{"gene":"CDK11B","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2004,"finding":"CDK11(p110/p58)-null mice die at the blastocyst stage (E3.5) due to apoptosis, with cells showing both proliferative defects and mitotic arrest, establishing that CDK11 kinases are essential for cellular viability and early embryonic development.","method":"Homologous recombination knockout in mice; phenotypic analysis of null embryos","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype, replicated across multiple embryos","pmids":["15060143"],"is_preprint":false},{"year":2004,"finding":"CDK11(p110) is part of large-molecular-weight complexes containing RNA polymerase II, transcriptional elongation factors, and general pre-mRNA splicing factors, suggesting it couples transcription and pre-mRNA splicing.","method":"Biochemical complex purification/fractionation","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 3 — complex isolation described but detailed Co-IP/pulldown methods not elaborated in abstract","pmids":["15060143"],"is_preprint":false},{"year":2007,"finding":"CDK11(p58) is required for sister chromatid cohesion and completion of mitosis; its depletion causes misaligned/lagging chromosomes, premature sister chromatid separation, altered Shugoshin 1 (Sgo1) localization, and premature dissociation of cohesin complexes. This severe phenotype was rescued by CDK11(p58) but not by co-depletion with Plk1 or Sgo1.","method":"Hypomorphic siRNA knockdown with epistasis rescue experiments; fluorescence microscopy of chromosome behavior","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — clean KD with defined cellular phenotype and epistasis rescue, multiple siRNA doses used","pmids":["17606997"],"is_preprint":false},{"year":2011,"finding":"CDK11(p58) is required for centriole duplication; its depletion reduces centrosomal recruitment of Plk4 and Cep192 during mitosis. CDK11(p58) directly interacts with Plk4, and centrioles from CDK11-depleted cells cannot be over-duplicated following Plk4 overexpression.","method":"siRNA knockdown, Co-IP (CDK11(p58) with Plk4), immunofluorescence of centrosomal proteins, Plk4 overexpression rescue assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction demonstrated, functional rescue experiment, multiple cell lines","pmids":["21297952"],"is_preprint":false},{"year":2012,"finding":"CHK2 kinase phosphorylates CDK11(p110) at serine 737 in vitro in a DNA damage-independent manner; this phosphorylation promotes CDK11(p110) homodimerization and is required for its splicing-activating activity. CHK2 overexpression promotes pre-mRNA splicing, and mutation of S737 to alanine abrogates CDK11(p110) splicing activity.","method":"Tandem affinity purification, in vitro kinase assay, site-directed mutagenesis (S737A), pre-mRNA splicing assay, CHK2 knockdown/overexpression","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay with mutagenesis plus functional splicing assay, multiple orthogonal methods","pmids":["23178491"],"is_preprint":false},{"year":2010,"finding":"CDK11(p58) autophosphorylates at Thr-370, and this autophosphorylation is required for homodimerization and kinase activity. The kinase-dead mutant D224N fails to form homodimers. T370A mutant cannot dimerize or be phosphorylated by wild-type CDK11(p58), loses kinase activity, fails to repress androgen receptor transactivation, and cannot enhance apoptosis.","method":"In vitro kinase assay, site-directed mutagenesis (T370A, T370D, D224N), Co-IP for dimerization, transactivation assay, apoptosis assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay with mutagenesis plus multiple functional readouts","pmids":["21078675"],"is_preprint":false},{"year":2014,"finding":"CDK11(p58) kinase activity is required to protect sister chromatid cohesion at centromeres during mitosis. CDK11 depletion prevents Bub1 and Shugoshin 1 recruitment to centromeres; a kinase-dead version of CDK11(p58) fails to rescue CDK11 depletion-induced sister chromatid separation. Loss of cohesion occurs in mitosis but not G2.","method":"siRNA depletion, kinase-dead mutant rescue, immunofluorescence of Bub1, Sgo1, and histone H3K4me2","journal":"Chromosome research","confidence":"High","confidence_rationale":"Tier 2 — kinase-dead rescue distinguishes catalytic requirement; multiple