{"gene":"CDK10","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1994,"finding":"PISSLRE (CDK10) encodes a CDC2-related serine/threonine protein kinase with a PSTAIRE-like motif (PISSLRE), containing all structural elements of cyclin-dependent kinases including regulatory Tyr and Thr residues, with a predicted molecular weight of ~35.8 kDa.","method":"PCR-based cDNA cloning and amino acid sequence analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — independently cloned by two groups using PCR-based strategies, sequence analysis only, no enzymatic activity demonstrated","pmids":["8208557","8084611"],"is_preprint":false},{"year":1995,"finding":"CDK10 (PISSLRE) is essential for cell growth and acts in G2/M phase; dominant-negative and antisense constructs of PISSLRE overexpressed in U2OS cells suppress growth and halt cell cycle progression at G2-M.","method":"Antisense and dominant-negative mutant overexpression in U2OS cells with cell cycle analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype, two orthogonal constructs (antisense + dominant-negative), single lab","pmids":["7664269"],"is_preprint":false},{"year":2000,"finding":"CDK10 exists as multiple isoforms with different translation initiation sites and different subcellular distributions due to an alternatively spliced nuclear localization signal; isoform levels do not vary during the cell cycle except when cells enter the cell cycle.","method":"RT-PCR isoform analysis, subcellular fractionation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct subcellular localization experiment and RT-PCR, single lab","pmids":["11006117"],"is_preprint":false},{"year":2001,"finding":"CDK10 interacts with the N-terminus (Pointed domain and transactivation domain) of the ETS2 transcription factor both in vitro and in vivo, requiring an intact Pointed domain in ETS2, and inhibits ETS2 transactivation activity in mammalian cells; CDK10 does not bind ETS1 in the same assay.","method":"Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation in mammalian cells, transactivation reporter assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding confirmed in vitro and in vivo with multiple orthogonal methods, functional consequence (inhibition of transactivation) demonstrated","pmids":["11313931"],"is_preprint":false},{"year":2006,"finding":"Murine CDK10 binds ETS2 transcription factor in vitro but does not show direct involvement in G2/M transition in the mouse system and does not affect proliferation rate of analyzed cell lines.","method":"In vitro binding assay, cell proliferation analysis","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — in vitro binding confirmed, negative result for G2/M role in murine context; single lab","pmids":["16741970"],"is_preprint":false},{"year":2008,"finding":"CDK10 silencing increases ETS2-driven transcription of c-RAF, resulting in MAPK pathway activation and loss of tumor cell reliance on estrogen signaling, thereby conferring resistance to tamoxifen in breast cancer cells.","method":"RNAi screen, gene silencing, reporter assays, MAPK pathway analysis","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi screen plus mechanistic follow-up with pathway analysis, replicated concept in multiple subsequent studies","pmids":["18242510"],"is_preprint":false},{"year":2013,"finding":"CDK10 is activated by Cyclin M (product of FAM58A) as its cognate cyclin; the CDK10/Cyclin M complex phosphorylates ETS2 in vitro, and in cells it promotes ETS2 degradation by the proteasome; STAR syndrome-associated Cyclin M mutants cannot interact with CDK10; Cyclin M silencing phenocopies CDK10 silencing in increasing c-Raf and conferring tamoxifen resistance.","method":"Co-immunoprecipitation, in vitro kinase assay with recombinant proteins, proteasome inhibitor experiments, genetic complementation, cell-based ETS2 protein level measurement in STAR patient cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay combined with cell-based mechanistic studies, patient-derived cells, and multiple orthogonal methods in a single rigorous study","pmids":["24218572"],"is_preprint":false},{"year":2016,"finding":"CDK10/Cyclin M phosphorylates PKN2 on threonines 121 and 124 within PKN2's RhoA-binding domain; this phosphorylation stabilizes RhoA protein and the actin network architecture, thereby suppressing primary cilia assembly and elongation; CDK10/CycM deficiency promotes ciliogenesis; ectopic RhoA expression overrides CDK10/CycM knockdown-induced ciliogenesis.","method":"Unbiased kinase substrate screen, in vitro kinase assay with phosphosite mapping, co-immunoprecipitation, RhoA rescue experiments, cilia length/number measurements, patient kidney tissue analysis","journal":"Cell cycle (Georgetown, Tex.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with phosphosite identification, multiple orthogonal cellular assays, genetic rescue, and patient tissue validation","pmids":["27104747"],"is_preprint":false},{"year":2017,"finding":"CDK10 loss-of-function (knockout) in mice causes postnatal death with severe growth retardation, skeletal defects, and kidney/lung abnormalities; Cdk10-knockout MEFs develop longer cilia, consistent with CDK10 regulating ciliogenesis; CDK10 transduces signals from primary cilia to sustain embryonic and postnatal development.","method":"Conditional knockout mouse generation, MEF cilia length measurements, transcriptomic analysis","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout model with defined phenotypic readout, MEF-based cellular mechanistic analysis, transcriptomic data, independent validation of ciliogenesis role","pmids":["28886341"],"is_preprint":false},{"year":2017,"finding":"Inactivation of CDK10 kinase domain suppresses apoptosis and promotes tumor growth; kinase-defective CDK10 mutant colorectal cancer cells show exaggerated apoptotic response and reduced proliferative capacity; CDK10 upregulates Bcl-2 expression in a kinase-activity-dependent manner.","method":"Kinase-defective mutant expression, apoptosis assays, in vivo xenograft model with siRNA","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase-defective mutant with defined phenotype, in vivo validation, single lab","pmids":["28663269"],"is_preprint":false},{"year":2020,"finding":"An optimized peptide substrate for CDK10/CycM was identified; known CDK inhibitors including SNS-032, riviciclib, flavopiridol, dinaciclib, AZD4573, AT7519, and NVP-2 potently inhibit CDK10/CycM in vitro kinase assay.","method":"In vitro kinase assay with peptide substrate optimization, inhibitor profiling","journal":"Frontiers in chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with inhibitor panel, single lab, no mutagenesis or structural