclear Aurora kinase A switches m6A reader YTHDC1 to enhance an oncogenic RNA splicing of tumor suppressor RBM4.","date":"2022","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/35361747","citation_count":61,"is_preprint":false},{"pmid":"29138007","id":"PMC_29138007","title":"RBM4-SRSF3-MAP4K4 splicing cascade modulates the metastatic signature of colorectal cancer cell.","date":"2017","source":"Biochimica et biophysica acta. 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Drosophila genes.","date":"2020","source":"Genome biology","url":"https://pubmed.ncbi.nlm.nih.gov/31948480","citation_count":8,"is_preprint":false},{"pmid":"29101400","id":"PMC_29101400","title":"Clock gene is associated with individual variation in the activation of reproductive endocrine and behavior of Asian short toed lark.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29101400","citation_count":7,"is_preprint":false},{"pmid":"36601864","id":"PMC_36601864","title":"AMG232 inhibits angiogenesis in glioma through the p53-RBM4-VEGFR2 pathway.","date":"2023","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/36601864","citation_count":6,"is_preprint":false},{"pmid":"33250446","id":"PMC_33250446","title":"Multiple species delimitation approaches applied to the avian lark genus Alaudala.","date":"2020","source":"Molecular phylogenetics and 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gene dosage experiments showed decreased LARK causes early eclosion and increased LARK causes late eclosion, consistent with a repressor function.\",\n      \"method\": \"Genetic analysis, gene dosage experiments, sequence/domain analysis\",\n      \"journal\": \"Journal of neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with clear phenotypic readout, replicated by dosage series, single lab\",\n      \"pmids\": [\"9120432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Drosophila LARK protein exhibits circadian changes in abundance in CCAP peptidergic neurons and is present in the cytoplasm of these cells (unlike its nuclear distribution in most cell types), suggesting cell-type-specific cytoplasmic RNA-binding functions linked to circadian regulation of ecdysis.\",\n      \"method\": \"Immunocytochemistry, protein blotting, subcellular fractionation/localization\",\n      \"journal\": \"Journal of neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence tied to circadian behavior, single lab\",\n      \"pmids\": [\"10992253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Site-directed mutagenesis of Drosophila LARK demonstrated that RRM1, RRM2, and the RTZF zinc finger are each required for wild-type in vivo function; RRM1 and RRM2 are essential for viability, while RRM2 and RTZF act together for developmental and morphological functions.\",\n      \"method\": \"Site-directed mutagenesis, in vivo genetic analysis\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of each structural domain with clear in vivo phenotypic readouts, multiple domain mutations tested\",\n      \"pmids\": [\"11560900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RBM4 directly influences alpha-tropomyosin exon selection by binding to intronic pyrimidine-rich/CU-rich elements and antagonizing PTB-mediated exon exclusion; RBM4 activates skeletal muscle-specific exon inclusion by competing with PTB for a CU-rich element.\",\n      \"method\": \"Differential display, minigene splicing assays, co-immunoprecipitation, RNA-binding assays, overexpression/knockdown\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — minigene functional assays with mutagenesis of cis-elements, direct RNA-binding demonstrated, overexpression and knockdown both performed\",\n      \"pmids\": [\"16260624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RBM4 stimulates tau exon 10 inclusion by binding to a putative intronic splicing enhancer in intron 10; mutations in the RNA-binding domain of RBM4 abolish this splicing stimulatory activity.\",\n      \"method\": \"Expression cloning, tau minigene transfection, RBM4 overexpression/knockdown, RNA-binding domain mutagenesis, immunohistology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — minigene assay with domain mutagenesis, loss-of-function and gain-of-function, intronic enhancer mapped\",\n      \"pmids\": [\"16777844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RBM4 (shown to be identical to LARK) localizes to nuclear speckles and nucleoli; the C-terminus is required for targeting to speckles; upon transcription inhibition, RBM4 redistributes to perinucleolar clusters, a behavior distinct from other splicing factors.\",\n      \"method\": \"Immunofluorescence imaging, C-terminal deletion/mutation constructs, transcription inhibitor treatment\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional domain mapping, single lab, multiple constructs tested\",\n      \"pmids\": [\"16907643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"WT1(+KTS) isoform physically interacts with RBM4, colocalizes in nuclear speckles, cosediments with supraspliceosomes, and abrogates RBM4-mediated alternative splicing regulation in a dose-dependent, cell-specific manner; WT1(-KTS) does not interact with RBM4.\",\n      \"method\": \"Co-immunoprecipitation, glycerol gradient sedimentation, immunofluorescence colocalization, minigene splicing reporter assays, overexpression\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, colocalization, functional splicing assay, single lab\",\n      \"pmids\": [\"16934801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Cell stress (arsenite) induces phosphorylation of RBM4 at serine 309 via the MKK(3/6)-p38 signaling pathway, drives cytoplasmic accumulation and targeting to stress granules, suppresses cap-dependent translation in a cis-element-dependent manner, and activates IRES-mediated translation by promoting association of eIF4A with IRES-containing mRNAs; a nonphosphorylatable S309 mutant fails to activate IRES-mediated translation.