{"gene":"CDK15","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2014,"finding":"CDK15 (ALS2CR7) phosphorylates survivin at Thr34, and this phosphorylation promotes TRAIL resistance in cancer cells by increasing survivin expression and decreasing activation of caspases-3, -8, and -9 and PARP cleavage. CDK15 was shown to bind survivin directly (but not Bcl2, FLIP, XIAP, DR4, or DR5).","method":"Transfection/overexpression and siRNA knockdown of CDK15 in TRAIL-sensitive and -resistant cancer cell lines; co-immunoprecipitation/binding assay; viability and apoptosis assays; phospho-survivin immunoblotting","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2/3 — direct binding and phosphorylation demonstrated in cell-based assays with overexpression and knockdown; single lab, moderate orthogonality","pmids":["24866247"],"is_preprint":false},{"year":2021,"finding":"CDK15 binds PAK4 and phosphorylates PAK4 at Ser291, which activates β-catenin/c-Myc and MEK/ERK signaling to promote colorectal cancer cell proliferation and anchorage-independent growth. Inhibition of PAK4 reversed the tumorigenic effects of CDK15.","method":"Co-immunoprecipitation, site-specific phosphorylation assays (S291 mutant), CDK15 knockdown/knockout in cell lines and mouse models (AOM/DSS, CDX, PDX xenografts), PAK4 inhibitor rescue experiments","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP plus phospho-site mutagenesis, validated in multiple in vivo models; moderate-to-strong evidence from a single lab with multiple orthogonal methods","pmids":["34262144"],"is_preprint":false},{"year":2019,"finding":"PA28α/β (immunoproteasome activator) promotes degradation/downregulation of CDK15 protein, and loss of CDK15 is required for PA28α/β-mediated breast cancer cell invasion and metastasis.","method":"Knockdown of PA28α/β and β5i subunit with siRNA; immunoblotting for CDK15 protein levels; invasion/migration assays; CDK15 silencing to phenocopy the invasive effect","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, protein-level regulation shown by knockdown with functional readout; mechanism of CDK15 downregulation not fully resolved at molecular level","pmids":["31824858"],"is_preprint":false}],"current_model":"CDK15 is a cyclin-dependent kinase that directly binds and phosphorylates PAK4 at Ser291 to activate β-catenin/c-Myc and MEK/ERK signaling, and also binds and phosphorylates survivin at Thr34 to suppress TRAIL-induced apoptosis; its protein levels are negatively regulated by the PA28α/β immunoproteasome complex."},"narrative":{"teleology":[{"year":2014,"claim":"Identifying CDK15 as a kinase for survivin established its first known substrate and linked it to apoptosis resistance, answering the question of how TRAIL-resistant cancer cells stabilize survivin.","evidence":"Overexpression and siRNA knockdown of CDK15 in TRAIL-sensitive and -resistant cancer cell lines with co-immunoprecipitation, phospho-survivin immunoblotting, and apoptosis assays","pmids":["24866247"],"confidence":"Medium","gaps":["Binding and phosphorylation demonstrated only in overexpression systems without in vitro kinase assay using purified components","No cyclin partner identified for CDK15 in this context","Phosphorylation stoichiometry and kinetics not determined"]},{"year":2019,"claim":"Showing that PA28α/β promotes CDK15 protein degradation revealed a proteostatic control mechanism for CDK15 and connected immunoproteasome activity to CDK15-dependent suppression of invasion.","evidence":"siRNA knockdown of PA28α/β and β5i subunit with immunoblotting for CDK15 and functional invasion/migration assays in breast cancer cells","pmids":["31824858"],"confidence":"Medium","gaps":["Molecular mechanism of CDK15 degradation (direct ubiquitination, proteasomal targeting) not resolved","Whether CDK15 is a direct substrate of the immunoproteasome or is regulated indirectly remains unclear","Findings from a single cell system without in vivo validation"]},{"year":2021,"claim":"Identifying PAK4 Ser291 as a second CDK15 substrate and linking it to β-catenin/c-Myc and MEK/ERK signaling broadened CDK15's role from anti-apoptotic kinase to a driver of proliferative oncogenic signaling.","evidence":"Reciprocal co-immunoprecipitation, phospho-site mutagenesis (S291A), CDK15 knockout in AOM/DSS, CDX, and PDX mouse models, and PAK4 inhibitor rescue experiments in colorectal cancer cells","pmids":["34262144"],"confidence":"High","gaps":["No activating cyclin partner for CDK15 has been identified","Whether CDK15 phosphorylation of PAK4 is direct (in vitro kinase assay with purified proteins) was not explicitly shown","Structural