validation","pmids":["32175313"],"is_preprint":false},{"year":2021,"finding":"Recombinant CDK10/CycQ (Cyclin Q, same as CycM) complex phosphorylates RNA pol II CTD, c-MYC, and RB1 in vitro; an analogue-sensitive CDK10 mutant identifies 89 phosphosites on 66 proteins in HEK cells including targets in cell cycle, translation, stress response, growth signalling, and transcriptional regulation; CDK10 is itself phosphorylated in vitro by CDK1 and CDK5 at multiple sites.","method":"Recombinant protein in vitro kinase assay, analogue-sensitive kinase approach with mass spectrometry phosphoproteomics","journal":"Open biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro kinase assays combined with analogue-sensitive kinase chemical genetics and mass spectrometry, multiple substrates identified by orthogonal methods","pmids":["35291876"],"is_preprint":false},{"year":2021,"finding":"CDK10 truncated variants associated with Al Kaissi syndrome retain ability to form CDK10/CycM heterodimer; the CycM truncated variant partially activates CDK10 in vitro, while the CDK10 truncated variant remains inactive; both variants are degraded by the proteasome when expressed in human cells.","method":"Recombinant protein expression in insect cells, in vitro kinase assay, yeast two-hybrid, proteasome inhibitor treatment in human cells","journal":"Molecular genetics & genomic medicine","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with recombinant proteins, multiple orthogonal methods, single lab","pmids":["34369103"],"is_preprint":false},{"year":2023,"finding":"CDK10 binds ETS2 and promotes its degradation, thereby inactivating the downstream c-Raf/p-MEK/p-ERK pathway that drives EMT and MMP2/9 expression; the p-MEK/p-ERK pathway also conducts positive feedback regulation on ETS2 expression; CDK10 knockdown promotes metastatic foci formation in a xenograft mouse model.","method":"Co-immunoprecipitation, protein degradation assays, MAPK pathway analysis, xenograft mouse model","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP binding plus in vivo xenograft validation, single lab","pmids":["37737453"],"is_preprint":false},{"year":2024,"finding":"RNF115, an E3 ubiquitin ligase, ubiquitinates and degrades CDK10 in thyroid carcinoma cells, thereby activating the Raf-1 pathway and enhancing cancer cell cycle progression.","method":"Ubiquitination assay, co-immunoprecipitation, overexpression/knockdown experiments, in vivo tumor model","journal":"Cell biology and toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay plus functional rescue experiments, single lab","pmids":["38376606"],"is_preprint":false},{"year":2024,"finding":"CDK10 silencing activates the JNK/c-Jun signaling pathway in lung cancer cells, promoting proliferation, migration, and radioresistance; c-Jun depletion reverses the effects of CDK10 knockdown, placing CDK10 upstream of JNK/c-Jun in this context.","method":"CDK10 siRNA knockdown, pathway inhibition (c-Jun depletion), cell proliferation and radioresistance assays","journal":"BMB reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis by double knockdown with defined phenotypic readout, single lab","pmids":["38919013"],"is_preprint":false},{"year":2026,"finding":"CDK10 can partially compensate for the transcriptional function of CDK11 in RNA Polymerase II elongation regulation in metazoans.","method":"Functional genetic complementation experiments (context from CDK11 inhibition studies)","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, CDK10 finding is secondary to CDK11 focus, single mention without detailed CDK10-specific mechanistic data","pmids":["bio_10.1101_2025.09.27.678947"],"is_preprint":true},{"year":2026,"finding":"CDK10 phosphorylates DNMT1 and RAP80, reducing accumulation of double-stranded RNA and R-loops, thereby suppressing activation of innate immune pathways mediated by MDA5 and cGAS in tumor cells; genetic and pharmacological CDK10 inhibition activates MDA5 and cGAS pathways and fosters an immunoactive tumor microenvironment.","method":"In vivo kinome CRISPR screen, phosphorylation assays, kinase inhibitor screens (NVP-AST487, ponatinib identified as CDK10 inhibitors), mouse tumor models","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo CRISPR screen combined with mechanistic phosphorylation studies, pharmacological validation with identified inhibitors, multiple mouse tumor models","pmids":["41507536"],"is_preprint":false}],"current_model":"CDK10 is a cyclin-dependent serine/threonine kinase activated by Cyclin M (FAM58A product) that phosphorylates substrates including ETS2 (promoting its proteasomal degradation to suppress c-Raf/MAPK signaling), PKN2 (on T121/T124 to stabilize RhoA and the actin network, suppressing ciliogenesis), DNMT1 and RAP80 (suppressing dsRNA/R-loop accumulation and innate immune activation via MDA5/cGAS), as well as RNA pol II CTD, c-MYC, and RB1 in vitro; it is itself degraded via ubiquitination by E3 ligase RNF115, and CDK10/CycM deficiency—whether from loss-of-function mutations causing Al Kaissi or STAR syndromes, or from tumor-associated silencing—leads to MAPK pathway hyperactivation, cilia elongation, and altered immune surveillance."},"narrative":{"mechanistic_narrative":"CDK10 is a CDC2-related serine/threonine cyclin-dependent kinase that becomes catalytically active upon binding its cognate cyclin, Cyclin M (the FAM58A/Cyclin Q product), and through this complex restrains growth, MAPK, ciliogenesis, and immune-surveillance programs [PMID:8208557, PMID:8084611, PMID:24218572]. Its best-defined output is suppression of MAPK signaling: CDK10/CycM binds and phosphorylates the transcription factor ETS2, driving its proteasomal degradation, and loss of CDK10 derepresses ETS2-driven c-Raf transcription to activate the MEK/ERK cascade, conferring tamoxifen resistance and promoting EMT and metastasis in cancer cells [PMID:11313931, PMID:18242510, PMID:24218572, PMID:37737453]. Independently, CDK10/CycM phosphorylates PKN2 on threonines 121 and 124 within its RhoA-binding domain, stabilizing RhoA and the actin cytoskeleton to suppress primary cilium assembly; CDK10 deficiency in cells, knockout mice, and patient tissue produces elongated cilia and developmental defects [PMID:27104747, PMID:28886341]. The kinase also phosphorylates DNMT1 and RAP80 to limit dsRNA and R-loop accumulation, thereby dampening MDA5/cGAS innate-immune activation in tumors [PMID:41507536]. Reconstituted and analogue-sensitive kinase studies extend its substrate repertoire to RNA pol II CTD, c-MYC, RB1, and dozens of phosphosites across cell-cycle, translation, and signaling proteins [PMID:35291876]. CDK10 protein abundance is controlled by RNF115-mediated ubiquitination and degradation, which relieves its restraint on the Raf-1 pathway [PMID:38376606]. Loss-of-function mutations in CDK10 or Cyclin M cause STAR and Al Kaissi syndromes, with disease-associated variants failing to assemble or activate the kinase complex [PMID:24218572, PMID:34369103].","teleology":[{"year":1994,"claim":"Establishing whether PISSLRE/CDK10 was a bona fide kinase defined it as a CDC2-related enzyme rather than an uncharacterized ORF, anchoring all later mechanistic work.","evidence":"PCR-based cDNA cloning and sequence analysis identifying CDK structural elements and a PISSLRE PSTAIRE-like motif","pmids":["8208557","8084611"],"confidence":"Medium","gaps":["No enzymatic activity demonstrated","Cognate cyclin and substrates unknown at this stage"]},{"year":1995,"claim":"Loss-of-function in human cells first tied CDK10 to cell growth control, placing it at the G2/M transition.","evidence":"Antisense and dominant-negative overexpression in U2OS cells with cell cycle analysis","pmids":["7664269"],"confidence":"Medium","gaps":["No molecular substrate identified","G2/M role not confirmed in other systems (later contradicted in murine cells)"]},{"year":2001,"claim":"Identification of ETS2 as a CDK10 interactor gave the kinase its first physiologically relevant binding partner and a transcriptional readout.","evidence":"Yeast two-hybrid, in vitro binding, co-IP, and transactivation reporter assays in mammalian cells","pmids":["11313931"],"confidence":"High","gaps":["Did not show ETS2 is a direct phosphosubstrate","Cyclin partner still unknown"]},{"year":2008,"claim":"Linking CDK10 silencing to ETS2-driven c-RAF transcription connected the kinase to MAPK pathway activation and clinical tamoxifen resistance.","evidence":"RNAi screen, gene silencing, reporter assays, and MAPK pathway analysis in breast cancer cells","pmids":["18242510"],"confidence":"High","gaps":["Mechanism of ETS2 regulation (phosphorylation vs. binding) not resolved","Activating cyclin not yet identified"]},{"year":2013,"claim":"Discovery of Cyclin M as the activating partner converted CDK10 into a defined active kinase complex and explained ETS2 control via phosphorylation-driven proteasomal degradation, linking the axis to STAR syndrome.","evidence":"Co-IP, in vitro kinase assays with recombinant proteins, proteasome inhibition, genetic complementation, and STAR patient cell analysis","pmids":["24218572"],"confidence":"High","gaps":["Did not map ETS2 phosphosites","Full substrate range beyond ETS2 unknown"]},{"year":2016,"claim":"Identifying PKN2 as a phosphosubstrate revealed a distinct CDK10 function in cytoskeletal/RhoA control that suppresses ciliogenesis, separate from MAPK.","evidence":"Unbiased substrate screen, in vitro kinase assay with phosphosite mapping (T121/T124), RhoA rescue, cilia measurements, and patient kidney tissue","pmids":["27104747"],"confidence":"High","gaps":["In vivo significance of RhoA stabilization not tested at organismal level here","Link between cilia and developmental phenotypes not yet established"]},{"year":2017,"claim":"A CDK10 knockout mouse established the kinase as essential for development and confirmed cilia elongation in vivo, tying molecular function to organismal phenotype.","evidence":"Conditional knockout mouse, MEF cilia length measurements, and transcriptomic analysis","pmids":["28886341"],"confidence":"High","gaps":["Direct substrate driving developmental defects not pinpointed","Tissue-specific contributions not separated"]},{"year":2017,"claim":"Kinase-activity-dependent regulation of apoptosis and Bcl-2 indicated a context-specific pro-survival role in colorectal cancer cells.","evidence":"Kinase-defective mutant expression, apoptosis assays, and xenograft with siRNA","pmids":["28663269"],"confidence":"Medium","gaps":["Direct substrate connecting CDK10 to Bcl-2 not identified","Apparent pro-tumor role contrasts with tumor-suppressive MAPK findings"]},{"year":2020,"claim":"An optimized peptide substrate and inhibitor panel provided tractable in vitro tools for the CDK10/CycM complex.","evidence":"In vitro kinase assay with peptide optimization and profiling of clinical CDK inhibitors","pmids":["32175313"],"confidence":"Medium","gaps":["No CDK10-selective inhibitor identified","No structural or cellular validation of inhibitor specificity"]},{"year":2021,"claim":"Reconstituted and analogue-sensitive kinase approaches broadened the substrate landscape (RNA pol II CTD, c-MYC, RB1, 66 proteins) and showed CDK10 is itself phosphorylated by CDK1/CDK5.","evidence":"Recombinant in vitro kinase assays plus analogue-sensitive chemical genetics with mass spectrometry phosphoproteomics","pmids":["35291876"],"confidence":"High","gaps":["Cellular significance of most identified phosphosites untested","Functional consequence of CDK1/CDK5 phosphorylation of CDK10 unknown"]},{"year":2021,"claim":"Biochemical analysis of Al Kaissi syndrome variants explained disease mechanism as failed complex activation and accelerated proteasomal degradation.","evidence":"Recombinant expression in insect cells, in vitro kinase assays, yeast two-hybrid, and proteasome inhibition in human cells","pmids":["34369103"],"confidence":"Medium","gaps":["Patient-tissue confirmation limited","Quantitative residual activity of variants in vivo unclear"]},{"year":2023,"claim":"Extending the ETS2/MAPK axis to EMT, MMP2/9, and metastasis defined CDK10 as a metastasis suppressor with positive feedback on ETS2.","evidence":"Co-IP, protein degradation assays, MAPK pathway analysis, and xenograft metastasis model","pmids":["37737453"],"confidence":"Medium","gaps":["ETS2 phosphosite not mapped in this context","Single lab"]},{"year":2024,"claim":"Identifying RNF115 as the E3 ligase degrading CDK10 defined an upstream control point that releases Raf-1 signaling in cancer.","evidence":"Ubiquitination assay, co-IP, knockdown/overexpression, and in vivo tumor model in thyroid carcinoma","pmids":["38376606"],"confidence":"Medium","gaps":["Ubiquitination site on CDK10 not mapped","Signals controlling RNF115 activity unknown"]},{"year":2024,"claim":"Placing CDK10 upstream of JNK/c-Jun in lung cancer extended its growth-suppressive signaling reach beyond ERK.","evidence":"siRNA knockdown with c-Jun epistasis and proliferation/radioresistance assays","pmids":["38919013"],"confidence":"Medium","gaps":["Direct substrate linking CDK10 to JNK/c-Jun not identified","Single context"]},{"year":2026,"claim":"Defining DNMT1 and RAP80 as substrates connected CDK10 to nucleic-acid stress control and innate immune surveillance, opening an immunotherapy-relevant axis.","evidence":"In vivo kinome CRISPR screen, phosphorylation assays, inhibitor identification, and mouse tumor models","pmids":["41507536"],"confidence":"High","gaps":["Phosphosites on DNMT1/RAP80 