\",\n      \"method\": \"Phospho-specific analysis, p38 pathway inhibition, stress granule imaging, cap-dependent/IRES reporter assays, Co-IP (RBM4-eIF4A), S309A mutant, polysome profiling\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (phospho-mutant, IRES reporter, Co-IP, pathway inhibition, localization) in single rigorous study\",\n      \"pmids\": [\"17284590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Mouse LARK (mLARK/RBM4) directly binds a cis-element in the 3' UTR of mPer1 mRNA and activates mPER1 protein expression through translational regulation; mLARK knockdown shortens circadian period and overexpression lengthens it in cycling cells.\",\n      \"method\": \"RNA pulldown/direct binding assay, siRNA knockdown, overexpression, circadian period measurement in cycling cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding to 3'UTR demonstrated, both loss- and gain-of-function with quantitative period phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"17264215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Drosophila FMRP (dFMRP) physically interacts with LARK, the two proteins are present in a complex in vivo, LARK promotes stability of dFMRP, and genetic interactions demonstrate they function together to regulate eye development and circadian behavior.\",\n      \"method\": \"Co-immunoprecipitation, in vivo complex analysis, genetic epistasis, protein stability assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical interaction (Co-IP) plus genetic epistasis, single lab\",\n      \"pmids\": [\"18842880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RBM4 and CoAA counter-regulate tau exon 10 splicing and undergo trans-splicing during stem/progenitor cell neural differentiation; CoAA and RBM4 splice variants generated by trans-splicing affect each other's splicing activities and lineage-specific gene expression.\",\n      \"method\": \"Trans-splicing variant identification, overexpression, minigene reporter assays, embryoid body formation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional trans-splicing validated with splicing reporters and cellular differentiation assay, single lab\",\n      \"pmids\": [\"19416963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RBM4 down-regulates PTB and nPTB expression during myogenesis by activating exon skipping of their transcripts, coupling to nonsense-mediated mRNA decay; RBM4 and PTB target a common set of transcripts for muscle cell-specific alternative splicing, with RBM4 promoting muscle-specific isoforms and PTB acting oppositely, establishing a hierarchical splicing cascade.\",\n      \"method\": \"Alternative splicing analysis, NMD assays, overexpression/knockdown, isoform-specific RT-PCR, minigene assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mechanistic cascade demonstrated with multiple methods (AS-NMD, minigene, KO/OE), clearly defined epistatic relationship\",\n      \"pmids\": [\"21518792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RBM4 knockout mice exhibit hyperglycemia, reduced insulin, and reduced pancreatic islet size; RBM4 promotes insulin gene expression and pancreas cell differentiation by altering isoform balance of transcription factors Isl1 and Pax4 via alternative splicing, and overexpression of RBM4 is sufficient to convert AR42J acinar cells into insulin-producing cells.\",\n      \"method\": \"Gene knockout (mouse), pancreas histology, glucose/insulin measurement, overexpression in AR42J cells, minigene/RT-PCR splicing analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO phenotype plus cell-based reconstitution showing isoform-specific mechanism, multiple orthogonal methods\",\n      \"pmids\": [\"23129807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TLR4-induced miR-146a promotes cytoplasmic accumulation of RBM4 by preventing phosphorylation of RBM4 at serine-309 by p38 MAPK; cytoplasmic RBM4 then interacts with Ago2, forming a translation-repressor complex that inhibits TNFα and IL-6 cytokine synthesis in endotoxin-adapted monocytes.\",\n      \"method\": \"miR-146a antagomirs, phosphatase inhibitor (okadaic acid), Co-IP (RBM4-Ago2), subcellular fractionation, cytokine measurement\",\n      \"journal\": \"Immunology and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, subcellular localization, functional cytokine output, multiple perturbations, single lab\",\n      \"pmids\": [\"23897118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RBM4 homologs from multiple species can be phosphorylated by SR protein kinases; the C-terminal domain of RBM4 influences subnuclear localization and functional divergence between homologs, while the N-terminal RNA-binding domain has a dominant role in determining splicing outcome.\",\n      \"method\": \"In vitro kinase assay, chimeric construct analysis, immunofluorescence, minigene splicing reporter assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus chimeric domain swap with functional splicing readout, single lab\",\n      \"pmids\": [\"23527094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RBM4 suppresses cancer cell proliferation and migration by regulating cancer-related alternative splicing; specifically, RBM4 regulates Bcl-x splicing to induce apoptosis (coexpression of Bcl-xL partially reverses RBM4-mediated tumor suppression), and RBM4 antagonizes SRSF1 to inhibit mTOR activation.