chromatin markers assessed","pmids":["24436071"],"is_preprint":false},{"year":2019,"finding":"CDK11p58 forms a complex with cyclin L1β during late cytokinesis and localizes to the stem body (intercellular bridge). CDK11p58 kinase activity is required for ESCRT-III filament formation at the abscission site and for completion of abscission; this activity opposes Aurora B kinase to enable abscission.","method":"Co-immunoprecipitation, live-cell imaging/immunofluorescence, siRNA depletion, kinase-dead rescue, Aurora B inhibitor epistasis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, functional rescue with kinase-dead, epistasis with Aurora B inhibitor","pmids":["31653703"],"is_preprint":false},{"year":2020,"finding":"CDK11/p58 phosphorylates eIF3F (a subunit of the eIF3 translation initiation complex) during M phase, repressing cap-dependent translation. Knockdown of CDK11/p58 abolishes M phase translational repression; alanine substitution of CDK11/p58 target sites in eIF3F nullifies cell cycle-dependent translational regulation.","method":"Ectopic expression/knockdown of CDK11/p58, in vitro phosphorylation assay, site-directed mutagenesis of eIF3F phosphorylation sites, cap-dependent translation reporter assay","journal":"Cellular and molecular life sciences","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay with mutagenesis plus functional translation assay, mechanistically thorough","pmids":["32030451"],"is_preprint":false},{"year":2020,"finding":"B4GALT1 (beta-1,4-galactosyltransferase 1) interacts with and stabilizes CDK11p110 via N-linked glycosylation, promoting cancer progression and chemoresistance. Elevated NF-κB p65 activity transcriptionally upregulates B4GALT1, forming a p65-B4GALT1-CDK11p110 signaling axis.","method":"Co-IP, glycosylation inhibition assay, genetic knockdown/overexpression, orthotopic PDAC xenograft model","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus functional model, but N-glycosylation site not mapped by mutagenesis","pmids":["33309857"],"is_preprint":false},{"year":2005,"finding":"CDK11(p58)-mediated apoptosis (enhanced by cycloheximide treatment) involves cytochrome c release, caspase-3 activation, and subsequent caspase-3 cleavage of CDK11(p58) itself. Beta-1,4-galactosyltransferase 1 (beta1,4-GT1) promotes this apoptotic pathway, and its knockdown inhibits it.","method":"siRNA knockdown of beta1,4-GT1, caspase-3 cleavage assay, cytochrome c release assay, flow cytometry","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 — functional assays with specific molecular readouts in single study","pmids":["15629159"],"is_preprint":false},{"year":2007,"finding":"CDK11(p58) down-regulates Bcl-2 expression and its Ser70/Ser87 phosphorylation during cycloheximide-induced apoptosis; overexpression of Bcl-2 counteracts CDK11(p58) pro-apoptotic activity. Kinase activity of CDK11(p58) is essential for Bcl-2 down-regulation and apoptosis induction.","method":"Ectopic overexpression, kinase-dead mutant, western blot, apoptosis assay","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 — kinase-dead mutant distinguishes catalytic requirement; single lab with defined molecular readout","pmids":["17516030"],"is_preprint":false},{"year":2010,"finding":"Cyclin D3 interacts with CDK11(p58), and the cyclin D3/CDK11(p58) complex localizes primarily to the nucleus, where it represses Schwann cell proliferation and induces apoptosis. Silencing cyclin D3 reverses CDK11(p58)-mediated proliferation repression.","method":"Co-IP, immunofluorescence localization, siRNA silencing, overexpression, proliferation/apoptosis assays","journal":"Inflammation","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP with functional knockdown, single study","pmids":["20066559"],"is_preprint":false},{"year":2011,"finding":"Polypyrimidine tract-binding protein (PTB) directly binds to the IRES region of CDK11(p58) mRNA and represses its IRES-dependent translation in embryonic stem cells. Loss of PTB leads to elevated CDK11(p58) protein and prolonged G2/M phase.","method":"RNA immunoprecipitation, IRES reporter assay, PTB knockout ES cells, proliferation analysis","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 — direct RNA binding demonstrated plus functional consequence; single