Affinage

CCNY

Cyclin-Y · UniProt Q8ND76

Round 2 corrected
Length
341 aa
Mass
39.3 kDa
Annotated
2026-04-28
70 papers in source corpus 11 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Cyclin Y (CCNY) is a membrane-associated cyclin that partners with CDK14 and CDK16 to couple cell-cycle progression with signaling outputs, most notably phosphorylation of the Wnt co-receptor LRP6 at PPPSP motifs during G2/M, thereby placing Wnt/β-catenin pathway activation under cell-cycle control (PMID:20059949). The CDK16/CCNY complex also phosphorylates PRC1 at Thr481 to regulate cytokinesis, spindle integrity, and cell viability, and this axis is co-opted in NSCLC to drive tumor growth (PMID:30992425, PMID:40665337). CCNY additionally activates MEK/ERK signaling and cyclin E expression to promote G1/S progression (PMID:32606977), functions as an AMPK substrate linking energy sensing to autophagy (PMID:32401167), and exerts neuroprotective transcriptional effects on epilepsy-associated genes in hippocampal neurons (PMID:32739426). CCNY function is context-dependent: it is dispensable for spermatogenesis (unlike paralog CCNYL1) and for intestinal epithelial homeostasis where CDK14 expression is low (PMID:26305884, PMID:34571979).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2009 High

    Identification of CCNY as a membrane-tethered G2/M cyclin that activates CDK14 to phosphorylate LRP6 established the first molecular mechanism by which Wnt signaling is gated by cell-cycle phase.

    Evidence Kinome-wide RNAi screen in Drosophila, co-immunoprecipitation of CCNY–CDK14–LRP6, in vivo Xenopus anteroposterior patterning rescue

    PMID:20059949

    Open questions at the time
    • Structural basis of CCNY membrane tethering and CDK14 activation not resolved
    • Whether additional CCNY–CDK14 substrates beyond LRP6 exist was unknown
    • Relevance of the axis in mammalian tissues not yet tested
  2. 2015 High

    Knockout mouse studies clarified that CCNY is dispensable for spermatogenesis, distinguishing it from paralog CCNYL1 and revealing non-redundant cyclin-Y subfamily functions.

    Evidence Ccny−/− and Ccnyl1−/− mouse fertility phenotyping; reciprocal Co-IP and kinase assays showing CCNYL1–CDK16 specificity

    PMID:26305884

    Open questions at the time
    • Tissues where CCNY loss produces overt phenotypes remained unidentified
    • Whether CCNY binds CDK16 in any physiological context was unresolved
  3. 2019 High

    Identification of PRC1 Thr481 as a direct CDK16/CCNY substrate established a second effector pathway linking the complex to cytokinesis regulation and cell viability.

    Evidence Analog-sensitive CDK16 (CRISPR-engineered) with phosphosite-specific readout; epistasis analysis of PRC1 and CDK16 on viability

    PMID:30992425

    Open questions at the time
    • Whether CCNY or CCNYL1 preferentially drives CDK16-PRC1 phosphorylation in vivo not determined
    • Downstream consequences of PRC1 dephosphorylation beyond nuclear mislocalization were unexplored
  4. 2020 Medium

    Multiple studies expanded CCNY's functional repertoire: CCNY activates MEK/ERK/cyclin E in laryngeal carcinoma, is an AMPK substrate in autophagy, and protects against kainic acid-induced epilepsy by regulating epilepsy-associated gene expression in hippocampal neurons.

    Evidence CRISPR KO with rescue and pMEK/pERK western blots (Hep2 cells); AMPK substrate biochemistry; Ccny KO mouse seizure model with RNA-seq

    PMID:32401167 PMID:32606977 PMID:32739426

    Open questions at the time
    • MEK/ERK activation mechanism (direct CDK14/16 substrate vs. indirect) not delineated
    • AMPK phosphorylation sites on CCNY and functional consequence for CDK16 activity not fully mapped
    • Transcriptional mechanism by which a cyclin regulates epilepsy gene expression is unclear
  5. 2021 Medium

    Conditional intestinal Ccny knockout showed no effect on proliferation, Wnt signaling, or colitis, demonstrating that CCNY function is gated by CDK14 co-expression and is therefore tissue-context-dependent.