\",\n      \"method\": \"Overexpression/knockdown, splicing reporter assays, apoptosis assays, migration assays, xenograft models, epistasis by Bcl-xL coexpression\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cancer cell lines, genetic epistasis (Bcl-xL rescue), mTOR pathway analysis, in vivo xenograft, multiple orthogonal methods\",\n      \"pmids\": [\"25203323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Elevated SRPK1 causes cytoplasmic accumulation of RBM4 in breast cancer cells; RBM4 binds CU-rich elements within MCL-1 exon 2 and downstream intron to facilitate exon exclusion, generating the pro-apoptotic MCL-1S isoform; SRPK1-RBM4 network modulates apoptotic sensitivity through IR-B and MCL-1S splicing.\",\n      \"method\": \"Overexpression/siRNA knockdown, RNA-immunoprecipitation, minigene splicing assays, Co-IP, subcellular fractionation\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct RNA binding mapped to CU-rich elements, minigene functional validation, subcellular localization linked to mechanism, multiple methods\",\n      \"pmids\": [\"25140042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Drosophila LARK directly regulates translation of dbt (DOUBLETIME/CKIδ/ε) transcripts in clock cells; LARK promotes translation of dbt-RC and light-induced dbt-RE transcripts, and altered LARK abundance affects circadian period length in a dbt allele-dependent manner; LARK delays nuclear degradation of PER, consistent with DBT regulation.\",\n      \"method\": \"Translational reporter assays, genetic epistasis with dbt alleles, circadian period measurement, in vivo translation analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional translational reporter plus allele-specific epistasis, single lab\",\n      \"pmids\": [\"25211129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"During brown adipocyte differentiation, RBM4 enhances skipping of the MEF2Cγ exon; the resulting MEF2Cγ- isoform in turn induces transcriptional activity of the RBM4 promoter, establishing a positive feed-forward circuit; this network induces miR-1 expression to promote brown adipogenesis.\",\n      \"method\": \"Overexpression, splicing reporter assays, promoter-luciferase reporter, differentiation assays in C3H10T1/2 cells\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — splicing and promoter reporter assays with functional differentiation readout, single lab\",\n      \"pmids\": [\"25826570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RBM4 directly regulates alternative splicing of pyruvate kinase M (PKM), promoting the PKM2-to-PKM1 isoform switch during neuronal differentiation; RBM4 antagonizes PTB in PKM splicing; overexpression of RBM4 or PKM1 increases mitochondrial respiration capacity and promotes neuronal differentiation of mesenchymal stem cells.\",\n      \"method\": \"RBM4 knockout mouse, PKM minigene assay, siRNA knockdown, overexpression, mitochondrial respiration (Seahorse), splicing RT-PCR\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — minigene functional assay, in vivo KO, mitochondrial function measurement, PKM1 overexpression rescue, multiple orthogonal methods\",\n      \"pmids\": [\"27821480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RBM4 modulates Numb isoform expression by promoting exon 3 inclusion and exon 9 exclusion; RBM4-depleted embryonic mouse brain shows aberrant Numb splicing; the RBM4-induced Numb isoform (with exon 3, without exon 9) restores Mash1 expression and neuronal differentiation; this Numb isoform also rescues neurite outgrowth defects in RBM4-depleted neurons.\",\n      \"method\": \"RBM4 knockout mouse, splicing minigene reporter, siRNA knockdown, overexpression, in utero electroporation, neurite outgrowth assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO, minigene, rescue by specific isoform, multiple orthogonal methods\",\n      \"pmids\": [\"27009199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RBM4a ablation increases PTBP1, PTBP2, and Nova1 proteins; elevated RBM4a reduces PTBP1/2 via AS-coupled NMD; RBM4a indirectly shortens Nova1 transcript half-life through PTBP2 regulation; RBM4a counteracts PTBP2's effects on FGFR2 and PKM splicing during brown adipogenesis.\",\n      \"method\": \"RNA-sequencing, RT-PCR, overexpression/knockout, NMD assays, transcript stability assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq plus functional AS-NMD validation, multiple targets analyzed, single lab\",\n      \"pmids\": [\"26857472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RBM4a ablation enhances Nova1 exon 4-excluded isoform; Nova1 isoforms differentially repress brown adipocyte development; overexpression of Nova1 reduces SRSF6 by enhancing intron 2-retained SRSF6 transcripts (AS-NMD); SRSF6 positively affects brown adipocyte development, establishing an RBM4a-Nova1-SRSF6 splicing cascade.\",\n      \"method\": \"RNA-sequencing, KO mouse, overexpression/knockdown, RT-PCR, differentiation assays\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq with functional validation in KO cells, cascade confirmed by overexpression, single lab\",\n      \"pmids\": [\"27535496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RBM4 reprograms splicing profile of SRSF3; upregulated SRSF3 modulates MAP4K4 exon 16 utilization in a sequence-dependent manner; alternatively spliced MAP4K4 variants exhibit differential phosphorylation of JNK1 and modulate E-cadherin, N-cadherin, vimentin expression, controlling migration/invasion of colorectal cancer cells.