lab","pmids":["22037210"],"is_preprint":false},{"year":2019,"finding":"CDK11p110 (but not CDK11p58) directly binds the CBFβ gene promoter and transcriptionally activates CBFβ expression in osteosarcoma cells. CDK11p110-dependent CBFβ upregulation promotes osteosarcoma cell proliferation.","method":"Promoter luciferase assay, chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA/Gel Shift), gene array","journal":"Cell communication and signaling","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal methods (ChIP + EMSA + luciferase) confirming direct promoter binding in single study","pmids":["31610798"],"is_preprint":false},{"year":2020,"finding":"CDK11B promotes ubiquitin-proteasome-mediated degradation of the transcription factor SPDEF in hepatocellular carcinoma stem cells. SPDEF degradation relieves its suppression of miR-448, which in turn represses DOT1L, promoting HCC stem cell self-renewal.","method":"Co-IP, ubiquitination-IP, ChIP assay, sphere/colony formation assay, in vivo xenograft","journal":"Cancer gene therapy","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and ubiquitination-IP demonstrate interaction and modification; pathway validated in vivo","pmids":["33328586"],"is_preprint":false},{"year":2022,"finding":"CDK11-p58 (referred to as CDK11A isoform in this study but confirmed as CDK11 p58 isoform) phosphorylates MRPS23 at serine 11, as shown by in vitro kinase assay and MALDI-ToF/ToF analysis. MRPS23 S11 phosphorylation activates PI3K-AKT and anti-apoptotic pathways to promote breast cancer cell proliferation.","method":"Co-IP, phosphoprotein enrichment, in vitro kinase assay with CDK11/cyclin D3, MALDI-ToF/ToF mass spectrometry, site-directed mutagenesis (S11A/S11G)","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro kinase assay with mass spectrometry identification of phosphosite and mutagenesis; single study","pmids":["35962848"],"is_preprint":false},{"year":2011,"finding":"CDK11(p58) activates p38 and JNK MAPK pathways in astrocytes upon LPS stimulation, promoting inflammatory response. CDK11(p58) knockdown reduces LPS-induced inflammatory response, and overexpression enhances it.","method":"siRNA knockdown, overexpression, western blot of p38 and JNK phosphorylation, LPS stimulation assay","journal":"Neurochemical research","confidence":"Low","confidence_rationale":"Tier 3 — single lab, pathway phosphorylation assay without direct substrate identification","pmids":["22120654"],"is_preprint":false},{"year":2015,"finding":"CDK11(p58) inhibits VEGF transcription and promoter activity in breast cancer cells in a kinase-activity-dependent manner, thereby suppressing angiogenesis both in vitro and in vivo in nude mice. Kinase-dead CDK11(p58) fails to inhibit VEGF mRNA or promoter activity.","method":"Dual-luciferase reporter for VEGF promoter, real-time PCR, kinase-dead mutant, xenograft tumor model, immunohistochemistry","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 — kinase-dead mutant distinguishes catalytic requirement, in vivo validation; single lab","pmids":["26470709"],"is_preprint":false}],"current_model":"CDK11B encodes two major isoforms—CDK11(p110), expressed throughout the cell cycle in complexes with RNA pol II and splicing factors to couple transcription and pre-mRNA splicing (phosphorylated by CHK2 at S737 to promote dimerization and splicing activity), and CDK11(p58), translated specifically in G2/M via an IRES and required for centrosome maturation, centriole duplication (via direct interaction with Plk4), sister chromatid cohesion (by recruiting Bub1 and Shugoshin 1), abscission (forming a complex with cyclin L1β to promote ESCRT-III assembly opposing Aurora B), and global translational repression during mitosis (by phosphorylating eIF3F), with its autophosphorylation at Thr-370 being essential for dimerization and all downstream kinase-dependent functions."