{"gene":"CCNYL1","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2015,"finding":"CCNYL1 directly interacts with CDK16, and this interaction mutually increases the protein stability of both CCNYL1 and CDK16 (without affecting CDK16 mRNA levels), and increases CDK16 kinase activity. Phosphorylation sites on the N-terminal region of CDK16 (identified by mass spectrometry) are indispensable for CCNYL1 binding and modulation of CDK16 kinase activity. Loss of Ccnyl1 in mice causes male infertility with impaired sperm motility and structural defects.","method":"Co-immunoprecipitation, kinase activity assay, mass spectrometry phosphorylation mapping, site-directed mutagenesis of CDK16 phosphorylation sites, Ccnyl1 knockout mouse model","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal interaction confirmed, kinase assay, mutagenesis of phosphorylation sites, and KO phenotype, all in a single focused study with multiple orthogonal methods","pmids":["26305884"],"is_preprint":false},{"year":2016,"finding":"CCNYL1 (together with CCNY) promotes Wnt/β-catenin signaling during mitosis by supporting LRP6 phosphorylation. Double knockout of Ccnyl1 and Ccny reduces LRP6 phosphorylation, impairs β-catenin activity, and abolishes mammary stem/progenitor cell expansion. Constitutively active β-catenin rescues the regeneration defect, placing CCNYL1 upstream of β-catenin in the WNT/STOP pathway.","method":"Double Ccnyl1/Ccny knockout mice, mammary transplantation assays, lineage tracing, Western blot for LRP6 phosphorylation, β-catenin reporter assays, rescue with constitutively active β-catenin","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via double KO, phosphorylation readout, and functional rescue with constitutively active β-catenin across multiple orthogonal assays","pmids":["27203244"],"is_preprint":false},{"year":2021,"finding":"CCNYL1 (together with CCNY) regulates WNT/STOP signalling during G2/M to inhibit GSK3-mediated protein degradation in neural progenitors. Ccny/l1 double-mutant mice show reduced neurogenesis, decreased basal progenitors, and impaired asymmetric division of apical progenitors. Sox4 and Sox11 are identified as direct GSK3 targets stabilized by WNT/STOP signalling in basal progenitors during mitosis.","method":"Ccny/Ccnyl1 double-mutant mouse model, immunofluorescence, cell division analysis, identification of GSK3 substrates Sox4/Sox11","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — double-mutant mice with defined cellular phenotype, substrate identification, and pathway placement via epistasis with GSK3","pmids":["34431536"],"is_preprint":false},{"year":2021,"finding":"Loss of Cabs1 leads to increased CCNYL1 protein levels in mouse sperm, suggesting that CCNYL1 protein abundance is regulated in the context of sperm structural integrity and cytoskeletal organization, though the direction of causality (whether CCNYL1 increase is compensatory or pathological) is not resolved.","method":"Western blot and immunofluorescence in Cabs1 knockout mouse testes/sperm","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single observation in a KO of a different gene; no direct mechanistic experiment on CCNYL1 itself","pmids":["33440775"],"is_preprint":false}],"current_model":"CCNYL1 is a cyclin family member that functions as a regulatory subunit for CDK16, binding to CDK16 via phosphorylated N-terminal sites to mutually stabilize both proteins and enhance CDK16 kinase activity; CCNYL1 also acts as a key activator of mitotic WNT/STOP signalling by promoting LRP6 phosphorylation and inhibiting GSK3-mediated protein degradation during G2/M, thereby controlling β-catenin activity, neural progenitor fate decisions, and mammary stem/progenitor cell maintenance, with loss of function causing male infertility through impaired sperm motility."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2015,"claim":"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","pmids":["26305884"],"confidence":"High","gaps":["Does not resolve which CDK16 substrates are relevant to the sperm phenotype","Mechanism linking CDK16 activation to sperm motility not defined"]},{"year":2016,"claim":"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","pmids":["27203244"],"confidence":"High","gaps":["Functional redundancy with CCNY obscures CCNYL1-specific contribution","Kinase mediating LRP6 phosphorylation in this context not identified within the finding"]},{"year":2021,"claim":"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","pmids":["34431536"],"confidence":"High","gaps":["Direct biochemical demonstration of GSK3 acting on Sox4/Sox11 within this model not detailed","CCNYL1-specific versus CCNY-specific roles not separated"]},{"year":2021,"claim":"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","pmids":["33440775"],"confidence":"Low","gaps":["Single observation in a knockout of a different gene with no direct mechanistic test on CCNYL1","Direction of causality (compensatory vs pathological) unresolved"]},{"year":null,"claim":"How CCNYL1/CDK16 kinase activity mechanistically links to WNT/STOP signalling and to sperm motility remains unresolved.","evidence":"No timeline finding connects the CDK16 activation function to the LRP6/GSK3 axis","pmids":[],"confidence":"Low","gaps":["No demonstrated CDK16 substrate in the WNT/STOP or sperm pathways","No structural model of the CCNYL1–CDK16 complex"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,2]}],"complexes":[],"partners":["CDK16","CCNY","LRP6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N7R7","full_name":"Cyclin-Y-like