\",\n      \"method\": \"RNA-sequencing, RT-PCR, overexpression/knockdown, minigene assays, JNK phosphorylation assay, migration/invasion assays\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cascade validated by splicing reporter and downstream signaling/phenotypic assays, single lab\",\n      \"pmids\": [\"29138007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RBM4 promotes inclusion of Dab1 exons 7/8 and directly counteracts PTBP1-mediated exon skipping; Rbm4a knockout brain shows altered Dab1 isoform ratios and delayed cortical neuronal migration; full-length Dab1 (but not exon 7/8-truncated Dab1) rescues neuronal migration defects in RBM4-depleted neurons.\",\n      \"method\": \"RBM4 knockout mouse, RNA immunoprecipitation with high-throughput sequencing (RIP-seq), in utero electroporation, splicing minigene, overexpression/knockdown, migration assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RIP-seq identifies target, in vivo KO plus in utero electroporation, isoform-specific rescue experiment, multiple orthogonal methods\",\n      \"pmids\": [\"29581187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RBM4a enhances production of PRDM16-ex16 transcripts (encoding PRDM16S isoform) by simultaneously interacting with exonic and intronic CU elements; the PRDM16S isoform more strongly enhances RBM4a and PGC-1α promoter activity and BAT-related gene programs than PRDM16L.\",\n      \"method\": \"RNA-sequencing, RT-PCR, overexpression, RNA-immunoprecipitation, promoter reporter assay\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA binding to CU elements shown by RIP, functional promoter reporter, single lab\",\n      \"pmids\": [\"30327195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LARK/RBM4 is a G-quadruplex (G4)-binding protein; RBM4 from multiple species (including human) binds G4 structures in promoters of target genes; upon binding, RBM4 facilitates G4 formation and stability, enhancing transcription of target genes.\",\n      \"method\": \"EMSA, G4 pull-down, reporter assays, immunofluorescence (G4 visualization in vivo), overexpression/knockdown\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — EMSA demonstrates direct binding, reporter assays show functional consequence, single lab\",\n      \"pmids\": [\"31165881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SRSF1 and RBM4 antagonistically regulate HIF-1α exon 14 utilization in a CU element-dependent manner: SRSF1 facilitates HIF-1α-ex14 (short isoform), while RBM4 enhances HIF-1α+ex14 (long isoform) production.\",\n      \"method\": \"Transcriptome analysis, splicing reporter assay, overexpression/knockdown, CU-element mutant reporters\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — splicing reporter with CU-element mutagenesis, overexpression/knockdown, single lab\",\n      \"pmids\": [\"31491447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RBM4 directly binds HERV-K and HERV-H endogenous retroviral transcripts at CGG consensus elements; loss of RBM4 elevates HERV-K/-H transcript levels and HERV-K envelope protein expression; a conserved CGG-containing LTR element mediates RBM4 regulation of HERV-K.\",\n      \"method\": \"PAR-CLIP (photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation), siRNA knockdown, luciferase reporter assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — PAR-CLIP directly maps binding sites, reporter assay validates functional element, loss-of-function phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"33020268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RBM4 suppresses IFN-γ-induced M1 macrophage polarization by inhibiting glycolysis; RBM4 knockdown promotes STAT1 activation by increasing STAT1 mRNA stability; RBM4 interacts with YTHDF2 to degrade m6A-modified STAT1 mRNA, thereby reducing glycolysis-related gene transcription and M1 polarization.\",\n      \"method\": \"RNA-sequencing, protein immunoprecipitation with mass spectrometry, extracellular acidification rate (Seahorse), Co-IP (RBM4-YTHDF2), mRNA stability assay, overexpression/knockdown\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifies YTHDF2 interaction, mRNA stability assay, metabolic measurement, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32248017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Drosophila Lark/RBM4 is induced by enteric infection; overexpression of lark promotes intron retention preferentially at the 5' end of transcripts, mimicking infection-induced splicing changes; Lark binding motif is enriched in retained intron sequences; lark overexpression and knockdown alter survival upon infection.\",\n      \"method\": \"Genome-wide splicing analysis across 38 inbred lines, overexpression/knockdown with survival assay, motif enrichment analysis\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systems splicing analysis plus overexpression/KD functional validation, single lab\",\n      \"pmids\": [\"31948480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Nuclear AURKA promotes oncogenic splicing of RBM4 (from full-length RBM4-FL to short RBM4-S isoform) in a kinase-independent manner by disrupting SRSF3 binding to YTHDC1 and recruiting hnRNP K to YTHDC1, resulting in m6A-YTHDC1-hnRNP K-dependent exon skipping; RBM4-S abolishes RBM4-FL-mediated inhibition of SRSF1-mTORC1 signaling.\",\n      \"method\": \"Co-IP, nuclear fractionation, splicing reporter assays, overexpression/knockdown, kinase-dead AURKA mutant, mTORC1 pathway analysis\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic dissection with kinase-dead mutant, multiple protein interactions (Co-IP), splicing reporters, pathway analysis, multiple orthogonal methods\",\n      \"pmids\": [\"35361747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RBM4 promotes VEGFA mRNA translation by directly binding the G4 structure within the IRES-A element of the VEGFA 5'UTR; disruption of the G4 structure reduces IRES activity; G4 stabilizer increases IRES activity; RBM4 knockdown reduces and overexpression increases IRES-mediated translation.