Affinage

RBM4

RNA-binding protein 4 · UniProt Q9BWF3

Length
364 aa
Mass
40.3 kDa
Annotated
2026-06-10
77 papers in source corpus 41 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1996 Medium

    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

    PMID:9120432

    Open questions at the time
    • No molecular RNA targets identified
    • Repressor mechanism not defined at the biochemical level
  2. 2000 Medium

    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

    PMID:10992253

    Open questions at the time
    • Cytoplasmic RNA targets unknown
    • Mechanism coupling localization to circadian output undefined
  3. 2001 High

    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

    PMID:11560900

    Open questions at the time
    • Specific RNA contacts of each domain not mapped
    • No biochemical binding affinities determined
  4. 2005 High

    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

    PMID:16260624

    Open questions at the time
    • Whether antagonism is competitive binding or downstream effect not fully resolved
    • Genome-wide target scope unknown at this stage
  5. 2006 High

    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

    PMID:16777844 PMID:16907643 PMID:16934801

    Open questions at the time
    • How WT1(+KTS) abrogates RBM4 splicing activity mechanistically unclear
    • Speckle-targeting signal in C-terminus not defined at residue level
  6. 2007 High

    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

    PMID:17264215 PMID:17284590

    Open questions at the time
    • Full set of stress-regulated IRES mRNAs unknown
    • How eIF4A recruitment is selectively directed to IRES mRNAs unresolved
  7. 2008 Medium

    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

    PMID:18842880

    Open questions at the time
    • Direct vs indirect interaction not established
    • Functional consequence on shared mRNA targets not defined
  8. 2011 High

    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

    PMID:21518792

    Open questions at the time
    • Genome-wide overlap of RBM4 and PTB targets incompletely mapped
    • Quantitative contribution of direct splicing vs PTB suppression not separated
  9. 2012 High

    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

    PMID:23129807

    Open questions at the time
    • Direct RBM4 binding sites on Isl1/Pax4 not mapped
    • Relationship of splicing role to translational role in islets unclear
  10. 2013 Medium

    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

    PMID:23527094 PMID:23897118

    Open questions at the time
    • mRNA targets of the RBM4-Ago2 repressor complex not enumerated
    • Which SR kinase acts physiologically in each context unresolved
  11. 2014 High

    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

    PMID:25140042 PMID:25203323

    Open questions at the time
    • Mechanism by which RBM4 antagonizes SRSF1 at shared elements not fully defined
    • Contribution of nuclear vs cytoplasmic RBM4 to tumor suppression not dissected
  12. 2016 High

    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

    PMID:25826570 PMID:26857472 PMID:27009199 PMID:27535496 PMID:27821480

    Open questions at the time
    • Hierarchy among multiple downstream splicing factors not fully ordered
    • Direct vs cascade-mediated effects on individual targets sometimes inferred
  13. 2018 High

    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

    PMID:29581187 PMID:30327195

    Open questions at the time
    • Full RIP-seq target set not exhaustively functionally validated
    • Interplay with translational regulation in migrating neurons unaddressed
  14. 2019 Medium

    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

    PMID:31165881 PMID:31491447

    Open questions at the time
    • Genome-wide G4 binding repertoire not defined
    • Mechanism linking G4 stabilization to transcriptional activation unresolved
  15. 2020 High

    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

    PMID:31948480 PMID:32248017 PMID:33020268

    Open questions at the time
    • How RBM4 selects CGG vs CU-rich elements mechanistically unclear
    • Relationship between m6A-reader recruitment and direct binding not unified
  16. 2022 High

    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

    PMID:35054929 PMID:35361747

    Open questions at the time
    • Physiological signals controlling RBM4 isoform choice beyond AURKA unknown
    • Generality of G4-IRES mechanism across mRNAs untested
  17. 2023 Medium

    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

    PMID:36601864 PMID:36639375 PMID:37080995 PMID:37670183 PMID:37698901 PMID:39118568

    Open questions at the time
    • Direct RBM4-LKB1 binding interface not structurally defined
    • Integration of RBM4's protein-degradation role with its RNA roles unclear
  18. 2024 High