protein 1","aliases":[],"length_aa":359,"mass_kda":40.7,"function":"Key regulator of Wnt signaling implicated in various biological processes including male fertility, embryonic neurogenesis and cortex development. Activates the cyclin-dependent kinase CDK16, and promotes sperm maturation","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8N7R7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CCNYL1","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CCNYL1","total_profiled":1310},"omim":[{"mim_id":"620559","title":"CYCLIN Y-LIKE 1; CCNYL1","url":"https://www.omim.org/entry/620559"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CCNYL1"},"hgnc":{"alias_symbol":["FLJ40432"],"prev_symbol":[]},"alphafold":{"accession":"Q8N7R7","domains":[{"cath_id":"1.10.472.10","chopping":"89-100_135-313","consensus_level":"high","plddt":93.0909,"start":89,"end":313}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N7R7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N7R7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N7R7-F1-predicted_aligned_error_v6.png","plddt_mean":73.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCNYL1","jax_strain_url":"https://www.jax.org/strain/search?query=CCNYL1"},"sequence":{"accession":"Q8N7R7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N7R7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N7R7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N7R7"}},"corpus_meta":[{"pmid":"26305884","id":"PMC_26305884","title":"CCNYL1, but Not CCNY, Cooperates with CDK16 to Regulate Spermatogenesis in Mouse.","date":"2015","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26305884","citation_count":46,"is_preprint":false},{"pmid":"34431536","id":"PMC_34431536","title":"Mitotic WNT signalling orchestrates neurogenesis in the developing neocortex.","date":"2021","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/34431536","citation_count":35,"is_preprint":false},{"pmid":"27203244","id":"PMC_27203244","title":"Essential Roles of Cyclin Y-Like 1 and Cyclin Y in Dividing Wnt-Responsive Mammary Stem/Progenitor Cells.","date":"2016","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27203244","citation_count":26,"is_preprint":false},{"pmid":"33440775","id":"PMC_33440775","title":"Cabs1 Maintains Structural Integrity of Mouse Sperm Flagella during Epididymal Transit of Sperm.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33440775","citation_count":20,"is_preprint":false},{"pmid":"37956402","id":"PMC_37956402","title":"Dopamine receptor D2 regulates genes involved in germ cell movement and sperm motility in rat testes†.","date":"2024","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/37956402","citation_count":7,"is_preprint":false},{"pmid":"35535691","id":"PMC_35535691","title":"GWAS of thyroid dysgenesis identifies a risk locus at 2q33.3 linked to regulation of Wnt signaling.","date":"2022","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35535691","citation_count":6,"is_preprint":false},{"pmid":"40945274","id":"PMC_40945274","title":"Insights into histone deacetylase inhibitors-induced cell death in cancer cell lines.","date":"2025","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/40945274","citation_count":1,"is_preprint":false},{"pmid":"41851027","id":"PMC_41851027","title":"An Assembly of the Global Phosphoproteomic Network of an Underexplored Kinase CDK17: Possible Implications in Cell Cycle Regulation.","date":"2026","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/41851027","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6330,"output_tokens":1278,"usd":0.01908,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7921,"output_tokens":1867,"usd":0.04314,"stage2_stop_reason":"end_turn"},"total_usd":0.06222,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"CCNYL1 directly interacts with CDK16, and this interaction mutually increases the protein stability of both CCNYL1 and CDK16 (without affecting CDK16 mRNA levels), and increases CDK16 kinase activity. Phosphorylation sites on the N-terminal region of CDK16 (identified by mass spectrometry) are indispensable for CCNYL1 binding and modulation of CDK16 kinase activity. Loss of Ccnyl1 in mice causes male infertility with impaired sperm motility and structural defects.\",\n      \"method\": \"Co-immunoprecipitation, kinase activity assay, mass spectrometry phosphorylation mapping, site-directed mutagenesis of CDK16 phosphorylation sites, Ccnyl1 knockout mouse model\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal interaction confirmed, kinase assay, mutagenesis of phosphorylation sites, and KO phenotype, all in a single focused study with multiple orthogonal methods\",\n      \"pmids\": [\"26305884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CCNYL1 (together with CCNY) promotes Wnt/β-catenin signaling during mitosis by supporting LRP6 phosphorylation. Double knockout of Ccnyl1 and Ccny reduces LRP6 phosphorylation, impairs β-catenin activity, and abolishes mammary stem/progenitor cell expansion. Constitutively active β-catenin rescues the regeneration defect, placing CCNYL1 upstream of β-catenin in the WNT/STOP pathway.