\",\n      \"method\": \"EMSA, dicistronic reporter assay, G4 structure mutation, G4 stabilizer (PDS) treatment, siRNA knockdown, overexpression\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct binding by EMSA, functional reporter with G4 mutation, pharmacological G4 stabilization, single lab\",\n      \"pmids\": [\"35054929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RBM4 competitively binds LKB1 to disrupt the LKB1/STRAD/MO25 heterotrimeric complex, recruits E3 ligase TRIM26 to LKB1, promotes LKB1 ubiquitination and nuclear degradation, and thereby suppresses LKB1-AMPK-mTOR signaling to allow bypass of senescence and promote glutamine-dependent proliferation in ESCC cells.\",\n      \"method\": \"Co-IP, ubiquitination assay, overexpression/knockdown, AMPK-mTOR pathway analysis, ESCC cell and xenograft models\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrates complex disruption, ubiquitination assay, pathway analysis, single lab with multiple methods\",\n      \"pmids\": [\"37080995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RBM4 depletion reduces miR-1244 levels by promoting degradation of primary miR-1244 transcripts (pri-miR1244), leading to increased SERPINE1 expression and induction of cellular senescence; either SERPINE1 inhibitor or miR-1244 mimics attenuate RBM4 depletion-induced senescence.\",\n      \"method\": \"siRNA knockdown, miR-1244 mimic/antagomir, luciferase 3'UTR reporter, pri-miRNA stability assay, senescence assays (SA-β-gal, p21/p27), SERPINE1 inhibitor\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pri-miRNA stability assay, 3'UTR reporter, multiple perturbation rescue experiments, single lab\",\n      \"pmids\": [\"36639375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RBM4 promotes expression of BDNF and full-length TrkB; constitutive knockout of both Rbm4 homologs reduces BDNF levels and causes cerebellar foliation defects and delayed motor learning; prenatal supplementation with TrkB agonist 7,8-dihydroxyflavone rescues cerebellar malformation and motor learning in Rbm4 double KO mice.\",\n      \"method\": \"Rbm4 double knockout mouse, cerebellar histology, BDNF/TrkB expression analysis, TrkB agonist supplementation, motor learning behavioral assay\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo double KO with rescue by downstream pathway agonist, multiple phenotypic readouts, mechanistic link to BDNF-TrkB established\",\n      \"pmids\": [\"37670183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In cardiomyocytes, Ang II-induced m6A methylation of RBM4 mRNA enhances YTHDF1-mediated translation of RBM4; elevated RBM4 localizes in the nucleus and down-regulates PTBP1 expression to prevent cardiomyocyte hypertrophy.\",\n      \"method\": \"Overexpression/knockdown, m6A MeRIP, YTHDF1 interaction assay, subcellular fractionation, cardiomyocyte hypertrophy assay\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A MeRIP confirms methylation, YTHDF1 interaction shown, functional hypertrophy assay, single lab\",\n      \"pmids\": [\"39118568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The m6A demethylase FTO stabilizes RBM4 mRNA by reducing its m6A methylation; FTO knockdown increases m6A on RBM4 mRNA and destabilizes it, reducing RBM4 expression; RBM4 in turn promotes RUNX2 exon 5 inclusion; overexpression of RBM4 in Fto-knockout cells restores RUNX2 exon 5 inclusion and odontoblast differentiation capacity.\",\n      \"method\": \"m6A MeRIP, mRNA stability assay, RBM4 overexpression/KO, splicing RT-PCR, mineralization assay, Fto knockout mouse\",\n      \"journal\": \"International endodontic journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A MeRIP, stability assay, in vivo KO, rescue by RBM4 overexpression, single lab\",\n      \"pmids\": [\"37698901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AMG232 upregulates p53 which transcriptionally activates RBM4; RBM4 directly binds VEGFR2 mRNA and shortens its half-life, promoting its degradation and inhibiting glioma endothelial cell angiogenesis; both p53 silencing and RBM4 silencing reverse AMG232's anti-angiogenic effects.\",\n      \"method\": \"In vitro/in vivo angiogenesis assays, siRNA knockdown, p53-RBM4 promoter-reporter, mRNA half-life assay, RNA binding assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mRNA stability assay, promoter reporter, in vivo xenograft, rescue experiments, single lab\",\n      \"pmids\": [\"36601864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RBM4 recognizes CU-rich sequences in intron 8 of TFEB, increasing production of the TFEB-L spliceosome which promotes autophagy; RBM4 overexpression increases autophagy and promotes differentiation of AML cells.\",\n      \"method\": \"Splicing reporter assay, CU-rich motif analysis, overexpression, autophagy assay, differentiation assay in THP-1/K562 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct CU-rich motif identified, splicing reporter, functional autophagy/differentiation readout, single lab\",\n      \"pmids\": [\"39214303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RBM4 promotes excision of Hsf1 intron 6; Rbm4 knockout induces intron 6 retention in Hsf1, downregulating HSF1 protein and its downstream target BDNF; NMDAR signaling promotes RBM4 nuclear translocation and RBM4-mediated intron excision via a CU-rich motif; RBM4 and PTB proteins play antagonistic roles in Hsf1 intron excision; ectopic HSF1 restores cerebellar foliation and motor learning in Rbm4-knockout mice.