    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

    PMID:39214303 PMID:39738787

    Open questions at the time
    • Signal transduction from NMDAR to RBM4 translocation incompletely mapped
    • Whether autophagy and developmental roles share common direct targets unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 6 GO:0140098 catalytic activity, acting on RNA 5 GO:0045182 translation regulator activity 3 GO:0098772 molecular function regulator activity 1 GO:0140110 transcription regulator activity 1
Localization
GO:0005829 cytosol 4 GO:0005634 nucleus 3 GO:0005654 nucleoplasm 2 GO:0005730 nucleolus 1
Pathway
R-HSA-8953854 Metabolism of RNA 5 R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 4 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-9909396 Circadian clock 2
Partners
AGO2EIF4ALKB1PTBP1SRSF1TRIM26WT1YTHDF2
Complex memberships
nuclear specklestress granule

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 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. Genetic analysis, gene dosage experiments, sequence/domain analysis Journal of neurobiology Medium 9120432
2000 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. Immunocytochemistry, protein blotting, subcellular fractionation/localization Journal of neurobiology Medium 10992253
2001 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. Site-directed mutagenesis, in vivo genetic analysis Genetics High 11560900
2005 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. Differential display, minigene splicing assays, co-immunoprecipitation, RNA-binding assays, overexpression/knockdown Molecular and cellular biology High 16260624
2006 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. Expression cloning, tau minigene transfection, RBM4 overexpression/knockdown, RNA-binding domain mutagenesis, immunohistology The Journal of biological chemistry High 16777844
2006 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. Immunofluorescence imaging, C-terminal deletion/mutation constructs, transcription inhibitor treatment DNA and cell biology Medium 16907643
2006 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. Co-immunoprecipitation, glycerol gradient sedimentation, immunofluorescence colocalization, minigene splicing reporter assays, overexpression Experimental cell research Medium 16934801
2007 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. Phospho-specific analysis, p38 pathway inhibition, stress granule imaging, cap-dependent/IRES reporter assays, Co-IP (RBM4-eIF4A), S309A mutant, polysome profiling Proceedings of the National Academy of Sciences of the United States of America High 17284590
2007 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. RNA pulldown/direct binding assay, siRNA knockdown, overexpression, circadian period measurement in cycling cells Proceedings of the National Academy of Sciences of the United States of America High 17264215
2008 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. Co-immunoprecipitation, in vivo complex analysis, genetic epistasis, protein stability assay The Journal of neuroscience Medium 18842880
2009 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. Trans-splicing variant identification, overexpression, minigene reporter assays, embryoid body formation assay The Journal of biological chemistry Medium 19416963
2011 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. Alternative splicing analysis, NMD assays, overexpression/knockdown, isoform-specific RT-PCR, minigene assays The Journal of cell biology High 21518792
2012 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. Gene knockout (mouse), pancreas histology, glucose/insulin measurement, overexpression in AR42J cells, minigene/RT-PCR splicing analysis Molecular and cellular biology High 23129807
2013 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. miR-146a antagomirs, phosphatase inhibitor (okadaic acid), Co-IP (RBM4-Ago2), subcellular fractionation, cytokine measurement Immunology and cell biology Medium 23897118
2013 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. In vitro kinase assay, chimeric construct analysis, immunofluorescence, minigene splicing reporter assays PloS one Medium 23527094
2014 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. Overexpression/knockdown, splicing reporter assays, apoptosis assays, migration assays, xenograft models, epistasis by Bcl-xL coexpression Cancer cell High 25203323
2014 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. Overexpression/siRNA knockdown, RNA-immunoprecipitation, minigene splicing assays, Co-IP, subcellular fractionation RNA (New York, N.Y.) High 25140042
2014 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. Translational reporter assays, genetic epistasis with dbt alleles, circadian period measurement, in vivo translation analysis PLoS genetics Medium 25211129
2015 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. Overexpression, splicing reporter assays, promoter-luciferase reporter, differentiation assays in C3H10T1/2 cells RNA biology Medium 25826570
