SRSF4

SRSF4 (SRp75) is a phosphorylated SR-family pre-mRNA splicing factor built from an N-terminal RRM, a glycine-rich region, an internal RRM-homologous region, and a long C-terminal SR domain whose serines are phosphorylated, and it restores splicing activity to S100-depleted extracts (PMID:8321209). Nuclear import of SRSF4 depends on the RS-rich domain together with additional basic NLS-like stretches, indicating use of at least two distinct import pathways (PMID:32050040), and the SR domain is selectively hyperphosphorylated by CLK-family kinases, which reshapes its nuclear distribution and modulates 5' splice-site choice (PMID:18298798). Within the nucleus, SRSF4 associates with hundreds of distinct endogenous mRNPs and regulates their levels (PMID:20639886), operating as both a positive and negative regulator of alternative splicing depending on context: it inhibits tau exon 10 inclusion by binding the downstream intronic FTDP-17 hotspot while interacting with hnRNPG and hnRNPE2 (PMID:21723381), inhibits splicing at HIV-1 exon 3 (PMID:20685659), and promotes Fas exon 6 inclusion by binding an exonic splicing enhancer, thereby biasing toward the pro-apoptotic membrane-bound isoform (PMID:30376989). Consistent with a role in cell-fate decisions, SRSF4 is required for most cisplatin-induced alternative splicing changes and for cisplatin-induced apoptosis via a class I PI3K (p110β)-dependent, ATM/ATR/p53-independent pathway (PMID:25884497). A patient-derived p.R235W missense variant that lowers SRSF4 protein causes mitochondrial dysfunction rescuable by wild-type SRSF4, linking the factor to energetic metabolism (PMID:38396760).

1. 1993 High

   Established SRSF4 as a bona fide SR splicing factor by defining its modular RRM–glycine–RRM-homology–SR domain architecture and showing it can functionally complement splicing activity.

   Evidence cDNA cloning with S100 complementation splicing assay and dephosphorylation/mobility-shift analysis

   PMID:8321209

   Open questions at the time

   • Did not identify endogenous target transcripts
   • Functional role of SR-domain phosphorylation not established
2. 2003 Medium

   Placed SRSF4 within a defined nuclear-speckle protein complex by identifying physical partners, addressing how it is organized with the splicing machinery.

   Evidence Yeast two-hybrid and reciprocal co-immunoprecipitation in corneal epithelial cells

   PMID:14578391

   Open questions at the time

   • Functional consequence of Pinin interaction on splicing not tested
   • Single cell type
3. 2008 Medium

   Identified CLK kinases as the specific regulators of SRSF4 hyperphosphorylation and linked this modification to nuclear distribution and 5' splice-site selection.

   Evidence Comparative SR kinase assay, CLK inhibitor TG003, live-cell imaging, and E1A alternative splicing reporter

   PMID:18298798

   Open questions at the time

   • Phosphosites on SRSF4 not mapped
   • Effect generality across targets beyond E1A not shown
4. 2010 High

   Demonstrated genome-wide that SRSF4 binds hundreds of endogenous mRNPs and that these associations functionally control transcript levels, establishing its role beyond single reporters.

   Evidence GFP-SR immunopurification of mRNPs with genome-wide target ID, siRNA knockdown, and GFP-SR rescue in P19 cells

   PMID:20639886

   Open questions at the time

   • Direct binding sites not resolved at nucleotide level
   • Splicing vs. stability contributions not separated
5. 2010 Medium

   Showed SRSF4 acts as a splicing inhibitor at a viral splice site, distinguishing its activity from related SR proteins.

   Evidence Transfection-based HIV-1 splicing assay with SR protein expression constructs

   PMID:20685659

   Open questions at the time

   • RNA element bound by SRSF4 not mapped
   • Single viral context
6. 2011 Medium

   Defined SRSF4 as a context-dependent splicing repressor at a disease-relevant exon and identified hnRNP cofactors, clarifying its regulatory mechanism at tau exon 10.

   Evidence Co-transfection splicing assay, co-IP, and RNAi knockdown

   PMID:21723381

   Open questions at the time

   • Stoichiometry/order of complex assembly unknown
   • In vivo relevance to tauopathy not tested
7. 2015 Medium

   Connected SRSF4 to a stress-response apoptotic program, showing it drives cisplatin-induced splicing changes and cell death through PI3K rather than canonical DNA-damage kinases.

   Evidence siRNA knockdown with transcriptome-wide sequencing, RT-PCR, FACS apoptosis, and pathway-specific inhibitors/knockout cells

   PMID:25884497

   Open questions at the time

   • Direct SRSF4 targets mediating apoptosis not isolated
   • Mechanistic link to PI3K not biochemically defined
8. 2015 Medium

   Identified upstream transcriptional control of SRSF4 by androgen receptor, showing its expression is hormonally repressed in Sertoli cells.

   Evidence AR ChIP/ARE binding, promoter assay, testosterone treatment of TM4 cells, immunofluorescence, and S-AR knockout comparison

   PMID:26308373

   Open questions at the time

   • Functional splicing consequence in Sertoli cells not defined
   • Single regulatory element
9. 2018 Medium

   Resolved SRSF4 as a positive splicing regulator that binds an exonic enhancer to control an apoptotic isoform switch, demonstrating bidirectional splicing activity.

   Evidence SRSF4 overexpression/knockdown, 5' splice-site mutagenesis, and enhancer mapping on Fas pre-mRNA

   PMID:30376989

   Open questions at the time

   • Enhancer sequence consensus not generalized
   • Endogenous physiological context not tested
10. 2020 Medium

    Dissected the determinants of SRSF4 nuclear import, showing reliance on the RS domain plus additional basic NLS motifs and multiple import routes.

    Evidence Pyruvate kinase fusion nuclear localization assay with serial deletion/domain mapping

    PMID:32050040

    Open questions at the time

    • Import receptors not identified
    • Link between import route and function not established
11. 2021 Low

    Implicated SRSF4 in cardiac hypertrophy through a GAS5 lncRNA/glucocorticoid receptor axis.

    Evidence Not fully described in available abstract

    PMID:34333993

    Open questions at the time

    • Experimental detail not extractable from abstract
    • Direct molecular role of SRSF4 in the axis undefined
12. 2023 Low

    Linked SRSF4 to DNA double-strand break repair and chemoresistance via positive regulation of MDC1 in glioma.

    Evidence Colony formation, flow cytometry, western blot, immunofluorescence, and orthotopic xenograft with SRSF4 manipulation

    PMID:37014544

    Open questions at the time

    • Biochemical mechanism linking SRSF4 to MDC1 not defined
    • Whether effect is splicing-mediated unknown
13. 2024 Medium

    Provided human genetic and functional evidence tying SRSF4 dosage to mitochondrial function via a rescuable missense variant.

    Evidence Whole genome sequencing, patient lymphocyte/lymphoblast analysis, mitochondrial function assays, and wild-type SRSF4 rescue transfection

    PMID:38396760

    Open questions at the time

    • Splicing targets mediating mitochondrial phenotype not identified
    • Single-patient case study

• How SRSF4's diverse non-splicing phenotypes (apoptosis, DNA repair, mitochondrial and cardiac function) connect to its core RNA-binding/splicing activity remains unresolved.
• No unifying set of direct RNA targets links the disparate phenotypes
• Phosphorylation-state-specific target maps lacking
• Structural basis of enhancer vs. silencer recognition unknown