not detailed","Relative contribution of dsRNA vs. R-loop suppression unresolved"]},{"year":null,"claim":"How CDK10's many described axes (ETS2/MAPK, PKN2/cilia, DNMT1-RAP80/immunity, and CDK11-like pol II elongation) are coordinated, prioritized, and integrated within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying model linking substrate selection to physiological context","Apparent pro- vs. anti-tumor roles not reconciled","No CDK10-selective inhibitor or structural model of substrate recognition"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[6,7,11,17]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[6,7,11]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,13,15]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[17]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,8]}],"complexes":["CDK10/Cyclin M (CDK10/CycM, CDK10/CycQ)"],"partners":["CCNQ","ETS2","PKN2","DNMT1","RAP80","RNF115"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15131","full_name":"Cyclin-dependent kinase 10","aliases":["Cell division protein kinase 10","Serine/threonine-protein kinase PISSLRE"],"length_aa":360,"mass_kda":41.0,"function":"Cyclin-dependent kinase that phosphorylates the transcription factor ETS2 (in vitro) and positively controls its proteasomal degradation (in cells) (PubMed:24218572). Involved in the regulation of actin cytoskeleton organization through the phosphorylation of actin dynamics regulators such as PKN2. Is a negative regulator of ciliogenesis through phosphorylation of PKN2 and promotion of RhoA signaling (PubMed:27104747)","subcellular_location":"Cytoplasm, cytoskeleton, cilium basal body","url":"https://www.uniprot.org/uniprotkb/Q15131/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CDK10","classification":"Not Classified","n_dependent_lines":42,"n_total_lines":1208,"dependency_fraction":0.0347682119205298},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CDK10","total_profiled":1310},"omim":[{"mim_id":"620030","title":"ARGININE- AND SERINE-RICH PROTEIN 1; RSRP1","url":"https://www.omim.org/entry/620030"},{"mim_id":"617694","title":"AL KAISSI SYNDROME; ALKAS","url":"https://www.omim.org/entry/617694"},{"mim_id":"607139","title":"FANCA GENE; FANCA","url":"https://www.omim.org/entry/607139"},{"mim_id":"603464","title":"CYCLIN-DEPENDENT KINASE 10; CDK10","url":"https://www.omim.org/entry/603464"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CDK10"},"hgnc":{"alias_symbol":["PISSLRE"],"prev_symbol":[]},"alphafold":{"accession":"Q15131","domains":[{"cath_id":"3.30.200.20","chopping":"29-117","consensus_level":"high","plddt":86.0057,"start":29,"end":117},{"cath_id":"1.10.510.10","chopping":"121-333","consensus_level":"high","plddt":91.7722,"start":121,"end":333}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15131","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15131-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15131-F1-predicted_aligned_error_v6.png","plddt_mean":85.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CDK10","jax_strain_url":"https://www.jax.org/strain/search?query=CDK10"},"sequence":{"accession":"Q15131","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15131.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15131/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15131"}},"corpus_meta":[{"pmid":"18242510","id":"PMC_18242510","title":"Identification of CDK10 as an important determinant of resistance to endocrine therapy for breast cancer.","date":"2008","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/18242510","citation_count":178,"is_preprint":false},{"pmid":"7882308","id":"PMC_7882308","title":"Chromosomal mapping of members of the cdc2 family of protein kinases, cdk3, cdk6, PISSLRE, and PITALRE, and a cdk inhibitor, p27Kip1, to regions involved in human cancer.","date":"1995","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/7882308","citation_count":125,"is_preprint":false},{"pmid":"11313931","id":"PMC_11313931","title":"Cdk10, a Cdc2-related kinase, associates with the Ets2 transcription factor and modulates its transactivation activity.","date":"2001","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/11313931","citation_count":93,"is_preprint":false},{"pmid":"24218572","id":"PMC_24218572","title":"CDK10/cyclin M is a protein kinase that controls ETS2 degradation and is deficient in STAR syndrome.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24218572","citation_count":69,"is_preprint":false},{"pmid":"7664269","id":"PMC_7664269","title":"The cdc-2-related kinase, PISSLRE, is essential for cell growth and acts in G2 phase of the cell cycle.","date":"1995","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/7664269","citation_count":56,"is_preprint":false},{"pmid":"8208557","id":"PMC_8208557","title":"PISSLRE, a human novel CDC2-related protein kinase.","date":"1994","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/8208557","citation_count":55,"is_preprint":false},{"pmid":"8084611","id":"PMC_8084611","title":"Molecular cloning of PISSLRE, a novel putative member of the cdk family of protein serine/threonine kinases.","date":"1994","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/8084611","citation_count":44,"is_preprint":false},{"pmid":"22209942","id":"PMC_22209942","title":"CDK10 functions as a tumor suppressor gene and regulates survivability of biliary tract cancer cells.","date":"2011","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/22209942","citation_count":38,"is_preprint":false},{"pmid":"10036189","id":"PMC_10036189","title":"The PISSLRE gene: structure, exon skipping, and exclusion as tumor suppressor in breast cancer.","date":"1999","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/10036189","citation_count":37,"is_preprint":false},{"pmid":"27104747","id":"PMC_27104747","title":"STAR syndrome-associated CDK10/Cyclin M regulates actin network architecture and ciliogenesis.","date":"2016","source":"Cell cycle (Georgetown, 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corpus callosum, retinopathy, and deafness.","date":"2017","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/29130579","citation_count":22,"is_preprint":false},{"pmid":"23740091","id":"PMC_23740091","title":"Promoter hypermethylation contributes to the frequent suppression of the CDK10 gene in human nasopharyngeal carcinomas.","date":"2013","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/23740091","citation_count":22,"is_preprint":false},{"pmid":"11006117","id":"PMC_11006117","title":"Human CDK10 gene isoforms.","date":"2000","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11006117","citation_count":18,"is_preprint":false},{"pmid":"16741970","id":"PMC_16741970","title":"Identification of murine cdk10: association with Ets2 transcription factor and effects on the cell cycle.","date":"2006","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16741970","citation_count":18,"is_preprint":false},{"pmid":"28663269","id":"PMC_28663269","title":"Inactivation of the Kinase Domain of CDK10 Prevents Tumor Growth in a Preclinical Model of Colorectal Cancer, and Is Accompanied by Downregulation of Bcl-2.","date":"2017","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/28663269","citation_count":18,"is_preprint":false},{"pmid":"34277407","id":"PMC_34277407","title":"CDK10 in Gastrointestinal Cancers: Dual Roles as a Tumor Suppressor and Oncogene.