PRP4K

PRP4K (PRPF4B) is a dual-function serine kinase that operates both within the spliceosome and as a regulator of Hippo/YAP signaling, linking pre-mRNA processing to growth control (PMID:29695716, PMID:35281802, PMID:40531620). As a component of the U5 snRNP, it phosphorylates the spliceosomal proteins PRPF6 and PRPF31 to facilitate assembly of the spliceosome B complex (PMID:35281802), and through its splicing activity it controls processing of specific transcripts including the ESCRT-III gene CHMP4B, whose proper splicing is required for autophagosome–lysosome fusion (PMID:40531620). In the nucleus PRP4K phosphorylates YAP/Yki at a subset of Lats1/2 consensus sites and at a conserved serine within the YAP/Yki nuclear export signal; this blocks TEAD/Scalloped binding and drives CRM1-dependent nuclear export, thereby restricting Hippo target gene expression (PMID:29695716, PMID:37154687). This kinase activity is antagonized by competitive binders such as the LINC01315-encoded YAPer-ORF, which displaces YAP from PRP4K to promote YAP nuclear retention and CCND1 transcription (PMID:39962243). Beyond the nucleus, PRP4K localizes to late endosomes where it supports EGFR lysosomal degradation to enforce anoikis sensitivity (PMID:28892043), and it interacts with the RNA-binding protein TIA1 to modulate alternative splicing affecting NF-κB activity (PMID:41932413). PRP4K expression is set by upstream inputs including HER2 signaling, estrogen receptor alpha, eIF3e-dependent translation, and miR-371-5p, positioning it as a node coupling these pathways to cell cycle progression and drug sensitivity (PMID:25602630, PMID:26712520, PMID:34674320, PMID:23466643).

1. 2013 Medium

   Established that PRPF4B acts as a tumor-suppressive cell cycle regulator, answering whether its loss has growth consequences.

   Evidence shRNA knockdown, miR-371-5p overexpression with PRPF4B rescue, cell cycle analysis and xenograft in hepatocellular carcinoma cells

   PMID:23466643

   Open questions at the time

   • Did not define the molecular activity (splicing vs kinase) responsible for G1/S control
   • No direct substrate identified
2. 2015 Medium

   Placed PRP4K within the U5 snRNP and linked it to spindle assembly checkpoint function and taxane sensitivity downstream of HER2, connecting splicing machinery membership to a chemotherapy-relevant phenotype.

   Evidence Co-IP for U5 snRNP association, shRNA knockdown, drug sensitivity assays, correlation with HER2 status in tumors

   PMID:25602630

   Open questions at the time

   • Mechanism connecting splicing role to SAC unclear
   • Direct phosphorylation substrates within U5 snRNP not defined here
3. 2015 Medium

   Identified estrogen receptor alpha as an upstream transcriptional regulator of PRP4K, explaining how hormone receptor status modulates PRP4K levels and taxane response.

   Evidence ESR1 gain/loss-of-function, 4-OHT treatment, western blot/qRT-PCR, drug sensitivity assays across cell lines

   PMID:26712520

   Open questions at the time

   • Whether ESR1 binds the PRP4K promoter directly not shown
   • Did not connect expression change to a specific PRP4K molecular function
4. 2017 Medium

   Revealed a cytoplasmic, late-endosomal pool of PRP4K supporting EGFR lysosomal degradation, expanding its role beyond the nucleus to receptor trafficking and anoikis control.

   Evidence shRNA knockdown, subcellular fractionation/IF, EGFR trafficking assays, zebrafish xenograft and mouse ovarian cancer metastasis models

   PMID:28892043

   Open questions at the time

   • Kinase substrate at the endosome not identified
   • Mechanism by which PRP4K reaches late endosomes unknown
5. 2018 High

   Defined PRP4K as a direct YAP/Yki kinase that restricts Hippo signaling by blocking TEAD binding and promoting nuclear export, establishing a new arm of YAP regulation.

   Evidence Drosophila gain/loss-of-function genetics, phosphorylation assays, Co-IP, nuclear export assays, validated in mammalian breast cancer cells

   PMID:29695716

   Open questions at the time

   • Did not resolve which specific serines are phosphorylated for export vs TEAD blockade
   • Relationship to canonical Lats1/2 not fully delineated
6. 2021 Medium

   Positioned PRP4K downstream of eIF3e-dependent translation and EMT signaling in YAP control, showing its levels are set translationally to tune YAP activity.

   Evidence eIF3e knockdown, WNT-5a/TGF-β1 EMT induction, YAP localization assays, rescue by PRP4K overexpression

   PMID:34674320

   Open questions at the time

   • Direct mechanism of eIF3e selectivity for PRP4K mRNA not shown
   • In vivo relevance untested
7. 2023 Medium

   Pinpointed phosphorylation of a conserved NES serine as the molecular trigger for Yki–CRM1 interaction and export, separating the export mechanism from TEAD binding, and tied PRP4K to antimicrobial immune signaling.

   Evidence RNAi of PRP4K/CRM1 in crab hemocytes, phosphosite mutagenesis, Co-IP (Yki–CRM1, Yki–Sd), bacterial challenge

   PMID:37154687

   Open questions at the time

   • Conservation of this exact NES mechanism in human YAP not directly demonstrated
   • Invertebrate ortholog context
8. 2025 High

   Demonstrated that PRP4K controls autophagy through splicing of the ESCRT-III gene CHMP4B/vps32, defining a concrete splicing-target circuit linking the kinase to autophagosome–lysosome fusion.

   Evidence PRP4K KO in Dictyostelium and human cells, RNA splicing analysis, autophagosome-lysosome fusion assays, cDNA rescue

   PMID:40531620

   Open questions at the time

   • Whether kinase activity or scaffolding drives CHMP4B mis-splicing not separated
   • Other autophagy-relevant splicing targets not catalogued
9. 2025 Medium

   Identified YAPer-ORF as a competitive inhibitor of PRP4K–YAP binding, showing PRP4K's YAP-suppressing activity is itself regulated by a small protein to drive proliferation.

   Evidence Co-IP, competition binding assay, YAP phosphorylation and nuclear localization assays, CCND1 readout

   PMID:39962243

   Open questions at the time

   • Structural basis of competition not resolved
   • Single-lab finding without reciprocal in vivo validation
10. 2026 Medium

    Linked PRPF4B to TIA1-dependent alternative splicing controlling NF-κB activity and to genome-stability/cell-cycle phenotypes, broadening its splicing regulatory repertoire.

    Evidence Co-IP (PRPF4B–TIA1), shRNA knockdown, splicing analysis, NF-κB reporter, ROS/DNA damage and cell cycle assays in HCC cells

    PMID:41932413

    Open questions at the time

    • Whether TIA1 splice variant switch is a direct PRP4B catalytic effect unclear
    • Mechanism linking PRP4B loss to DNA damage not established

• How PRP4K coordinates its spliceosomal kinase activity with its distinct nuclear YAP-export and cytoplasmic EGFR-trafficking roles, and what governs its partitioning among these compartments, remains unresolved.
• No structural model distinguishing substrate recognition across roles
• Determinants of nuclear vs late-endosomal localization unknown
• Full substrate repertoire uncharacterized