basis for CDK15 substrate selectivity is unknown"]},{"year":null,"claim":"The activating cyclin partner of CDK15, its full substrate repertoire, and the structural basis of its substrate specificity remain uncharacterized.","evidence":"","pmids":[],"confidence":"Low","gaps":["No cyclin partner identified for CDK15","No crystal structure or cryo-EM structure available","Physiological roles outside oncogenic contexts are unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1]}],"localization":[],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1]}],"complexes":[],"partners":["BIRC5","PAK4"],"other_free_text":[]},"mechanistic_narrative":"CDK15 is a cyclin-dependent kinase that phosphorylates specific substrates to promote cell survival and proliferation. It directly binds and phosphorylates survivin at Thr34, stabilizing survivin expression and suppressing TRAIL-induced apoptosis by reducing activation of caspases-3, -8, and -9 and PARP cleavage [PMID:24866247]. CDK15 also binds and phosphorylates PAK4 at Ser291, thereby activating β-catenin/c-Myc and MEK/ERK signaling to drive colorectal cancer cell proliferation and anchorage-independent growth [PMID:34262144]. CDK15 protein levels are negatively regulated by the PA28α/β immunoproteasome activator complex, and loss of CDK15 is required for PA28α/β-mediated breast cancer cell invasion and metastasis [PMID:31824858]."},"prefetch_data":{"uniprot":{"accession":"Q96Q40","full_name":"Cyclin-dependent kinase 15","aliases":["Amyotrophic lateral sclerosis 2 chromosomal region candidate gene 7 protein","Cell division protein kinase 15","Serine/threonine-protein kinase ALS2CR7","Serine/threonine-protein kinase PFTAIRE-2"],"length_aa":435,"mass_kda":49.0,"function":"Serine/threonine-protein kinase that acts like an antiapoptotic protein that counters TRAIL/TNFSF10-induced apoptosis by inducing phosphorylation of BIRC5 at 'Thr-34'","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q96Q40/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CDK15","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CDK15","total_profiled":1310},"omim":[{"mim_id":"616147","title":"CYCLIN-DEPENDENT KINASE 15; CDK15","url":"https://www.omim.org/entry/616147"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"epididymis","ntpm":14.4},{"tissue":"ovary","ntpm":4.7}],"url":"https://www.proteinatlas.org/search/CDK15"},"hgnc":{"alias_symbol":["PFTAIRE2"],"prev_symbol":["ALS2CR7","PFTK2"]},"alphafold":{"accession":"Q96Q40","domains":[{"cath_id":"3.30.200.20","chopping":"107-180","consensus_level":"high","plddt":84.5476,"start":107,"end":180},{"cath_id":"1.10.510.10","chopping":"184-412","consensus_level":"high","plddt":88.7314,"start":184,"end":412}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96Q40","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96Q40-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96Q40-F1-predicted_aligned_error_v6.png","plddt_mean":72.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CDK15","jax_strain_url":"https://www.jax.org/strain/search?query=CDK15"},"sequence":{"accession":"Q96Q40","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96Q40.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96Q40/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96Q40"}},"corpus_meta":[{"pmid":"25526364","id":"PMC_25526364","title":"Integrated analysis of whole genome and transcriptome sequencing reveals diverse transcriptomic aberrations driven by somatic genomic changes in liver cancers.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25526364","citation_count":70,"is_preprint":false},{"pmid":"30867819","id":"PMC_30867819","title":"Genome-wide profiling of Epstein-Barr virus integration by targeted sequencing in Epstein-Barr virus associated malignancies.","date":"2019","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/30867819","citation_count":61,"is_preprint":false},{"pmid":"34262144","id":"PMC_34262144","title":"CDK15 promotes colorectal cancer progression via phosphorylating PAK4 and regulating β-catenin/ MEK-ERK signaling pathway.","date":"2021","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/34262144","citation_count":50,"is_preprint":false},{"pmid":"24362465","id":"PMC_24362465","title":"Dinaciclib (SCH727965) inhibits the unfolded protein response through a CDK1- and 5-dependent mechanism.","date":"2013","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/24362465","citation_count":37,"is_preprint":false},{"pmid":"24866247","id":"PMC_24866247","title":"ALS2CR7 (CDK15) attenuates TRAIL induced apoptosis by inducing phosphorylation of survivin