},"narrative":{"teleology":[{"year":2004,"claim":"Establishing that CDK11 is essential for viability resolved whether the two paralogous CDK11 loci are redundant: knockout of CDK11(p110/p58) causes blastocyst-stage lethality with mitotic arrest and apoptosis, demonstrating a non-redundant requirement in cell proliferation and survival.","evidence":"Homologous recombination knockout in mice with phenotypic analysis of null embryos","pmids":["15060143"],"confidence":"High","gaps":["Whether CDK11A can partially compensate for CDK11B loss was not tested","Specific mitotic substrates responsible for arrest not identified"]},{"year":2004,"claim":"Biochemical isolation of CDK11(p110) in complexes with RNA pol II and splicing factors established a molecular framework for how this isoform couples transcription to pre-mRNA splicing.","evidence":"Biochemical complex purification and fractionation from mammalian cells","pmids":["15060143"],"confidence":"Medium","gaps":["Direct substrates within the spliceosome not identified","No reconstitution of splicing stimulation with purified components"]},{"year":2007,"claim":"Demonstrating that CDK11(p58) depletion causes premature sister chromatid separation with altered Shugoshin 1 localization established its role as a protector of centromeric cohesion during mitosis, a function not rescued by co-depletion of Plk1 or Sgo1.","evidence":"Hypomorphic siRNA knockdown with epistasis rescue experiments; fluorescence microscopy in human cells","pmids":["17606997"],"confidence":"High","gaps":["Whether CDK11(p58) directly phosphorylates Sgo1 or Bub1 was not determined","Cyclin partner for cohesion function not identified"]},{"year":2010,"claim":"Identification of Thr-370 autophosphorylation as the switch for CDK11(p58) homodimerization and catalytic activation resolved how the kinase is activated, since T370A mutants lost all downstream functions including apoptosis induction and transcriptional repression.","evidence":"In vitro kinase assay with T370A/T370D/D224N site-directed mutants, Co-IP for dimerization, functional assays","pmids":["21078675"],"confidence":"High","gaps":["Structural basis of dimerization interface unknown","Whether Thr-370 phosphorylation is regulated by an upstream signal in vivo not established"]},{"year":2011,"claim":"Showing that CDK11(p58) interacts with Plk4 and is required for centrosomal recruitment of Plk4 and Cep192 extended its mitotic role to centriole duplication, a function upstream of Plk4-driven centriole biogenesis.","evidence":"Co-IP of CDK11(p58) with Plk4, siRNA depletion, Plk4 overexpression rescue in multiple cell lines","pmids":["21297952"],"confidence":"High","gaps":["Whether CDK11(p58) phosphorylates Plk4 directly not tested","Temporal regulation of the CDK11–Plk4 interaction during the cell cycle not mapped"]},{"year":2011,"claim":"Discovery that PTB directly binds the CDK11(p58) IRES and represses its translation in ES cells provided the first trans-acting regulator of isoform-specific CDK11(p58) production, explaining how CDK11(p58) levels are restricted to G2/M.","evidence":"RNA immunoprecipitation, IRES reporter assay, PTB knockout embryonic stem cells","pmids":["22037210"],"confidence":"Medium","gaps":["Whether PTB regulation operates in somatic mitotic cells not confirmed","Other IRES trans-acting factors not identified"]},{"year":2012,"claim":"Identification of CHK2 as the kinase that phosphorylates CDK11(p110) at S737 to promote dimerization and splicing activity resolved how the transcription-coupled splicing function of the p110 isoform is regulated, independently of DNA damage.","evidence":"Tandem affinity purification, in vitro kinase assay, S737A mutagenesis, pre-mRNA splicing assay, CHK2 knockdown/overexpression","pmids":["23178491"],"confidence":"High","gaps":["In vivo splicing targets affected by the CHK2–CDK11 axis not catalogued","Physiological stimulus that activates this DNA damage-independent CHK2 pathway unknown"]},{"year":2014,"claim":"Kinase-dead rescue experiments established that CDK11(p58) catalytic activity—not merely its presence—is required for Bub1 and Sgo1 centromeric recruitment and cohesion protection specifically in mitosis, not G2.","evidence":"siRNA depletion with kinase-dead mutant rescue, immunofluorescence of Bub1, Sgo1, H3K4me2 in human cells","pmids":["24436071"],"confidence":"High","gaps":["Direct phosphorylation substrate linking CDK11 to Bub1/Sgo1 recruitment not identified"]},{"year":2019,"claim":"ChIP and EMSA demonstration that CDK11(p110) directly binds the CBFβ promoter and activates its transcription revealed a direct transcription factor-like activity for CDK11, beyond its known kinase and splicing functions.","evidence":"ChIP, EMSA, luciferase promoter assay in osteosarcoma