    Evidence Conditional intestinal epithelial Ccny KO mouse; DSS colitis model; Wnt and autophagy assays

    PMID:34571979

    Open questions at the time
    • Which tissues express sufficient CDK14 to render CCNY essential remains incompletely catalogued
    • Whether compensatory mechanisms beyond low CDK14 contribute to the null phenotype is untested
  6. 2025 Medium

    Extension of the CCNY–PRC1 phosphorylation axis to NSCLC showed that CCNY inhibition impairs spindle formation, causes G2/M arrest and multinucleation, and reduces tumorigenesis in vivo, converging with TET2-BACH1-driven PRC1 transcription to drive disease.

    Evidence siRNA/shRNA and pharmaceutical CCNY inhibition; xenograft and orthotopic isograft models; phospho-PRC1 western blot; tissue microarray

    PMID:40665337

    Open questions at the time
    • Identity of the pharmaceutical inhibitor target specificity not independently validated
    • Whether the dual PRC1 regulation axis operates in non-lung cancers is unknown
    • Direct structural or biophysical evidence for CCNY–CDK16 complex in NSCLC cells not provided

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of CCNY membrane association and CDK14/16 activation, the complete substrate repertoire of CCNY-containing CDK complexes, and the mechanism by which CCNY influences transcription of epilepsy-related genes independently of canonical CDK activity.
  • No crystal or cryo-EM structure of CCNY–CDK14 or CCNY–CDK16 complex
  • Full phosphoproteomics of CCNY-dependent substrates across tissues not performed
  • Neuroprotective transcriptional mechanism is correlative and lacks direct target identification

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 1
Pathway
R-HSA-1640170 Cell Cycle 5 R-HSA-162582 Signal Transduction 2 R-HSA-9612973 Autophagy 1
Partners
CDK14CDK16LRP6PRC1
Complex memberships
CCNY–CDK14 complexCCNY–CDK16 complex