2016 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. RBM4 knockout mouse, PKM minigene assay, siRNA knockdown, overexpression, mitochondrial respiration (Seahorse), splicing RT-PCR Molecular and cellular biology High 27821480
2016 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. RBM4 knockout mouse, splicing minigene reporter, siRNA knockdown, overexpression, in utero electroporation, neurite outgrowth assay Molecular biology of the cell High 27009199
2016 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. RNA-sequencing, RT-PCR, overexpression/knockout, NMD assays, transcript stability assays Scientific reports Medium 26857472
2016 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. RNA-sequencing, KO mouse, overexpression/knockdown, RT-PCR, differentiation assays Biochimica et biophysica acta Medium 27535496
2017 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. RNA-sequencing, RT-PCR, overexpression/knockdown, minigene assays, JNK phosphorylation assay, migration/invasion assays Biochimica et biophysica acta. Molecular cell research Medium 29138007
2018 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. RBM4 knockout mouse, RNA immunoprecipitation with high-throughput sequencing (RIP-seq), in utero electroporation, splicing minigene, overexpression/knockdown, migration assay Molecular and cellular biology High 29581187
2018 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. RNA-sequencing, RT-PCR, overexpression, RNA-immunoprecipitation, promoter reporter assay Biochimica et biophysica acta. Molecular cell research Medium 30327195
2019 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. EMSA, G4 pull-down, reporter assays, immunofluorescence (G4 visualization in vivo), overexpression/knockdown Nucleic acids research Medium 31165881
2019 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. Transcriptome analysis, splicing reporter assay, overexpression/knockdown, CU-element mutant reporters Biochimica et biophysica acta. Molecular cell research Medium 31491447
2020 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. PAR-CLIP (photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation), siRNA knockdown, luciferase reporter assay Proceedings of the National Academy of Sciences of the United States of America High 33020268
2020 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. RNA-sequencing, protein immunoprecipitation with mass spectrometry, extracellular acidification rate (Seahorse), Co-IP (RBM4-YTHDF2), mRNA stability assay, overexpression/knockdown International immunopharmacology Medium 32248017
2020 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. Genome-wide splicing analysis across 38 inbred lines, overexpression/knockdown with survival assay, motif enrichment analysis Genome biology Medium 31948480
2022 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. Co-IP, nuclear fractionation, splicing reporter assays, overexpression/knockdown, kinase-dead AURKA mutant, mTORC1 pathway analysis Signal transduction and targeted therapy High 35361747
2022 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. EMSA, dicistronic reporter assay, G4 structure mutation, G4 stabilizer (PDS) treatment, siRNA knockdown, overexpression International journal of molecular sciences Medium 35054929
2023 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. Co-IP, ubiquitination assay, overexpression/knockdown, AMPK-mTOR pathway analysis, ESCC cell and xenograft models Signal transduction and targeted therapy Medium 37080995
2023 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. siRNA knockdown, miR-1244 mimic/antagomir, luciferase 3'UTR reporter, pri-miRNA stability assay, senescence assays (SA-β-gal, p21/p27), SERPINE1 inhibitor Cell death & disease Medium 36639375
2023 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. Rbm4 double knockout mouse, cerebellar histology, BDNF/TrkB expression analysis, TrkB agonist supplementation, motor learning behavioral assay Communications biology High 37670183
2023 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. Overexpression/knockdown, m6A MeRIP, YTHDF1 interaction assay, subcellular fractionation, cardiomyocyte hypertrophy assay Acta biochimica et biophysica Sinica Medium 39118568
2023 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. m6A MeRIP, mRNA stability assay, RBM4 overexpression/KO, splicing RT-PCR, mineralization assay, Fto knockout mouse International endodontic journal Medium 37698901
2023 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. In vitro/in vivo angiogenesis assays, siRNA knockdown, p53-RBM4 promoter-reporter, mRNA half-life assay, RNA binding assay Journal of cell science Medium 36601864
2024 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. Splicing reporter assay, CU-rich motif analysis, overexpression, autophagy assay, differentiation assay in THP-1/K562 cells The Journal of biological chemistry Medium 39214303
2024 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. Rbm4 knockout mouse, splicing analysis, NMDAR signaling perturbation, CU-rich motif mutagenesis, HSF1 rescue experiment, cerebellar foliation/motor learning assay Communications biology High 39738787