cells","pmids":["31610798"],"confidence":"High","gaps":["Whether promoter binding requires kinase activity or a cyclin partner not tested","Genome-wide scope of CDK11(p110) promoter occupancy unknown"]},{"year":2019,"claim":"Identifying a CDK11(p58)–cyclin L1β complex at the intercellular bridge that promotes ESCRT-III assembly for abscission, opposing Aurora B, revealed a new post-anaphase function for CDK11(p58) in cytokinesis completion.","evidence":"Co-IP, live-cell imaging, siRNA depletion, kinase-dead rescue, Aurora B inhibitor epistasis","pmids":["31653703"],"confidence":"High","gaps":["Direct substrate phosphorylated by CDK11(p58)–cyclin L1β to trigger ESCRT-III assembly not identified","Whether this opposes the NoCut checkpoint directly unknown"]},{"year":2020,"claim":"Demonstration that CDK11(p58) phosphorylates eIF3F during M phase to repress cap-dependent translation identified the first mechanism by which a CDK directly links mitotic entry to global translational repression.","evidence":"In vitro kinase assay, eIF3F phosphosite mutagenesis, cap-dependent translation reporter","pmids":["32030451"],"confidence":"High","gaps":["Whether eIF3F phosphorylation also affects IRES-dependent translation not addressed","In vivo validation of specific phosphosites during endogenous mitosis not shown"]},{"year":2022,"claim":"Identification of MRPS23 S11 as a CDK11/cyclin D3 phosphosite that activates PI3K-AKT signaling in breast cancer expanded the substrate repertoire of CDK11(p58) beyond canonical mitotic and splicing targets.","evidence":"In vitro kinase assay with CDK11/cyclin D3, MALDI-ToF/ToF mass spectrometry, S11A/S11G mutagenesis","pmids":["35962848"],"confidence":"Medium","gaps":["Physiological context of MRPS23 phosphorylation during the cell cycle not established","Mechanism connecting mitochondrial ribosomal protein phosphorylation to PI3K-AKT unclear"]},{"year":null,"claim":"Key unresolved questions include the direct substrates that mediate CDK11(p58)'s cohesion-protection and centriole-duplication functions, the structural basis of CDK11 dimerization, and the degree of functional overlap between CDK11A and CDK11B paralogs.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal structure of CDK11 or CDK11–cyclin complex available","Direct phosphorylation targets for cohesion and centrosome functions unidentified","CDK11A vs CDK11B paralog-specific functions not delineated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4,5,6,8,16]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[14]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[14]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[12,14]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[3]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[2,6]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,2,3,6,7,8]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,4]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5,10,11]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[8]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[14]}],"complexes":["RNA pol II / splicing factor complex","CDK11(p58)–cyclin L1β abscission complex","CDK11(p58)–cyclin D3 complex"],"partners":["PLK4","CCNL1","CCND3","CHEK2","SGO1","BUB1","EIF3F","B4GALT1"],"other_free_text":[]},"mechanistic_narrative":"CDK11B encodes a cyclin-dependent kinase that produces two major isoforms—CDK11(p110) and CDK11(p58)—with distinct roles in transcription-coupled splicing, mitotic progression, and translational control. CDK11(p110) resides in complexes with RNA polymerase II and splicing factors to couple transcription with pre-mRNA splicing, an activity regulated by CHK2-mediated phosphorylation at S737 that promotes homodimerization [PMID:15060143, PMID:23178491]; CDK11(p110) also directly binds gene promoters such as CBFβ to activate transcription [PMID:31610798]. The mitotic isoform CDK11(p58), translated via an IRES element repressed by PTB [PMID:22037210], autophosphorylates at Thr-370 to enable dimerization and kinase activity [PMID:21078675], and executes multiple mitotic functions: it recruits Bub1 and Shugoshin 1 to protect centromeric cohesion [PMID:17606997, PMID:24436071], interacts with Plk4 to drive centriole duplication [PMID:21297952], forms a complex with cyclin L1β to promote ESCRT-III–dependent abscission opposing Aurora B [PMID:31653703], and phosphorylates eIF3F to repress cap-dependent translation during M phase [PMID:32030451]. CDK11-null mice die at the blastocyst stage from proliferative failure and mitotic arrest, establishing the essential requirement for these kinases in cell viability [PMID:15060143]."