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 Cyclin Y (CCNY) is a membrane-tethered G2/M cyclin that binds and activates CDK14 (PFTAIRE/PFTK, the vertebrate homolog of Drosophila L63/PFTAIRE) at the plasma membrane; the CCNY–CDK14 complex phosphorylates the PPPSP motifs in the cytoplasmic tail of LRP6, priming it for Wnt/β-catenin signal transduction. LRP6 phosphorylation and Wnt signaling peak at G2/M phase, placing Wnt pathway activation under cell-cycle control. In Xenopus embryos, Cyclin Y is required in vivo for LRP6 phosphorylation, maternal Wnt signaling, and anteroposterior patterning. Kinome-wide RNAi screen in Drosophila; epistasis/rescue experiments; in vivo phosphorylation assays; Xenopus loss-of-function with anteroposterior patterning readout; co-immunoprecipitation of CCNY with CDK14/PFTK and LRP6 Developmental Cell High 20059949
2015 CCNYL1, but not CCNY, cooperates with CDK16 to regulate spermatogenesis: male Ccnyl1-/- mice are infertile while Ccny-/- mice (both sexes) display normal fertility. This establishes that CCNY is dispensable for spermatogenesis. CCNYL1 (not CCNY) interacts with CDK16, mutually stabilizes CDK16 protein, and increases CDK16 kinase activity; phosphorylation sites on the CDK16 N-terminus identified by mass spectrometry are required for CCNYL1 binding and CDK16 activity modulation. Ccny-/- and Ccnyl1-/- mouse knockout models; fertility assays; co-immunoprecipitation; in vitro kinase assay; mass spectrometry phosphopeptide mapping PLoS Genetics High 26305884
2019 The CDK16/CCNY complex phosphorylates PRC1 (Protein Regulator of Cytokinesis 1) at Thr481 during interphase. Using analog-sensitive CDK16 generated by CRISPR-Cas9, specific inhibition of CDK16 causes PRC1 dephosphorylation at Thr481 and its delocalization to the nucleus. CDK16 inhibition and PRC1 downregulation show epistatic effects on cell viability, placing PRC1 downstream of CDK16/CCNY in a single pathway controlling cell proliferation. Complementary proteomic substrate identification; analog-sensitive CDK16 generated by CRISPR-Cas9; in-cell phosphorylation assay; epistasis analysis of cell viability; immunofluorescence localization Experimental & Molecular Medicine High 30992425
2010 Lentivirus-mediated RNAi knockdown of CCNY in glioma cells inhibits cell proliferation, colony formation, and cell cycle progression, indicating that CCNY plays a role in supporting glioma cell growth. Lentiviral shRNA knockdown; proliferation assay; colony formation assay; flow cytometric cell cycle analysis Oncology Research Medium 20441050
2018 Fisetin reduces TET1 expression in renal cancer stem cells, decreasing 5-hydroxymethylcytosine (5hmC) levels at CpG islands in the promoters of CCNY and CDK16, thereby repressing their transcription and causing cell cycle arrest. ChIP-PCR confirmed reduced 5hmC at CCNY/CDK16 promoters after fisetin treatment, linking epigenetic regulation of CCNY expression to renal cancer stem cell proliferation. ChIP-PCR for 5hmC at CCNY/CDK16 promoters; qPCR/western blot for TET1, CCNY, CDK16; in vivo xenograft; cell cycle analysis Journal of Cellular and Molecular Medicine Medium 30411496
2020 The CCNY–CDK16 complex is identified as a novel AMPK substrate involved in autophagy activation during nutrient deprivation, placing CCNY downstream of AMPK in energy-sensing/autophagy regulation. Commentary on Dohmen et al. findings; AMPK substrate identification (biochemical assays reported in primary study) Autophagy Medium 32401167
2020 Ccny knockout mice show enhanced susceptibility to kainic acid-induced epilepsy compared to wild-type mice. RNA-seq of hippocampal neurons with altered CCNY levels reveals that CCNY regulates expression of numerous epilepsy-associated genes (e.g., Chrna4, Gabrd, Nhlrc1, Reln, Slc6a1), indicating a neuroprotective role for CCNY in the brain. Ccny knockout mouse model; kainic acid-induced seizure model; RNA-seq bioinformatic analysis; mRNA/protein validation in Ccny KO brain Pharmacological Research Medium 32739426
2020 CCNY accelerates cyclin E expression and activates MEK/ERK signaling in laryngeal carcinoma (Hep2) cells: CCNY knockout reduces phospho-MEK, phospho-ERK, and cyclin E protein levels, while CCNY overexpression increases them. CCNY knockout also causes G1 phase accumulation, and re-expression rescues proliferation. CRISPR/Cas9 CCNY knockout; CCNY overexpression rescue; western blot for pMEK, pERK, cyclin E; flow cytometric cell cycle analysis; MTS/colony formation assays Cancer Management and Research Medium 32606977
2021 Conditional intestinal epithelial knockout of Ccny in mice does not affect cell proliferation, Wnt signaling, autophagy, or disease activity in the DSS colitis model, demonstrating that CCNY is dispensable for intestinal epithelial homeostasis. This is attributed to exceedingly low CDK14 expression in intestinal epithelial cells. Conditional intestinal epithelial Ccny knockout mouse; DSS colitis model; proliferation assays; Wnt reporter assay; autophagy assay in model IECs Cells Medium 34571979
2020 A novel chromosomal rearrangement producing a CCNY-ALK fusion gene (C1:A20) was identified in a patient with ALK-positive NSCLC; the fusion showed sensitivity to the ALK inhibitor crizotinib, indicating that the CCNY gene locus can serve as a 5' fusion partner driving oncogenic ALK kinase activity. Next-generation sequencing (NGS) of tumor tissue; clinical response assessment to crizotinib Translational Lung Cancer Research Low 33489809
2025 CCNY promotes phosphorylation of PRC1 in NSCLC cells; genetic knockdown or pharmaceutical inhibition of CCNY substantially reduces cell growth, impairs spindle formation, promotes G2/M arrest, and increases multi-nucleated cells in vitro, while weakening tumorigenic activity in vivo. TET2-BACH1-mediated DNA demethylation independently activates PRC1 transcription, and these two pathways (CCNY-mediated phosphorylation and TET2-BACH1-driven demethylation) cooperate to drive NSCLC progression. siRNA/shRNA knockdown and pharmaceutical inhibition of CCNY; xenograft and orthotopic isograft tumor models; western blot for phospho-PRC1; flow cytometry for cell cycle; immunofluorescence for spindle formation; tissue microarray Journal of Experimental & Clinical Cancer Research Medium 40665337