Source papers

Stage 0 corpus · 77 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 The splicing factor RBM4 controls apoptosis, proliferation, and migration to suppress tumor progression. Cancer cell 185 25203323
2007 LARK activates posttranscriptional expression of an essential mammalian clock protein, PERIOD1. Proceedings of the National Academy of Sciences of the United States of America 87 17264215
2007 Cell stress modulates the function of splicing regulatory protein RBM4 in translation control. Proceedings of the National Academy of Sciences of the United States of America 87 17284590
2020 RBM4 regulates M1 macrophages polarization through targeting STAT1-mediated glycolysis. International immunopharmacology 78 32248017
2014 Elevated SRPK1 lessens apoptosis in breast cancer cells through RBM4-regulated splicing events. RNA (New York, N.Y.) 70 25140042
1996 Regulation of a specific circadian clock output pathway by lark, a putative RNA-binding protein with repressor activity. Journal of neurobiology 70 9120432
2011 RBM4 down-regulates PTB and antagonizes its activity in muscle cell-specific alternative splicing. The Journal of cell biology 65 21518792
2005 Exon selection in alpha-tropomyosin mRNA is regulated by the antagonistic action of RBM4 and PTB. Molecular and cellular biology 64 16260624
2022 Nuclear Aurora kinase A switches m6A reader YTHDC1 to enhance an oncogenic RNA splicing of tumor suppressor RBM4. Signal transduction and targeted therapy 61 35361747
2017 RBM4-SRSF3-MAP4K4 splicing cascade modulates the metastatic signature of colorectal cancer cell. Biochimica et biophysica acta. Molecular cell research 51 29138007
2006 RBM4 interacts with an intronic element and stimulates tau exon 10 inclusion. The Journal of biological chemistry 50 16777844
2017 RBM4 Regulates Neuronal Differentiation of Mesenchymal Stem Cells by Modulating Alternative Splicing of Pyruvate Kinase M. Molecular and cellular biology 44 27821480
2023 RBM4 dictates ESCC cell fate switch from cellular senescence to glutamine-addiction survival through inhibiting LKB1-AMPK-axis. Signal transduction and targeted therapy 43 37080995
2019 Identification of LARK as a novel and conserved G-quadruplex binding protein in invertebrates and vertebrates. Nucleic acids research 43 31165881
2013 MicroRNA-146a and RBM4 form a negative feed-forward loop that disrupts cytokine mRNA translation following TLR4 responses in human THP-1 monocytes. Immunology and cell biology 43 23897118
2012 RBM4 promotes pancreas cell differentiation and insulin expression. Molecular and cellular biology 42 23129807
2006 WT1 interacts with the splicing protein RBM4 and regulates its ability to modulate alternative splicing in vivo. Experimental cell research 41 16934801
2008 RBM4: a multifunctional RNA-binding protein. The international journal of biochemistry & cell biology 39 18723113
2000 Circadian regulation of the lark RNA-binding protein within identifiable neurosecretory cells. Journal of neurobiology 36 10992253
2019 SRSF1 and RBM4 differentially modulate the oncogenic effect of HIF-1α in lung cancer cells through alternative splicing mechanism. Biochimica et biophysica acta. Molecular cell research 32 31491447
2009 Functional pre- mRNA trans-splicing of coactivator CoAA and corepressor RBM4 during stem/progenitor cell differentiation. The Journal of biological chemistry 32 19416963
2016 RBM4 promotes neuronal differentiation and neurite outgrowth by modulating Numb isoform expression. Molecular biology of the cell 30 27009199
2016 RBM4-Nova1-SRSF6 splicing cascade modulates the development of brown adipocytes. Biochimica et biophysica acta 27 27535496
2014 Translational regulation of the DOUBLETIME/CKIδ/ε kinase by LARK contributes to circadian period modulation. PLoS genetics 27 25211129
2008 The Drosophila FMRP and LARK RNA-binding proteins function together to regulate eye development and circadian behavior. The Journal of neuroscience : the official journal of the Society for Neuroscience 27 18842880
