CCNYL1

CCNYL1 is a cyclin-family regulatory subunit that couples CDK16 activation to mitotic WNT/STOP signalling, controlling stem/progenitor cell fate and male fertility (PMID:26305884, PMID:27203244). It binds CDK16 directly through phosphorylated N-terminal sites; this interaction mutually stabilizes both proteins at the protein level and enhances CDK16 kinase activity (PMID:26305884). Acting redundantly with CCNY, CCNYL1 promotes LRP6 phosphorylation during mitosis to drive Wnt/β-catenin signalling, placing it upstream of β-catenin: double loss of Ccnyl1/Ccny abolishes mammary stem/progenitor expansion, a defect rescued by constitutively active β-catenin (PMID:27203244). During G2/M this WNT/STOP activity inhibits GSK3-mediated degradation of the transcription factors Sox4 and Sox11 in neural progenitors, supporting neurogenesis and asymmetric apical-progenitor division (PMID:34431536). Ccnyl1 knockout mice are male infertile with impaired sperm motility and structural defects (PMID:26305884).

1. 2015 High

   Established CCNYL1 as a bona fide cyclin partner of CDK16 and defined the molecular basis of the interaction, answering whether CCNYL1 has catalytic-subunit-regulating activity.

   Evidence Co-immunoprecipitation, kinase activity assay, mass-spectrometry phosphosite mapping, CDK16 phosphosite mutagenesis, and Ccnyl1 knockout mice

   PMID:26305884

   Open questions at the time

   • Does not resolve which CDK16 substrates are relevant to the sperm phenotype
   • Mechanism linking CDK16 activation to sperm motility not defined
2. 2016 High

   Placed CCNYL1 upstream of β-catenin in mitotic Wnt signalling and showed its role in stem/progenitor maintenance, addressing whether the cyclin acts in WNT/STOP rather than only via CDK16.

   Evidence Ccnyl1/Ccny double-knockout mice, mammary transplantation and lineage tracing, LRP6 phosphorylation Western blot, β-catenin reporters, and rescue with constitutively active β-catenin

   PMID:27203244

   Open questions at the time

   • Functional redundancy with CCNY obscures CCNYL1-specific contribution
   • Kinase mediating LRP6 phosphorylation in this context not identified within the finding
3. 2021 High

   Identified the downstream GSK3 substrates stabilized by CCNYL1-dependent WNT/STOP during G2/M, connecting the pathway to a cell-fate output in neural progenitors.

   Evidence Ccny/Ccnyl1 double-mutant mice, immunofluorescence, cell-division analysis, and identification of Sox4/Sox11 as GSK3 targets

   PMID:34431536

   Open questions at the time

   • Direct biochemical demonstration of GSK3 acting on Sox4/Sox11 within this model not detailed
   • CCNYL1-specific versus CCNY-specific roles not separated
4. 2021 Low

   Observed regulation of CCNYL1 protein abundance in a sperm structural context, raising the question of how CCNYL1 levels relate to flagellar integrity.

   Evidence Western blot and immunofluorescence in Cabs1 knockout mouse testes/sperm

   PMID:33440775

   Open questions at the time

   • Single observation in a knockout of a different gene with no direct mechanistic test on CCNYL1
   • Direction of causality (compensatory vs pathological) unresolved

• How CCNYL1/CDK16 kinase activity mechanistically links to WNT/STOP signalling and to sperm motility remains unresolved.
• No demonstrated CDK16 substrate in the WNT/STOP or sperm pathways
• No structural model of the CCNYL1–CDK16 complex