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34277407","citation_count":17,"is_preprint":false},{"pmid":"32175313","id":"PMC_32175313","title":"Development of a CDK10/CycM in vitro Kinase Screening Assay and Identification of First Small-Molecule Inhibitors.","date":"2020","source":"Frontiers in chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32175313","citation_count":17,"is_preprint":false},{"pmid":"35291876","id":"PMC_35291876","title":"Functional characterization of the human Cdk10/Cyclin Q complex.","date":"2022","source":"Open biology","url":"https://pubmed.ncbi.nlm.nih.gov/35291876","citation_count":16,"is_preprint":false},{"pmid":"26209438","id":"PMC_26209438","title":"Elevated C1orf63 expression is correlated with CDK10 and predicts better outcome for advanced breast cancers: a retrospective study.","date":"2015","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/26209438","citation_count":15,"is_preprint":false},{"pmid":"19846932","id":"PMC_19846932","title":"CDK10 is not a target for aberrant DNA methylation in breast cancer.","date":"2009","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/19846932","citation_count":12,"is_preprint":false},{"pmid":"38376606","id":"PMC_38376606","title":"RNF115 aggravates tumor progression through regulation of CDK10 degradation in thyroid carcinoma.","date":"2024","source":"Cell biology and toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/38376606","citation_count":9,"is_preprint":false},{"pmid":"33679896","id":"PMC_33679896","title":"Integrative Analysis of Omics Data Reveals Regulatory Network of CDK10 in Vitiligo Risk.","date":"2021","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33679896","citation_count":9,"is_preprint":false},{"pmid":"37737453","id":"PMC_37737453","title":"CDK10 suppresses metastasis of lung adenocarcinoma through inhibition of the ETS2/c-Raf/p-MEK/p-ERK signaling loop.","date":"2023","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/37737453","citation_count":8,"is_preprint":false},{"pmid":"34369103","id":"PMC_34369103","title":"Functional characterization of CDK10 and cyclin M truncated variants causing severe developmental disorders.","date":"2021","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34369103","citation_count":5,"is_preprint":false},{"pmid":"38919013","id":"PMC_38919013","title":"Downregulated CDK10 promotes cancer progression and radioresistance in lung cancer through activating the JNK/c-Jun signaling pathway.","date":"2024","source":"BMB reports","url":"https://pubmed.ncbi.nlm.nih.gov/38919013","citation_count":4,"is_preprint":false},{"pmid":"22298115","id":"PMC_22298115","title":"Effects of the cyclin-dependent kinase 10 (CDK10) on the tamoxifen sensitivity of keloid samples.","date":"2012","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/22298115","citation_count":2,"is_preprint":false},{"pmid":"41507536","id":"PMC_41507536","title":"CDK10 suppresses nucleic acid sensors-mediated antitumor immunity.","date":"2026","source":"Nature cancer","url":"https://pubmed.ncbi.nlm.nih.gov/41507536","citation_count":1,"is_preprint":false},{"pmid":"40960173","id":"PMC_40960173","title":"Two Siblings With Al Kaissi Syndrome: Clinical, Radiological, and Molecular Characterization of Compound Heterozygous CDK10 Variants.","date":"2025","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/40960173","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.27.678947","title":"CDK11 activates CDK12 to trigger the elongation of RNA Polymerase II","date":"2025-09-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.27.678947","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16167,"output_tokens":4155,"usd":0.055413,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12143,"output_tokens":4443,"usd":0.085895,"stage2_stop_reason":"end_turn"},"total_usd":0.141308,"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\": 1994,\n      \"finding\": \"PISSLRE (CDK10) encodes a CDC2-related serine/threonine protein kinase with a PSTAIRE-like motif (PISSLRE), containing all structural elements of cyclin-dependent kinases including regulatory Tyr and Thr residues, with a predicted molecular weight of ~35.8 kDa.\",\n      \"method\": \"PCR-based cDNA cloning and amino acid sequence analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — independently cloned by two groups using PCR-based strategies, sequence analysis only, no enzymatic activity demonstrated\",\n      \"pmids\": [\"8208557\", \"8084611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"CDK10 (PISSLRE) is essential for cell growth and acts in G2/M phase; dominant-negative and antisense constructs of PISSLRE overexpressed in U2OS cells suppress growth and halt cell cycle progression at G2-M.\",\n      \"method\": \"Antisense and dominant-negative mutant overexpression in U2OS cells with cell cycle analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype, two orthogonal constructs (antisense + dominant-negative), single lab\",\n      \"pmids\": [\"7664269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CDK10 exists as multiple isoforms with different translation initiation sites and different subcellular distributions due to an alternatively spliced nuclear localization signal; isoform levels do not vary during the cell cycle except when cells enter the cell cycle.\",\n      \"method\": \"RT-PCR isoform analysis, subcellular fractionation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct subcellular localization experiment and RT-PCR, single lab\",\n      \"pmids\": [\"11006117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CDK10 interacts with the N-terminus (Pointed domain and transactivation domain) of the ETS2 transcription factor both in vitro and in vivo, requiring an intact Pointed domain in ETS2, and inhibits ETS2 transactivation activity in mammalian cells; CDK10 does not bind ETS1 in the same assay.