WBP11

WBP11 is a nuclear pre-mRNA splicing factor that resides in nuclear speckles and the spliceosome and actively promotes splicing catalysis in intact cells (PMID:14640981, PMID:16162498). It is built around modular interaction surfaces: a proline-rich PGR motif that is recognized by the WW domain of the splicing-associated protein PQBP1/Npw38, and an RVXF motif through which it directly binds and inhibits protein phosphatase-1 (PP1), an inhibitory activity that is potentiated by CK1 phosphorylation (PMID:10593949, PMID:14640981). WBP11 carries nuclear localization signals required for nuclear import (and can be imported by piggy-back transport with PQBP1) while its proline-rich C-terminus directs targeting to speckles and mediates CRM1-dependent nuclear export that is triggered by UV or X-radiation, coupling its splicing-activating function to its nuclear concentration (PMID:14640981, PMID:16162498). Mechanistically, WBP11 suppresses intron retention in specific transcripts: it preserves correct splicing of TUBGCP6 to sustain γ-TuRC integrity and centriole duplication, and represses intron 4 retention of MCM7 to maintain MCM7 protein levels (PMID:31874114, PMID:38561505). This splicing function is essential for organogenesis, as heterozygous loss-of-function in mice causes congenital axial skeleton, kidney, and esophageal malformations while homozygous loss is embryonic lethal before E8.5 (PMID:33276377). WBP11 also acts in non-splicing contexts to drive cancer progression, including a FOXM1→WBP11→MCM7 axis in ovarian cancer and stabilization of the RNA-binding protein NONO by competitively blocking UFL1-mediated UFMylation at Lys198 in hepatocellular carcinoma (PMID:38561505, PMID:41184530).

1. 1999 Medium

   Established WBP11's first molecular partnership, defining a proline-rich PGR motif as the docking site for the WW domain of PQBP1/Npw38 and revealing nucleic-acid binding by its N-terminus.

   Evidence Reciprocal Co-IP of epitope-tagged proteins in COS7 cells, oligopeptide membrane binding, GFP co-localization, and poly(rG)/ssDNA binding assays

   PMID:10593949

   Open questions at the time

   • Functional consequence of the PQBP1 interaction for splicing not defined
   • Significance of N-terminal nucleic-acid binding unresolved
   • Single-lab interaction without independent confirmation
2. 2004 High

   Placed WBP11 in the spliceosome and identified it as an RVXF-motif PP1 inhibitor whose potency is tuned by CK1 phosphorylation, while showing a WBP11 fragment can block splicing catalysis independently of PP1.

   Evidence Yeast two-hybrid, co-sedimentation, PP1 activity and CK1 kinase assays, in vitro nuclear extract splicing, EGFP localization and domain mapping

   PMID:14640981

   Open questions at the time

   • Physiological splicing substrates not identified
   • How PP1 inhibition relates to splicing activation unclear
   • Mechanism by which the fragment blocks catalysis undefined
3. 2005 High

   Resolved WBP11 trafficking, showing it shuttles between nucleus and cytoplasm with CRM1-dependent export induced by radiation, and that its nuclear concentration determines the degree of splicing activation.

   Evidence GFP-fusion localization, radiation treatment, CRM1 export inhibition, PQBP1 co-expression, and splicing activation assays in intact cells with domain deletions

   PMID:16162498

   Open questions at the time

   • Signaling link between radiation stress and export not mapped
   • Direct splicing targets still unknown at this stage
   • Whether cytoplasmic relocation has a distinct function unresolved
4. 2019 High

   Connected WBP11 splicing activity to a concrete cellular outcome by showing it suppresses intron retention in TUBGCP6 to sustain γ-TuRC and centriole duplication, embedding it in a network of centriole-promoting splicing factors.

   Evidence siRNA/shRNA depletion, RNA-seq intron-retention analysis, centriole immunofluorescence, TUBGCP6 Western blot, and Co-IP of splicing factors

   PMID:31874114

   Open questions at the time

   • How WBP11 selects retained-intron targets unknown
   • Direct vs indirect role on TUBGCP6 splicing not dissected
   • Identity of the spliceosomal subcomplex WBP11 acts within unclear
5. 2019 Low

   Implicated WBP11 in cancer signaling as a downstream effector of KIAA1199 affecting cadherin expression and gastric cancer behavior.

   Evidence Co-IP of KIAA1199-WBP11, overexpression/knockdown in gastric cancer lines, and migration/proliferation assays in vitro and in vivo

   PMID:30626935

   Open questions at the time

   • Single Co-IP without reciprocal validation; WBP11 role secondary to KIAA1199 narrative
   • Molecular mechanism linking WBP11 to cadherin pathways undefined
   • No splicing-based mechanism tested
6. 2020 High

   Demonstrated that WBP11 is essential for development in vivo, with heterozygous loss producing congenital malformations and homozygous loss causing early embryonic lethality, tying its splicing function to organogenesis.

   Evidence CRISPR-Cas9 null mouse generation, embryonic lethality phenotyping, and characterization of skeletal/renal/esophageal defects in heterozygotes

   PMID:33276377

   Open questions at the time

   • Specific developmental transcripts mis-spliced in vivo not fully enumerated
   • Tissue-specific requirements not dissected
   • Mechanism linking haploinsufficiency to each organ defect incomplete
7. 2024 Medium

   Defined a transcriptional-to-splicing cascade in which FOXM1 activates WBP11, which in turn represses MCM7 intron 4 retention to maintain MCM7 and drive ovarian cancer progression.

   Evidence RNA-seq/splicing analysis, siRNA knockdown, FOXM1 ChIP on the WBP11 promoter, and proliferation/migration plus rescue assays in vitro and in vivo

   PMID:38561505

   Open questions at the time

   • Generality of MCM7 intron regulation beyond ovarian cancer untested
   • Direct binding of WBP11 to MCM7 pre-mRNA not shown
   • Single-lab axis
8. 2025 Medium

   Revealed a splicing-independent role in which WBP11 stabilizes NONO by competitively blocking UFL1-mediated UFMylation at Lys198, enhancing glycolysis and hepatocellular carcinoma progression.

   Evidence Co-IP with domain mapping (WBP11 N-terminus to NONO RRM), UFMylation assays with UFL1 and a Lys198 mutant, glycolysis measurements, knockdown, and rescue in vitro and in vivo

   PMID:41184530

   Open questions at the time

   • Whether NONO stabilization is independent of WBP11's nuclear splicing role unclear
   • Structural basis of competition with UFL1 unknown
   • Single-lab axis

• How WBP11 selects its specific intron-retention targets and integrates PP1 inhibition, PQBP1 binding, radiation-regulated shuttling, and its non-splicing protein-stabilization activities into a unified mechanism remains unresolved.
• No structure of WBP11 or its spliceosomal complex
• Rules governing target intron selection unknown
• Relationship between PP1 inhibition and splicing activation undefined