2001 Genetic analysis of functional domains within the Drosophila LARK RNA-binding protein. Genetics 24 11560900
2018 RBM4 Modulates Radial Migration via Alternative Splicing of Dab1 during Cortex Development. Molecular and cellular biology 22 29581187
2020 USP3 promotes proliferation of non-small cell lung cancer through regulating RBM4. European review for medical and pharmacological sciences 21 32271432
2007 Genetic and phenotypic variation among geographically isolated populations of the globally threatened Dupont's lark Chersophilus duponti. Molecular phylogenetics and evolution 21 17719801
2003 Cell-specific expression of the lark RNA-binding protein in Drosophila results in morphological and circadian behavioral phenotypes. Journal of neurogenetics 21 14668198
2016 RBM4a-regulated splicing cascade modulates the differentiation and metabolic activities of brown adipocytes. Scientific reports 20 26857472
2006 Lark is the splicing factor RBM4 and exhibits unique subnuclear localization properties. DNA and cell biology 20 16907643
2018 RBM4a-SRSF3-MAP4K4 Splicing Cascade Constitutes a Molecular Mechanism for Regulating Brown Adipogenesis. International journal of molecular sciences 19 30200638
2016 Transcriptome-wide targets of alternative splicing by RBM4 and possible role in cancer. Genomics 19 26898347
2015 RBM4-MEF2C network constitutes a feed-forward circuit that facilitates the differentiation of brown adipocytes. RNA biology 19 25826570
2012 Cellular requirements for LARK in the Drosophila circadian system. Journal of biological rhythms 19 22653887
2017 The impact of the RBM4-initiated splicing cascade on modulating the carcinogenic signature of colorectal cancer cells. Scientific reports 17 28276498
2019 RNA-Binding Motif 4 (RBM4) Suppresses Tumor Growth and Metastasis in Human Gastric Cancer. Medical science monitor : international medical journal of experimental and clinical research 15 31145716
2023 RBM4 regulates cellular senescence via miR1244/SERPINE1 axis. Cell death & disease 14 36639375
2018 RBM4a modulates the impact of PRDM16 on development of brown adipocytes through an alternative splicing mechanism. Biochimica et biophysica acta. Molecular cell research 14 30327195
2009 Altered LARK expression perturbs development and physiology of the Drosophila PDF clock neurons. Molecular and cellular neurosciences 14 19303442
2022 G-Quadruplex Regulation of VEGFA mRNA Translation by RBM4. International journal of molecular sciences 13 35054929
2020 Posttranscriptional regulation of human endogenous retroviruses by RNA-binding motif protein 4, RBM4. Proceedings of the National Academy of Sciences of the United States of America 13 33020268
2012 Multiple roles of RBM4 in muscle cell differentiation. Frontiers in bioscience (Scholar edition) 13 22202052
2019 RBM4 modulates the proliferation and expression of inflammatory factors via the alternative splicing of regulatory factors in HeLa cells. Molecular genetics and genomics : MGG 12 31489484
2004 The Drosophila RNA-binding protein Lark is required for the organization of the actin cytoskeleton and Hu-li tai shao localization during oogenesis. Genesis (New York, N.Y. : 2000) 10 15452872
2014 RBM4-regulated alternative splicing suppresses tumorigenesis. Cancer discovery 9 25367940
2021 miR-504 Promoted Gastric Cancer Cell Proliferation and Inhibited Cell Apoptosis by Targeting RBM4. Journal of immunology research 8 34195294
2020 Enteric infection induces Lark-mediated intron retention at the 5' end of Drosophila genes. Genome biology 8 31948480
2013 Phylogenetic and molecular characterization of the splicing factor RBM4. PloS one 8 23527094
2017 Clock gene is associated with individual variation in the activation of reproductive endocrine and behavior of Asian short toed lark. Scientific reports 7 29101400
2023 AMG232 inhibits angiogenesis in glioma through the p53-RBM4-VEGFR2 pathway. Journal of cell science 6 36601864
2020 Multiple species delimitation approaches applied to the avian lark genus Alaudala. Molecular phylogenetics and evolution 6 33250446