\",\n      \"method\": \"Double Ccnyl1/Ccny knockout mice, mammary transplantation assays, lineage tracing, Western blot for LRP6 phosphorylation, β-catenin reporter assays, rescue with constitutively active β-catenin\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via double KO, phosphorylation readout, and functional rescue with constitutively active β-catenin across multiple orthogonal assays\",\n      \"pmids\": [\"27203244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CCNYL1 (together with CCNY) regulates WNT/STOP signalling during G2/M to inhibit GSK3-mediated protein degradation in neural progenitors. Ccny/l1 double-mutant mice show reduced neurogenesis, decreased basal progenitors, and impaired asymmetric division of apical progenitors. Sox4 and Sox11 are identified as direct GSK3 targets stabilized by WNT/STOP signalling in basal progenitors during mitosis.\",\n      \"method\": \"Ccny/Ccnyl1 double-mutant mouse model, immunofluorescence, cell division analysis, identification of GSK3 substrates Sox4/Sox11\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double-mutant mice with defined cellular phenotype, substrate identification, and pathway placement via epistasis with GSK3\",\n      \"pmids\": [\"34431536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of Cabs1 leads to increased CCNYL1 protein levels in mouse sperm, suggesting that CCNYL1 protein abundance is regulated in the context of sperm structural integrity and cytoskeletal organization, though the direction of causality (whether CCNYL1 increase is compensatory or pathological) is not resolved.\",\n      \"method\": \"Western blot and immunofluorescence in Cabs1 knockout mouse testes/sperm\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single observation in a KO of a different gene; no direct mechanistic experiment on CCNYL1 itself\",\n      \"pmids\": [\"33440775\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCNYL1 is a cyclin family member that functions as a regulatory subunit for CDK16, binding to CDK16 via phosphorylated N-terminal sites to mutually stabilize both proteins and enhance CDK16 kinase activity; CCNYL1 also acts as a key activator of mitotic WNT/STOP signalling by promoting LRP6 phosphorylation and inhibiting GSK3-mediated protein degradation during G2/M, thereby controlling β-catenin activity, neural progenitor fate decisions, and mammary stem/progenitor cell maintenance, with loss of function causing male infertility through impaired sperm motility.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CCNYL1 is a cyclin-family regulatory subunit that couples CDK16 activation to mitotic WNT/STOP signalling, controlling stem/progenitor cell fate and male fertility [#0, #1]. It binds CDK16 directly through phosphorylated N-terminal sites; this interaction mutually stabilizes both proteins at the protein level and enhances CDK16 kinase activity [#0]. Acting redundantly with CCNY, CCNYL1 promotes LRP6 phosphorylation during mitosis to drive Wnt/\\u03b2-catenin signalling, placing it upstream of \\u03b2-catenin: double loss of Ccnyl1/Ccny abolishes mammary stem/progenitor expansion, a defect rescued by constitutively active \\u03b2-catenin [#1]. 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 [#2]. Ccnyl1 knockout mice are male infertile with impaired sperm motility and structural defects [#0].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-immunoprecipitation, kinase activity assay, mass-spectrometry phosphosite mapping, CDK16 phosphosite mutagenesis, and Ccnyl1 knockout mice\",\n      \"pmids\": [\"26305884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve which CDK16 substrates are relevant to the sperm phenotype\", \"Mechanism linking CDK16 activation to sperm motility not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed CCNYL1 upstream of \\u03b2-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.\",\n      \"evidence\": \"Ccnyl1/Ccny double-knockout mice, mammary transplantation and lineage tracing, LRP6 phosphorylation Western blot, \\u03b2-catenin reporters, and rescue with constitutively active \\u03b2-catenin\",\n      \"pmids\": [\"27203244\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional redundancy with CCNY obscures CCNYL1-specific contribution\", \"Kinase mediating LRP6 phosphorylation in this context not identified within the finding\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"Ccny/Ccnyl1 double-mutant mice, immunofluorescence, cell-division analysis, and identification of Sox4/Sox11 as GSK3 targets\",\n      \"pmids\": [\"34431536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical demonstration of GSK3 acting on Sox4/Sox11 within this model not detailed\", \"CCNYL1-specific versus CCNY-specific roles not separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Observed regulation of CCNYL1 protein abundance in a sperm structural context, raising the question of how CCNYL1 levels relate to flagellar integrity.\",\n      \"evidence\": \"Western blot and immunofluorescence in Cabs1 knockout mouse testes/sperm\",\n      \"pmids\": [\"33440775\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single observation in a knockout of a different gene with no direct mechanistic test on CCNYL1\", \"Direction of causality (compensatory vs pathological) unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CCNYL1/CDK16 kinase activity mechanistically links to WNT/STOP signalling and to sperm motility remains unresolved.\",\n      \"evidence\": \"No timeline finding connects the CDK16 activation function to the LRP6/GSK3 axis\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No demonstrated CDK16 substrate in the WNT/STOP or sperm pathways\", \"No structural model of the CCNYL1\\u2013CDK16 complex\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CDK16\", \"CCNY\", \"LRP6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":5,"faith_pct":60.0}}