\",\n      \"method\": \"Rbm4 knockout mouse, splicing analysis, NMDAR signaling perturbation, CU-rich motif mutagenesis, HSF1 rescue experiment, cerebellar foliation/motor learning assay\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO, motif mutagenesis, NMDAR-RBM4 axis, downstream rescue by HSF1 overexpression, multiple orthogonal methods\",\n      \"pmids\": [\"39738787\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RBM4 is a multifunctional RNA-binding protein containing two RRM domains and a CCHC-type zinc finger that (1) regulates alternative pre-mRNA splicing by binding CU-rich/pyrimidine-rich intronic and exonic elements, antagonizing PTB/SRSF1 activity to promote tissue-specific isoforms during muscle, neuronal, pancreatic, and adipocyte differentiation; (2) controls translation by switching between suppression of cap-dependent translation and activation of IRES-mediated translation in response to stress, a switch dependent on p38-mediated phosphorylation at serine 309; (3) shuttles between nucleus and cytoplasm under stress or oncogenic signals (e.g., SRPK1, miR-146a, AURKA-YTHDC1), altering its function in splicing versus translational control; (4) promotes posttranscriptional repression of ERV transcripts and VEGFR2 mRNA by binding and destabilizing them; and (5) interacts with partners including PTB, SRSF1, WT1(+KTS), eIF4A, Ago2, YTHDF2, TRIM26, and LKB1 to mediate its diverse roles in cancer suppression, innate immunity, circadian rhythms, and organogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RBM4 (the vertebrate ortholog of Drosophila LARK) is a multifunctional RNA-binding protein that controls cell-type-specific gene expression through both alternative pre-mRNA splicing and translational regulation [#0, #3, #7]. As a splicing regulator it binds intronic and exonic CU-rich/pyrimidine-rich elements and acts antagonistically to PTB-family proteins, promoting tissue-specific exon usage in targets including alpha-tropomyosin, tau, Numb, Dab1, and PKM during muscle, neuronal, and other differentiation programs [#3, #4, #11, #19, #20, #24]. RBM4 establishes hierarchical splicing cascades by downregulating PTBP1/PTBP2 and Nova1 through alternative-splicing-coupled nonsense-mediated decay, thereby reinforcing differentiation-specific isoform landscapes [#11, #21, #22]. Beyond splicing, cell stress drives p38 MAPK-mediated phosphorylation of RBM4 at serine 309, triggering cytoplasmic relocalization to stress granules, suppression of cap-dependent translation, and activation of IRES-mediated translation via association with eIF4A [#7]; this nucleocytoplasmic switch is further tuned in circadian, immune, and oncogenic contexts (e.g., translational control of Per1, miR-146a/Ago2-dependent cytokine repression, SRPK1- and AURKA-driven relocalization) [#8, #13, #16, #31]. RBM4 also binds and stabilizes G-quadruplex structures to regulate transcription and IRES-driven VEGFA translation [#26, #32], and it post-transcriptionally represses targets such as endogenous retroviral transcripts and VEGFR2 mRNA [#28, #38]. Functionally, RBM4 acts as a tumor suppressor by antagonizing SRSF1-mTOR signaling and shifting Bcl-x and MCL-1 splicing toward pro-apoptotic isoforms [#15, #16], and it is required in vivo for pancreatic islet function, cortical neuronal migration, and cerebellar development through control of insulin gene expression, neuronal isoform balance, and the BDNF-TrkB axis [#12, #20, #24, #35, #40].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that the RBM4 ortholog LARK is an RRM/zinc-finger RNA-binding protein acting as a repressor in a behavioral output pathway, framing RBM4 as a post-transcriptional regulator rather than a structural protein.\",\n      \"evidence\": \"Genetic dosage series and domain analysis in Drosophila\",\n      \"pmids\": [\"9120432\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular RNA targets identified\", \"Repressor mechanism not defined at the biochemical level\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed that LARK abundance cycles and that it can localize to the cytoplasm in specific neurons, the first hint that subcellular distribution gates its function and links it to circadian regulation.\",\n      \"evidence\": \"Immunocytochemistry and fractionation in Drosophila neurons\",\n      \"pmids\": [\"10992253\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cytoplasmic RNA targets unknown\", \"Mechanism coupling localization to circadian output undefined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrated that both RRM domains and the zinc finger are individually required in vivo, establishing the structural basis of RNA recognition and function.\",\n      \"evidence\": \"Site-directed mutagenesis with in vivo phenotypic readout in Drosophila\",\n      \"pmids\": [\"11560900\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific RNA contacts of each domain not mapped\", \"No biochemical binding affinities determined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined RBM4's first mechanistic splicing role: binding CU-rich intronic elements to antagonize PTB and activate muscle-specific exon inclusion, establishing the RBM4-versus-PTB antagonism paradigm.