2020 The LARK protein is involved in antiviral and antibacterial responses in shrimp by regulating humoral immunity. Developmental and comparative immunology 5 32784011
2008 The LARK/RBM4a protein is highly expressed in cerebellum as compared to cerebrum. Neuroscience letters 5 18708123
2008 The Drosophila RNA-binding protein Lark is required for localization of Dmoesin to the oocyte cortex during oogenesis. Development genes and evolution 5 18958492
2006 Expression analysis of two types of transcripts from circadian output gene lark in Bombyx mori. Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 5 17287137
2005 Identification and expression pattern of Bmlark, a homolog of the Drosophila gene lark in Bombyx mori. DNA sequence : the journal of DNA sequencing and mapping 5 16147879
2023 Hypergravity enhances RBM4 expression in human bone marrow-derived mesenchymal stem cells and accelerates their differentiation into neurons. Regenerative therapy 4 36712961
2023 Activation of TrkB signaling mitigates cerebellar anomalies caused by Rbm4-Bdnf deficiency. Communications biology 4 37670183
2023 The N6-methyladenosine demethylase FTO is required for odontoblast differentiation in vitro and dentine formation in mice by promoting RUNX2 exon 5 inclusion through RBM4. International endodontic journal 4 37698901
2022 RBM4 inhibits the growth of clear cell renal cell carcinoma by enhancing the stability of p53 mRNA. Molecular carcinogenesis 4 36585906
2024 Selected Lark Mitochondrial Genomes Provide Insights into the Evolution of Second Control Region with Tandem Repeats in Alaudidae (Aves, Passeriformes). Life (Basel, Switzerland) 3 39063634
2024 Overexpression of RBM4 promotes acute myeloid leukemia cell differentiation by regulating alternative splicing of TFEB. The Journal of biological chemistry 3 39214303
2020 De Novo Assembly of a High-Quality Reference Genome for the Horned Lark (Eremophila alpestris). G3 (Bethesda, Md.) 3 31857331
2019 Molecular and morphological analysis of a Caryospora-like isolate (Apicomplexa: Eimeriidae) from the magpie-lark (Grallina cyanoleuca) (Latham, 1801) in Western Australia. Parasitology research 3 31754855
2024 PURPL Promotes M2 Macrophage Polarization in Lung Cancer by Regulating RBM4/xCT Signaling. Critical reviews in eukaryotic gene expression 2 38842204
2024 Endogenous RBM4 prevents Ang II-induced cardiomyocyte hypertrophy via downregulating the expression of PTBP1. Acta biochimica et biophysica Sinica 2 39118568
2024 RBM4-mediated intron excision of Hsf1 induces BDNF for cerebellar foliation. Communications biology 2 39738787
2017 Complete mitochondrial genome of the Mongolian lark, Melanocorypha mongolica (Aves: Passeriformes). Mitochondrial DNA. Part B, Resources 2 33473794
2015 Characterization of major histocompatibility complex class I loci of the lark sparrow (Chondestes grammacus) and insights into avian MHC evolution. Genetica 1 26071093
2026 m5C-Modified tRF3b-CysGCA-23 Suppresses Bladder Cancer Malignancy by Repressing H3K18 Lactylation via Stabilizing RBM4. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 41757512
2026 The translation landscape of ovarian clear cell carcinoma indicates that RBM4 plays a pro-oncogenic role in tumor progression. Oncogene 0 42249082
2025 Hsa_circ_0075451 promotes NSCLC proliferation, metastasis, and glycolysis through interaction with the RNA-binding protein RBM4. Discover oncology 0 41003853
2023 Immunity and Growth Plasticity of Asian Short-Toed Lark Nestlings in Response to Changes in Food Conditions: Can It Buffer the Challenge of Climate Change-Induced Trophic Mismatch? Animals : an open access journal from MDPI 0 36899717
2021 The complete mitochondrial genome of Asian short-toed Lark Alaudala cheleensis (Aves: Passeriformes: Alaudidae). Mitochondrial DNA. Part B, Resources 0 33628912
2021 Complete Mitochondrial Genome Sequence of the Magpie-Lark (Grallina cyanoleuca). Microbiology resource announcements 0 34137635

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