Thr34.","date":"2014","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/24866247","citation_count":31,"is_preprint":false},{"pmid":"35659970","id":"PMC_35659970","title":"Identification of exosomal hsa-miR-483-5p as a potential biomarker for hepatocellular carcinoma via microRNA expression profiling of tumor-derived exosomes.","date":"2022","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/35659970","citation_count":22,"is_preprint":false},{"pmid":"22351109","id":"PMC_22351109","title":"Stable mutated tau441 transfected SH-SY5Y cells as screening tool for Alzheimer's disease drug candidates.","date":"2012","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/22351109","citation_count":17,"is_preprint":false},{"pmid":"31824858","id":"PMC_31824858","title":"PA28α/β Promote Breast Cancer Cell Invasion and Metastasis via Down-Regulation of CDK15.","date":"2019","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31824858","citation_count":16,"is_preprint":false},{"pmid":"23589856","id":"PMC_23589856","title":"High NaCl- and urea-induced posttranslational modifications that increase glycerophosphocholine by inhibiting GDPD5 phosphodiesterase.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/23589856","citation_count":10,"is_preprint":false},{"pmid":"33157918","id":"PMC_33157918","title":"A rare double ALK fusion variant EML4-ALK and CDK15-ALK in lung adenocarcinoma and response to crizotinib: A case report.","date":"2020","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33157918","citation_count":8,"is_preprint":false},{"pmid":"38084427","id":"PMC_38084427","title":"Molecular mechanisms underlying TNFα-induced mitochondrial fragmentation in human airway smooth muscle cells.","date":"2023","source":"American journal of physiology. Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/38084427","citation_count":7,"is_preprint":false},{"pmid":"36852056","id":"PMC_36852056","title":"Rohitukine content across the geographical distribution of Dysoxylum binectariferum Hook F. and its natural derivatives as potential sources of CDK inhibitors.","date":"2023","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/36852056","citation_count":4,"is_preprint":false},{"pmid":"31175010","id":"PMC_31175010","title":"Synthesis and structure activity relationships of a series of 4-amino-1H-pyrazoles as covalent inhibitors of CDK14.","date":"2019","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/31175010","citation_count":2,"is_preprint":false},{"pmid":"41994380","id":"PMC_41994380","title":"Association of CDK15 and L1CAM Expression in Cervical Cancer Tissues with Clinicopathological Characteristics and Recurrence/Metastasis After Radical Hysterectomy.","date":"2026","source":"Pakistan journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41994380","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9030,"output_tokens":899,"usd":0.020287},"stage2":{"model":"claude-opus-4-6","input_tokens":4125,"output_tokens":1214,"usd":0.076463},"total_usd":0.09675,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"CDK15 (ALS2CR7) phosphorylates survivin at Thr34, and this phosphorylation promotes TRAIL resistance in cancer cells by increasing survivin expression and decreasing activation of caspases-3, -8, and -9 and PARP cleavage. CDK15 was shown to bind survivin directly (but not Bcl2, FLIP, XIAP, DR4, or DR5).\",\n      \"method\": \"Transfection/overexpression and siRNA knockdown of CDK15 in TRAIL-sensitive and -resistant cancer cell lines; co-immunoprecipitation/binding assay; viability and apoptosis assays; phospho-survivin immunoblotting\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — direct binding and phosphorylation demonstrated in cell-based assays with overexpression and knockdown; single lab, moderate orthogonality\",\n      \"pmids\": [\"24866247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CDK15 binds PAK4 and phosphorylates PAK4 at Ser291, which activates β-catenin/c-Myc and MEK/ERK signaling to promote colorectal cancer cell proliferation and anchorage-independent growth. Inhibition of PAK4 reversed the tumorigenic effects of CDK15.\",\n      \"method\": \"Co-immunoprecipitation, site-specific phosphorylation assays (S291 mutant), CDK15 knockdown/knockout in cell lines and mouse models (AOM/DSS, CDX, PDX xenografts), PAK4 inhibitor rescue experiments\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP plus phospho-site mutagenesis, validated in multiple in vivo models; moderate-to-strong evidence from a single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34262144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PA28α/β (immunoproteasome activator) promotes degradation/downregulation of CDK15 protein, and loss of CDK15 is required for PA28α/β-mediated breast cancer cell invasion and metastasis.