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation in mammalian cells, transactivation reporter assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding confirmed in vitro and in vivo with multiple orthogonal methods, functional consequence (inhibition of transactivation) demonstrated\",\n      \"pmids\": [\"11313931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Murine CDK10 binds ETS2 transcription factor in vitro but does not show direct involvement in G2/M transition in the mouse system and does not affect proliferation rate of analyzed cell lines.\",\n      \"method\": \"In vitro binding assay, cell proliferation analysis\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — in vitro binding confirmed, negative result for G2/M role in murine context; single lab\",\n      \"pmids\": [\"16741970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CDK10 silencing increases ETS2-driven transcription of c-RAF, resulting in MAPK pathway activation and loss of tumor cell reliance on estrogen signaling, thereby conferring resistance to tamoxifen in breast cancer cells.\",\n      \"method\": \"RNAi screen, gene silencing, reporter assays, MAPK pathway analysis\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi screen plus mechanistic follow-up with pathway analysis, replicated concept in multiple subsequent studies\",\n      \"pmids\": [\"18242510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CDK10 is activated by Cyclin M (product of FAM58A) as its cognate cyclin; the CDK10/Cyclin M complex phosphorylates ETS2 in vitro, and in cells it promotes ETS2 degradation by the proteasome; STAR syndrome-associated Cyclin M mutants cannot interact with CDK10; Cyclin M silencing phenocopies CDK10 silencing in increasing c-Raf and conferring tamoxifen resistance.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay with recombinant proteins, proteasome inhibitor experiments, genetic complementation, cell-based ETS2 protein level measurement in STAR patient cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay combined with cell-based mechanistic studies, patient-derived cells, and multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"24218572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CDK10/Cyclin M phosphorylates PKN2 on threonines 121 and 124 within PKN2's RhoA-binding domain; this phosphorylation stabilizes RhoA protein and the actin network architecture, thereby suppressing primary cilia assembly and elongation; CDK10/CycM deficiency promotes ciliogenesis; ectopic RhoA expression overrides CDK10/CycM knockdown-induced ciliogenesis.\",\n      \"method\": \"Unbiased kinase substrate screen, in vitro kinase assay with phosphosite mapping, co-immunoprecipitation, RhoA rescue experiments, cilia length/number measurements, patient kidney tissue analysis\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with phosphosite identification, multiple orthogonal cellular assays, genetic rescue, and patient tissue validation\",\n      \"pmids\": [\"27104747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CDK10 loss-of-function (knockout) in mice causes postnatal death with severe growth retardation, skeletal defects, and kidney/lung abnormalities; Cdk10-knockout MEFs develop longer cilia, consistent with CDK10 regulating ciliogenesis; CDK10 transduces signals from primary cilia to sustain embryonic and postnatal development.\",\n      \"method\": \"Conditional knockout mouse generation, MEF cilia length measurements, transcriptomic analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout model with defined phenotypic readout, MEF-based cellular mechanistic analysis, transcriptomic data, independent validation of ciliogenesis role\",\n      \"pmids\": [\"28886341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Inactivation of CDK10 kinase domain suppresses apoptosis and promotes tumor growth; kinase-defective CDK10 mutant colorectal cancer cells show exaggerated apoptotic response and reduced proliferative capacity; CDK10 upregulates Bcl-2 expression in a kinase-activity-dependent manner.\",\n      \"method\": \"Kinase-defective mutant expression, apoptosis assays, in vivo xenograft model with siRNA\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase-defective mutant with defined phenotype, in vivo validation, single lab\",\n      \"pmids\": [\"28663269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"An optimized peptide substrate for CDK10/CycM was identified; known CDK inhibitors including SNS-032, riviciclib, flavopiridol, dinaciclib, AZD4573, AT7519, and NVP-2 potently inhibit CDK10/CycM in vitro kinase assay.\",\n      \"method\": \"In vitro kinase assay with peptide substrate optimization, inhibitor profiling\",\n      \"journal\": \"Frontiers in chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with inhibitor panel, single lab, no mutagenesis or structural validation\",\n      \"pmids\": [\"32175313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Recombinant CDK10/CycQ (Cyclin Q, same as CycM) complex phosphorylates RNA pol II CTD, c-MYC, and RB1 in vitro; an analogue-sensitive CDK10 mutant identifies 89 phosphosites on 66 proteins in HEK cells including targets in cell cycle, translation, stress response, growth signalling, and transcriptional regulation; CDK10 is itself phosphorylated in vitro by CDK1 and CDK5 at multiple sites.\",\n      \"method\": \"Recombinant protein in vitro kinase assay, analogue-sensitive kinase approach with mass spectrometry phosphoproteomics\",\n      \"journal\": \"Open biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro kinase assays combined with analogue-sensitive kinase chemical genetics and mass spectrometry, multiple substrates identified by orthogonal methods\",\n      \"pmids\": [\"35291876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CDK10 truncated variants associated with Al Kaissi syndrome retain ability to form CDK10/CycM heterodimer; the CycM truncated variant partially activates CDK10 in vitro, while the CDK10 truncated variant remains inactive; both variants are degraded by the proteasome when expressed in human cells.\",\n      \"method\": \"Recombinant protein expression in insect cells, in vitro kinase assay, yeast two-hybrid, proteasome inhibitor treatment in human cells\",\n      \"journal\": \"Molecular genetics & genomic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with recombinant proteins, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"34369103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CDK10 binds ETS2 and promotes its degradation, thereby inactivating the downstream c-Raf/p-MEK/p-ERK pathway that drives EMT and MMP2/9 expression; the p-MEK/p-ERK pathway also conducts positive feedback regulation on ETS2 expression; CDK10 knockdown promotes metastatic foci formation in a xenograft mouse model.