\",\n      \"evidence\": \"Minigene splicing assays, RNA-binding, and Co-IP with cis-element mutagenesis\",\n      \"pmids\": [\"16260624\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether antagonism is competitive binding or downstream effect not fully resolved\", \"Genome-wide target scope unknown at this stage\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Extended splicing activation to tau exon 10 via an intronic enhancer and tied function to the RNA-binding domain, while localization and partner studies (WT1+KTS) placed RBM4 in nuclear speckles within the spliceosomal machinery.\",\n      \"evidence\": \"Tau minigene assays with domain mutagenesis; Co-IP, gradient sedimentation, and immunofluorescence\",\n      \"pmids\": [\"16777844\", \"16907643\", \"16934801\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How WT1(+KTS) abrogates RBM4 splicing activity mechanistically unclear\", \"Speckle-targeting signal in C-terminus not defined at residue level\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolved RBM4's translational arm: stress-induced p38/S309 phosphorylation relocalizes RBM4 to the cytoplasm to suppress cap-dependent and activate IRES-mediated translation, and in parallel RBM4 was shown to translationally activate Per1 to set circadian period.\",\n      \"evidence\": \"Phospho-mutant (S309A), IRES reporters, polysome profiling, eIF4A Co-IP; RNA pulldown and circadian period measurement\",\n      \"pmids\": [\"17284590\", \"17264215\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of stress-regulated IRES mRNAs unknown\", \"How eIF4A recruitment is selectively directed to IRES mRNAs unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified a stabilizing protein partner (FMRP) and genetic cofunction in circadian and developmental contexts, linking RBM4 to a broader RNP regulatory network.\",\n      \"evidence\": \"Co-IP, in vivo complex analysis, and genetic epistasis in Drosophila\",\n      \"pmids\": [\"18842880\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect interaction not established\", \"Functional consequence on shared mRNA targets not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established a hierarchical splicing cascade in myogenesis whereby RBM4 downregulates PTB/nPTB via AS-coupled NMD, showing RBM4 reshapes the splicing regulatory environment rather than acting only on individual exons.\",\n      \"evidence\": \"AS-NMD assays, minigene reporters, and gain/loss-of-function during myogenesis\",\n      \"pmids\": [\"21518792\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide overlap of RBM4 and PTB targets incompletely mapped\", \"Quantitative contribution of direct splicing vs PTB suppression not separated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Provided the first in vivo loss-of-function phenotype, showing RBM4 is required for pancreatic islet development and insulin expression through isoform control of Isl1 and Pax4.\",\n      \"evidence\": \"Rbm4 knockout mice plus AR42J reprogramming and minigene splicing analysis\",\n      \"pmids\": [\"23129807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct RBM4 binding sites on Isl1/Pax4 not mapped\", \"Relationship of splicing role to translational role in islets unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed RBM4's cytoplasmic, kinase-gated state extends to innate immunity, where miR-146a blocks S309 phosphorylation to retain RBM4 in the cytoplasm where it forms an Ago2 repressor complex limiting cytokine synthesis; phosphorylation by SR kinases and domain-dependent localization were also characterized.\",\n      \"evidence\": \"Antagomirs, phosphatase inhibition, Ago2 Co-IP, fractionation; in vitro kinase assays and chimeric construct analysis\",\n      \"pmids\": [\"23897118\", \"23527094\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mRNA targets of the RBM4-Ago2 repressor complex not enumerated\", \"Which SR kinase acts physiologically in each context unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined RBM4 as a tumor suppressor by antagonizing SRSF1-mTOR signaling and shifting Bcl-x/MCL-1 splicing toward pro-apoptotic isoforms, with SRPK1-driven cytoplasmic relocalization modulating this output.\",\n      \"evidence\": \"Splicing/apoptosis/migration assays, Bcl-xL epistasis rescue, xenografts; RIP and minigene mapping of MCL-1 CU elements\",\n      \"pmids\": [\"25203323\", \"25140042\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which RBM4 antagonizes SRSF1 at shared elements not fully defined\", \"Contribution of nuclear vs cytoplasmic RBM4 to tumor suppression not dissected\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mapped RBM4-driven differentiation programs in detail: control of PKM, Numb, and an RBM4-Nova1-SRSF6 cascade governing neuronal differentiation and brown adipogenesis, establishing RBM4 as a master regulator of differentiation-coupled splicing networks.\",\n      \"evidence\": \"Rbm4 KO mice, minigenes, RNA-seq, AS-NMD assays, in utero electroporation, Seahorse respirometry, isoform-specific rescue\",\n      \"pmids\": [\"27821480\", \"27009199\", \"26857472\", \"27535496\", \"25826570\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy among multiple downstream splicing factors not fully ordered\", \"Direct vs cascade-mediated effects on individual targets sometimes inferred\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Strengthened the in vivo neuronal role by showing RBM4 controls Dab1 isoforms required for cortical neuronal migration, with RIP-seq providing direct target evidence and isoform-specific rescue confirming causality.