Source papers

Stage 0 corpus · 70 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2010 Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nature genetics 2036 21102463
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2011 Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nature genetics 1078 21297633
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2010 CpG islands influence chromatin structure via the CpG-binding protein Cfp1. Nature 475 20393567
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
2004 Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization. Current biology : CB 386 15324660
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2008 Replication of signals from recent studies of Crohn's disease identifies previously unknown disease loci for ulcerative colitis. Nature genetics 306 18438405
2017 Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing. Proceedings of the National Academy of Sciences of the United States of America 282 28611215
2000 Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing. EMBO reports 281 11256614
2009 Cell cycle control of wnt receptor activation. Developmental cell 221 20059949
2012 Cfp1 integrates both CpG content and gene activity for accurate H3K4me3 deposition in embryonic stem cells. Genes & development 212 22855832
2009 Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer's disease. Molecular psychiatry 170 19204726
2008 Investigation of Crohn's disease risk loci in ulcerative colitis further defines their molecular relationship. Gastroenterology 159 19068216
2010 Comparative genetic analysis of inflammatory bowel disease and type 1 diabetes implicates multiple loci with opposite effects. Human molecular genetics 148 20176734
2009 Ubiquitin-mediated proteolysis of HuR by heat shock. The EMBO journal 142 19322201
2005 A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease. American journal of human genetics 137 16385451
2013 Proteomic analysis of podocyte exosome-enriched fraction from normal human urine. Journal of proteomics 126 23376485
2019 The Functional Proximal Proteome of Oncogenic Ras Includes mTORC2. Molecular cell 124 30639242
2009 Genetic risk profiling and prediction of disease course in Crohn's disease patients. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 117 19422935
2011 The structural basis for selective binding of non-methylated CpG islands by the CFP1 CXXC domain. Nature communications 105 21407193
2017 CFP1 Regulates Histone H3K4 Trimethylation and Developmental Potential in Mouse Oocytes. Cell reports 82 28768200
2018 CFP1 coordinates histone H3 lysine-4 trimethylation and meiotic cell cycle progression in mouse oocytes. Nature communications 58 30154440
2008 CFP1 interacts with DNMT1 independently of association with the Setd1 Histone H3K4 methyltransferase complexes. DNA and cell biology 46 18680430
2018 Fisetin decreases TET1 activity and CCNY/CDK16 promoter 5hmC levels to inhibit the proliferation and invasion of renal cancer stem cell. Journal of cellular and molecular medicine 45 30411496
2015 CCNYL1, but Not CCNY, Cooperates with CDK16 to Regulate Spermatogenesis in Mouse. PLoS genetics 45 26305884
2016 Characterization and genome sequencing of a Citrobacter freundii phage CfP1 harboring a lysin active against multidrug-resistant isolates. Applied microbiology and biotechnology 44 27683211
2019 Physical and functional interaction between SET1/COMPASS complex component CFP-1 and a Sin3S HDAC complex in C. elegans. Nucleic acids research 41 31602465
2010 Lentivirus-mediated knockdown of cyclin Y (CCNY) inhibits glioma cell proliferation. Oncology research 35 20441050
2019 Phosphoregulation of the oncogenic protein regulator of cytokinesis 1 (PRC1) by the atypical CDK16/CCNY complex. Experimental & molecular medicine 26 30992425
2019 CFP1-dependent histone H3K4 trimethylation in murine oocytes facilitates ovarian follicle recruitment and ovulation in a cell-nonautonomous manner. Cellular and molecular life sciences : CMLS 23 31676962
2018 CpG binding protein (CFP1) occupies open chromatin regions of active genes, including enhancers and non-CpG islands. Epigenetics & chromatin 18 30292235