\",\n      \"method\": \"Co-immunoprecipitation, protein degradation assays, MAPK pathway analysis, xenograft mouse model\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP binding plus in vivo xenograft validation, single lab\",\n      \"pmids\": [\"37737453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RNF115, an E3 ubiquitin ligase, ubiquitinates and degrades CDK10 in thyroid carcinoma cells, thereby activating the Raf-1 pathway and enhancing cancer cell cycle progression.\",\n      \"method\": \"Ubiquitination assay, co-immunoprecipitation, overexpression/knockdown experiments, in vivo tumor model\",\n      \"journal\": \"Cell biology and toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay plus functional rescue experiments, single lab\",\n      \"pmids\": [\"38376606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CDK10 silencing activates the JNK/c-Jun signaling pathway in lung cancer cells, promoting proliferation, migration, and radioresistance; c-Jun depletion reverses the effects of CDK10 knockdown, placing CDK10 upstream of JNK/c-Jun in this context.\",\n      \"method\": \"CDK10 siRNA knockdown, pathway inhibition (c-Jun depletion), cell proliferation and radioresistance assays\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis by double knockdown with defined phenotypic readout, single lab\",\n      \"pmids\": [\"38919013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CDK10 can partially compensate for the transcriptional function of CDK11 in RNA Polymerase II elongation regulation in metazoans.\",\n      \"method\": \"Functional genetic complementation experiments (context from CDK11 inhibition studies)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, CDK10 finding is secondary to CDK11 focus, single mention without detailed CDK10-specific mechanistic data\",\n      \"pmids\": [\"bio_10.1101_2025.09.27.678947\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CDK10 phosphorylates DNMT1 and RAP80, reducing accumulation of double-stranded RNA and R-loops, thereby suppressing activation of innate immune pathways mediated by MDA5 and cGAS in tumor cells; genetic and pharmacological CDK10 inhibition activates MDA5 and cGAS pathways and fosters an immunoactive tumor microenvironment.\",\n      \"method\": \"In vivo kinome CRISPR screen, phosphorylation assays, kinase inhibitor screens (NVP-AST487, ponatinib identified as CDK10 inhibitors), mouse tumor models\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo CRISPR screen combined with mechanistic phosphorylation studies, pharmacological validation with identified inhibitors, multiple mouse tumor models\",\n      \"pmids\": [\"41507536\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDK10 is a cyclin-dependent serine/threonine kinase activated by Cyclin M (FAM58A product) that phosphorylates substrates including ETS2 (promoting its proteasomal degradation to suppress c-Raf/MAPK signaling), PKN2 (on T121/T124 to stabilize RhoA and the actin network, suppressing ciliogenesis), DNMT1 and RAP80 (suppressing dsRNA/R-loop accumulation and innate immune activation via MDA5/cGAS), as well as RNA pol II CTD, c-MYC, and RB1 in vitro; it is itself degraded via ubiquitination by E3 ligase RNF115, and CDK10/CycM deficiency—whether from loss-of-function mutations causing Al Kaissi or STAR syndromes, or from tumor-associated silencing—leads to MAPK pathway hyperactivation, cilia elongation, and altered immune surveillance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CDK10 is a CDC2-related serine/threonine cyclin-dependent kinase that becomes catalytically active upon binding its cognate cyclin, Cyclin M (the FAM58A/Cyclin Q product), and through this complex restrains growth, MAPK, ciliogenesis, and immune-surveillance programs [#0, #6]. Its best-defined output is suppression of MAPK signaling: CDK10/CycM binds and phosphorylates the transcription factor ETS2, driving its proteasomal degradation, and loss of CDK10 derepresses ETS2-driven c-Raf transcription to activate the MEK/ERK cascade, conferring tamoxifen resistance and promoting EMT and metastasis in cancer cells [#3, #5, #6, #13]. Independently, CDK10/CycM phosphorylates PKN2 on threonines 121 and 124 within its RhoA-binding domain, stabilizing RhoA and the actin cytoskeleton to suppress primary cilium assembly; CDK10 deficiency in cells, knockout mice, and patient tissue produces elongated cilia and developmental defects [#7, #8]. The kinase also phosphorylates DNMT1 and RAP80 to limit dsRNA and R-loop accumulation, thereby dampening MDA5/cGAS innate-immune activation in tumors [#17]. Reconstituted and analogue-sensitive kinase studies extend its substrate repertoire to RNA pol II CTD, c-MYC, RB1, and dozens of phosphosites across cell-cycle, translation, and signaling proteins [#11]. CDK10 protein abundance is controlled by RNF115-mediated ubiquitination and degradation, which relieves its restraint on the Raf-1 pathway [#14]. Loss-of-function mutations in CDK10 or Cyclin M cause STAR and Al Kaissi syndromes, with disease-associated variants failing to assemble or activate the kinase complex [#6, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing whether PISSLRE/CDK10 was a bona fide kinase defined it as a CDC2-related enzyme rather than an uncharacterized ORF, anchoring all later mechanistic work.\",\n      \"evidence\": \"PCR-based cDNA cloning and sequence analysis identifying CDK structural elements and a PISSLRE PSTAIRE-like motif\",\n      \"pmids\": [\"8208557\", \"8084611\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No enzymatic activity demonstrated\", \"Cognate cyclin and substrates unknown at this stage\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Loss-of-function in human cells first tied CDK10 to cell growth control, placing it at the G2/M transition.\",\n      \"evidence\": \"Antisense and dominant-negative overexpression in U2OS cells with cell cycle analysis\",\n      \"pmids\": [\"7664269\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular substrate identified\", \"G2/M role not confirmed in other systems (later contradicted in murine cells)\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identification of ETS2 as a CDK10 interactor gave the kinase its first physiologically relevant binding partner and a transcriptional readout.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, co-IP, and transactivation reporter assays in mammalian cells\",\n      \"pmids\": [\"11313931\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not show ETS2 is a direct phosphosubstrate\", \"Cyclin partner still unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linking CDK10 silencing to ETS2-driven c-RAF transcription connected the kinase to MAPK pathway activation and clinical tamoxifen resistance.