\",\n      \"evidence\": \"Rbm4 KO mice, RIP-seq, in utero electroporation, minigene, and isoform rescue; PRDM16 splicing characterization\",\n      \"pmids\": [\"29581187\", \"30327195\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full RIP-seq target set not exhaustively functionally validated\", \"Interplay with translational regulation in migrating neurons unaddressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed a non-canonical activity in which RBM4 binds and stabilizes G-quadruplex structures to enhance transcription of target genes, and continued to define SRSF1-antagonistic splicing (HIF-1alpha).\",\n      \"evidence\": \"EMSA, G4 pull-down, reporters, in vivo G4 imaging; splicing reporters with CU-element mutagenesis\",\n      \"pmids\": [\"31165881\", \"31491447\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genome-wide G4 binding repertoire not defined\", \"Mechanism linking G4 stabilization to transcriptional activation unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Expanded RBM4 into mRNA-stability-based repression: PAR-CLIP defined direct binding to CGG elements in endogenous retroviral transcripts to silence them, and RBM4 was shown to recruit YTHDF2 to degrade m6A-modified STAT1 mRNA, restraining macrophage M1 polarization; Drosophila Lark also linked to infection-induced intron retention.\",\n      \"evidence\": \"PAR-CLIP, knockdown, reporters; RNA-seq, MS, Co-IP (YTHDF2), mRNA stability assays; genome-wide splicing analysis\",\n      \"pmids\": [\"33020268\", \"32248017\", \"31948480\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RBM4 selects CGG vs CU-rich elements mechanistically unclear\", \"Relationship between m6A-reader recruitment and direct binding not unified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified an oncogenic regulatory switch on RBM4 itself: nuclear AURKA reprograms m6A-YTHDC1-hnRNP K-dependent splicing of RBM4 to a short isoform that loses SRSF1-mTORC1 inhibition, and RBM4 was shown to drive VEGFA IRES translation via 5'UTR G4 binding.\",\n      \"evidence\": \"Co-IP, fractionation, kinase-dead AURKA mutant, splicing/mTORC1 analysis; EMSA, dicistronic reporters, G4 mutation and stabilizer\",\n      \"pmids\": [\"35361747\", \"35054929\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological signals controlling RBM4 isoform choice beyond AURKA unknown\", \"Generality of G4-IRES mechanism across mRNAs untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Broadened RBM4 functions to direct protein-complex regulation and additional in vivo developmental roles: it disrupts the LKB1/STRAD/MO25 complex and recruits TRIM26 to degrade LKB1, controls senescence via pri-miR-1244/SERPINE1, represses VEGFR2 downstream of p53, and is itself regulated by m6A (FTO/YTHDF1) while being required for the BDNF-TrkB axis in cerebellar development.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, ESCC xenografts; miRNA mimics and stability assays; MeRIP and m6A reader assays; Rbm4 double-KO mice with TrkB-agonist rescue\",\n      \"pmids\": [\"37080995\", \"36639375\", \"36601864\", \"37698901\", \"37670183\", \"39118568\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RBM4-LKB1 binding interface not structurally defined\", \"Integration of RBM4's protein-degradation role with its RNA roles unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected RBM4's splicing activity to neuronal-activity signaling and stress programs in vivo, showing NMDAR-driven RBM4 nuclear translocation promotes Hsf1 intron excision (antagonizing PTB) to sustain HSF1-BDNF for cerebellar development, and that RBM4 promotes autophagy-favoring TFEB splicing in leukemia cells.\",\n      \"evidence\": \"Rbm4 KO mice, CU-rich motif mutagenesis, NMDAR perturbation, HSF1 rescue, motor-learning assays; splicing/autophagy/differentiation assays in AML lines\",\n      \"pmids\": [\"39738787\", \"39214303\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal transduction from NMDAR to RBM4 translocation incompletely mapped\", \"Whether autophagy and developmental roles share common direct targets unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RBM4's multiple activities — CU-rich splicing antagonism of PTB/SRSF, G4 binding, mRNA destabilization, m6A-reader recruitment, and protein-complex disruption — are coordinated and selected within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking RNA-sequence preference (CU-rich vs CGG vs G4) to functional outcome\", \"No structural model of RBM4-RNA or RBM4-protein interfaces\", \"Determinants gating nuclear splicing vs cytoplasmic translational roles beyond S309 phosphorylation incompletely defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [3, 4, 16, 24, 28, 32]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [3, 11, 19, 24, 40]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [7, 8, 32]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [26]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [33]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 7, 13, 16]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 36, 40]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [3, 4, 11, 19, 24]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [7, 8, 32]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [12, 20, 24, 35]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [15, 16, 31, 33]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [13, 28, 29]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [8, 17]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [15, 31, 33]}\n    ],\n    \"complexes\": [\n      \"stress granule\",\n      \"nuclear speckle\"\n    ],\n    \"partners\": [\n      \"PTBP1\",\n      \"SRSF1\",\n      \"WT1\",\n      \"eIF4A\",\n      \"AGO2\",\n      \"YTHDF2\",\n      \"TRIM26\",\n      \"LKB1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}