\",\n      \"method\": \"Knockdown of PA28α/β and β5i subunit with siRNA; immunoblotting for CDK15 protein levels; invasion/migration assays; CDK15 silencing to phenocopy the invasive effect\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, protein-level regulation shown by knockdown with functional readout; mechanism of CDK15 downregulation not fully resolved at molecular level\",\n      \"pmids\": [\"31824858\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDK15 is a cyclin-dependent kinase that directly binds and phosphorylates PAK4 at Ser291 to activate β-catenin/c-Myc and MEK/ERK signaling, and also binds and phosphorylates survivin at Thr34 to suppress TRAIL-induced apoptosis; its protein levels are negatively regulated by the PA28α/β immunoproteasome complex.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CDK15 is a cyclin-dependent kinase that phosphorylates specific substrates to promote cell survival and proliferation. It directly binds and phosphorylates survivin at Thr34, stabilizing survivin expression and suppressing TRAIL-induced apoptosis by reducing activation of caspases-3, -8, and -9 and PARP cleavage [PMID:24866247]. CDK15 also binds and phosphorylates PAK4 at Ser291, thereby activating β-catenin/c-Myc and MEK/ERK signaling to drive colorectal cancer cell proliferation and anchorage-independent growth [PMID:34262144]. CDK15 protein levels are negatively regulated by the PA28α/β immunoproteasome activator complex, and loss of CDK15 is required for PA28α/β-mediated breast cancer cell invasion and metastasis [PMID:31824858].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying CDK15 as a kinase for survivin established its first known substrate and linked it to apoptosis resistance, answering the question of how TRAIL-resistant cancer cells stabilize survivin.\",\n      \"evidence\": \"Overexpression and siRNA knockdown of CDK15 in TRAIL-sensitive and -resistant cancer cell lines with co-immunoprecipitation, phospho-survivin immunoblotting, and apoptosis assays\",\n      \"pmids\": [\"24866247\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Binding and phosphorylation demonstrated only in overexpression systems without in vitro kinase assay using purified components\",\n        \"No cyclin partner identified for CDK15 in this context\",\n        \"Phosphorylation stoichiometry and kinetics not determined\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showing that PA28α/β promotes CDK15 protein degradation revealed a proteostatic control mechanism for CDK15 and connected immunoproteasome activity to CDK15-dependent suppression of invasion.\",\n      \"evidence\": \"siRNA knockdown of PA28α/β and β5i subunit with immunoblotting for CDK15 and functional invasion/migration assays in breast cancer cells\",\n      \"pmids\": [\"31824858\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular mechanism of CDK15 degradation (direct ubiquitination, proteasomal targeting) not resolved\",\n        \"Whether CDK15 is a direct substrate of the immunoproteasome or is regulated indirectly remains unclear\",\n        \"Findings from a single cell system without in vivo validation\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying PAK4 Ser291 as a second CDK15 substrate and linking it to β-catenin/c-Myc and MEK/ERK signaling broadened CDK15's role from anti-apoptotic kinase to a driver of proliferative oncogenic signaling.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, phospho-site mutagenesis (S291A), CDK15 knockout in AOM/DSS, CDX, and PDX mouse models, and PAK4 inhibitor rescue experiments in colorectal cancer cells\",\n      \"pmids\": [\"34262144\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No activating cyclin partner for CDK15 has been identified\",\n        \"Whether CDK15 phosphorylation of PAK4 is direct (in vitro kinase assay with purified proteins) was not explicitly shown\",\n        \"Structural basis for CDK15 substrate selectivity is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The activating cyclin partner of CDK15, its full substrate repertoire, and the structural basis of its substrate specificity remain uncharacterized.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No cyclin partner identified for CDK15\",\n        \"No crystal structure or cryo-EM structure available\",\n        \"Physiological roles outside oncogenic contexts are unexplored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"BIRC5\", \"PAK4\"],\n    \"other_free_text\": []\n  }\n}\n```"}