\",\n      \"evidence\": \"RNAi screen, gene silencing, reporter assays, and MAPK pathway analysis in breast cancer cells\",\n      \"pmids\": [\"18242510\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of ETS2 regulation (phosphorylation vs. binding) not resolved\", \"Activating cyclin not yet identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery of Cyclin M as the activating partner converted CDK10 into a defined active kinase complex and explained ETS2 control via phosphorylation-driven proteasomal degradation, linking the axis to STAR syndrome.\",\n      \"evidence\": \"Co-IP, in vitro kinase assays with recombinant proteins, proteasome inhibition, genetic complementation, and STAR patient cell analysis\",\n      \"pmids\": [\"24218572\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map ETS2 phosphosites\", \"Full substrate range beyond ETS2 unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identifying PKN2 as a phosphosubstrate revealed a distinct CDK10 function in cytoskeletal/RhoA control that suppresses ciliogenesis, separate from MAPK.\",\n      \"evidence\": \"Unbiased substrate screen, in vitro kinase assay with phosphosite mapping (T121/T124), RhoA rescue, cilia measurements, and patient kidney tissue\",\n      \"pmids\": [\"27104747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo significance of RhoA stabilization not tested at organismal level here\", \"Link between cilia and developmental phenotypes not yet established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"A CDK10 knockout mouse established the kinase as essential for development and confirmed cilia elongation in vivo, tying molecular function to organismal phenotype.\",\n      \"evidence\": \"Conditional knockout mouse, MEF cilia length measurements, and transcriptomic analysis\",\n      \"pmids\": [\"28886341\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrate driving developmental defects not pinpointed\", \"Tissue-specific contributions not separated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Kinase-activity-dependent regulation of apoptosis and Bcl-2 indicated a context-specific pro-survival role in colorectal cancer cells.\",\n      \"evidence\": \"Kinase-defective mutant expression, apoptosis assays, and xenograft with siRNA\",\n      \"pmids\": [\"28663269\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate connecting CDK10 to Bcl-2 not identified\", \"Apparent pro-tumor role contrasts with tumor-suppressive MAPK findings\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"An optimized peptide substrate and inhibitor panel provided tractable in vitro tools for the CDK10/CycM complex.\",\n      \"evidence\": \"In vitro kinase assay with peptide optimization and profiling of clinical CDK inhibitors\",\n      \"pmids\": [\"32175313\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No CDK10-selective inhibitor identified\", \"No structural or cellular validation of inhibitor specificity\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reconstituted and analogue-sensitive kinase approaches broadened the substrate landscape (RNA pol II CTD, c-MYC, RB1, 66 proteins) and showed CDK10 is itself phosphorylated by CDK1/CDK5.\",\n      \"evidence\": \"Recombinant in vitro kinase assays plus analogue-sensitive chemical genetics with mass spectrometry phosphoproteomics\",\n      \"pmids\": [\"35291876\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular significance of most identified phosphosites untested\", \"Functional consequence of CDK1/CDK5 phosphorylation of CDK10 unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Biochemical analysis of Al Kaissi syndrome variants explained disease mechanism as failed complex activation and accelerated proteasomal degradation.\",\n      \"evidence\": \"Recombinant expression in insect cells, in vitro kinase assays, yeast two-hybrid, and proteasome inhibition in human cells\",\n      \"pmids\": [\"34369103\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Patient-tissue confirmation limited\", \"Quantitative residual activity of variants in vivo unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extending the ETS2/MAPK axis to EMT, MMP2/9, and metastasis defined CDK10 as a metastasis suppressor with positive feedback on ETS2.\",\n      \"evidence\": \"Co-IP, protein degradation assays, MAPK pathway analysis, and xenograft metastasis model\",\n      \"pmids\": [\"37737453\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ETS2 phosphosite not mapped in this context\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying RNF115 as the E3 ligase degrading CDK10 defined an upstream control point that releases Raf-1 signaling in cancer.\",\n      \"evidence\": \"Ubiquitination assay, co-IP, knockdown/overexpression, and in vivo tumor model in thyroid carcinoma\",\n      \"pmids\": [\"38376606\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination site on CDK10 not mapped\", \"Signals controlling RNF115 activity unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placing CDK10 upstream of JNK/c-Jun in lung cancer extended its growth-suppressive signaling reach beyond ERK.\",\n      \"evidence\": \"siRNA knockdown with c-Jun epistasis and proliferation/radioresistance assays\",\n      \"pmids\": [\"38919013\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate linking CDK10 to JNK/c-Jun not identified\", \"Single context\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defining DNMT1 and RAP80 as substrates connected CDK10 to nucleic-acid stress control and innate immune surveillance, opening an immunotherapy-relevant axis.\",\n      \"evidence\": \"In vivo kinome CRISPR screen, phosphorylation assays, inhibitor identification, and mouse tumor models\",\n      \"pmids\": [\"41507536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphosites on DNMT1/RAP80 not detailed\", \"Relative contribution of dsRNA vs. R-loop suppression unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CDK10's many described axes (ETS2/MAPK, PKN2/cilia, DNMT1-RAP80/immunity, and CDK11-like pol II elongation) are coordinated, prioritized, and integrated within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying model linking substrate selection to physiological context\", \"Apparent pro- vs. anti-tumor roles not reconciled\", \"No CDK10-selective inhibitor or structural model of substrate recognition\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [6, 7, 11, 17]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [6, 7, 11]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 13, 15]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"complexes\": [\"CDK10/Cyclin M (CDK10/CycM, CDK10/CycQ)\"],\n    \"partners\": [\"CCNQ\", \"ETS2\", \"PKN2\", \"DNMT1\", \"RAP80\", \"RNF115\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}