2014 Specific inhibition of DNMT1/CFP1 reduces cancer phenotypes and enhances chemotherapy effectiveness. Epigenomics 18 25111481
2022 Expression of the histone lysine methyltransferases SETD1B, SETDB1, SETD2, and CFP1 exhibits significant changes in the oocytes and granulosa cells of aged mouse ovaries. Histochemistry and cell biology 17 35445296
2023 CFP1 governs uterine epigenetic landscapes to intervene in progesterone responses for uterine physiology and suppression of endometriosis. Nature communications 14 37270588
2013 Induction of activation-induced cytidine deaminase-targeting adaptor 14-3-3γ is mediated by NF-κB-dependent recruitment of CFP1 to the 5'-CpG-3'-rich 14-3-3γ promoter and is sustained by E2A. Journal of immunology (Baltimore, Md. : 1950) 14 23851690
2020 Coexistence of a novel CCNY-ALK and ATIC-ALK double-fusion in one patient with ALK-positive NSCLC and response to crizotinib: a case report. Translational lung cancer research 13 33489809
2022 CpG-binding protein CFP1 promotes ovarian cancer cell proliferation by regulating BST2 transcription. Cancer gene therapy 12 35864225
2019 The survival analysis and oncogenic effects of CFP1 and 14-3-3 expression on gastric cancer. Cancer cell international 11 31496919
2010 The epigenetic regulator Cfp1. Biomolecular concepts 10 25962006
2023 CXXC finger protein 1 (CFP1) bridges the reshaping of genomic H3K4me3 signature to the advancement of lung adenocarcinoma. Signal transduction and targeted therapy 9 37735441
2020 A non-canonical monovalent zinc finger stabilizes the integration of Cfp1 into the H3K4 methyltransferase complex COMPASS. Nucleic acids research 9 31724694
2021 Analyzing the impact of CFP1 mutational landscape on epigenetic signaling. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 8 34320252
2020 New tricks of an old autophagy regulator: AMPK-dependent regulation of autophagy through CCNY (cyclin Y)-CDK16. Autophagy 7 32401167
2019 CFP-1 interacts with HDAC1/2 complexes in C. elegans development. The FEBS journal 7 30941832
2020 Ccny knockout mice display an enhanced susceptibility to kainic acid-induced epilepsy. Pharmacological research 6 32739426
2024 Cfp1 Controls Cardiomyocyte Maturation by Modifying Histone H3K4me3 of Structural, Metabolic, and Contractile Related Genes. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 4 38196272
2022 Three Small Cysteine-Free Proteins (CFP1-3) Are Required for Insect-Pathogenic Lifestyle of Metarhizium robertsii. Journal of fungi (Basel, Switzerland) 4 35736089
2019 Establishing a detection method for CCNY: a potentially significant clinical investigative marker in NSCLC patients. OncoTargets and therapy 4 30774378
2025 CCNY-mediated phosphorylation and TET2-BACH1-driven DNA demethylation activate PRC1 to augment NSCLC progression. Journal of experimental & clinical cancer research : CR 2 40665337
2021 The Candidate IBD Risk Gene CCNY Is Dispensable for Intestinal Epithelial Homeostasis. Cells 2 34571979
2025 CFP1 promotes germinal center affinity maturation and restrains memory B cell differentiation through H3K4me3 modulation. Nature communications 1 40866336
2023 Post-transcriptional repression of CFP-1 expands the regulatory repertoire of LIN-41/TRIM71. Nucleic acids research 1 37670562
2020 CCNY Accelerates Cylcin E Expression to Regulate the Proliferation of Laryngeal Carcinoma Cells via MEK/ERK Signaling Pathway. Cancer management and research 1 32606977
2026 CFP1-mediated H3K4me3 broad domains control early B cell lineage fate determination. Nucleic acids research 0 41728956
2025 Protocol for the purification and crystallization of the Drosophila melanogaster Cfp1PHD domain in complex with an H3K4me3 peptide. STAR protocols 0 39985772
2025 Analysis of DNA methylation changes following Cfp1 knockout in mouse spermatocytes. Animal bioscience 0 40045604
2025 Exploration into the MLL4/WRAD Enzyme-Substrate Network: Systematic In Vitro Identification of CFP1 as a Potential Non-Histone Substrate of the MLL4 Lysine Methyltransferase. Epigenomes 0 41133716