},"prefetch_data":{"uniprot":{"accession":"P21127","full_name":"Cyclin-dependent kinase 11B","aliases":["Cell division cycle 2-like protein kinase 1","CLK-1","Cell division protein kinase 11B","Galactosyltransferase-associated protein kinase p58/GTA","PITSLRE serine/threonine-protein kinase CDC2L1","p58 CLK-1"],"length_aa":795,"mass_kda":92.6,"function":"Cyclin-dependent protein kinase that acts as a regulator of transcription and pre-mRNA splicing (PubMed:12501247, PubMed:18216018, PubMed:32367068, PubMed:36104565). Acts as a key regulator of pre-mRNA splicing by mediating phosphorylation of SF3B1, enabling the association between SF3B1 and U5 and U6 snRNAs in the activated spliceosome, thereby promoting spliceosome assembly (PubMed:36104565, PubMed:38059508). Also acts as a regulator of transcription by phosphorylating 'Ser-2' of the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAP II) POLR2A (PubMed:32367068, PubMed:40858114). Involved in replication-dependent transcription of histone genes: binds to histone genes and phosphorylates POLR2A at 'Ser-2' of the CTD to specifically control transcriptional elongation of histones and recruitment of 3'-end processing factors (PubMed:32367068). Part of a transcription checkpoint upstream of CDK9, which regulates promoter-proximal pausing by RNA polymerase II, a transcription halt following transcription initiation, but prior to elongation (PubMed:40858114). Probably regulates promoter-proximal pausing by mediating phosphorylation of POLR2A at 'Ser-2' of the CTD (PubMed:40858114) Isoform expressed in a non-cell cycle-dependent manner Isoform specifically expressed during the G2-M phases of the cell cycle (PubMed:12082095, PubMed:2217177). Phosphorylates 'Ser-2' of the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAP II) POLR2A (PubMed:38019613). Promotes centromeric transcription to maintain centromeric cohesion during mitosis (PubMed:24436071, PubMed:38019613)","subcellular_location":"Nucleus; Chromosome, centromere","url":"https://www.uniprot.org/uniprotkb/P21127/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CDK11B","classification":"Common Essential","n_dependent_lines":4,"n_total_lines":5,"dependency_fraction":0.8},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000248333","cell_line_id":"CID001144","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"chromatin","grade":2}],"interactors":[{"gene":"CDC37","stoichiometry":10.0},{"gene":"CDK11B;CDK11A","stoichiometry":10.0},{"gene":"SAP30BP","stoichiometry":10.0},{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"FKBP5","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001144","total_profiled":1310},"omim":[{"mim_id":"176873","title":"CYCLIN-DEPENDENT KINASE 11B; CDK11B","url":"https://www.omim.org/entry/176873"},{"mim_id":"116951","title":"CYCLIN-DEPENDENT KINASE 11A; CDK11A","url":"https://www.omim.org/entry/116951"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear speckles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CDK11B"},"hgnc":{"alias_symbol":["CDK11-p110","CDK11-p58","CDK11-p46"],"prev_symbol":["CDC2L1"]},"alphafold":{"accession":"P21127","domains":[{"cath_id":"3.30.200.20","chopping":"436-519","consensus_level":"high","plddt":83.2711,"start":436,"end":519},{"cath_id":"1.10.510.10","chopping":"523-742","consensus_level":"high","plddt":89.996,"start":523,"end":742}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P21127","model_url":"https://alphafold.ebi.ac.uk/files/AF-P21127-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P21127-F1-predicted_aligned_error_v6.png","plddt_mean":64.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CDK11B","jax_strain_url":"https://www.jax.org/strain/search?query=CDK11B"},"sequence":{"accession":"P21127","fasta_url":"https://rest.uniprot.org/uniprotkb/P21127.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P21127/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P21127"}},"corpus_meta":[{"pmid":"15060143","id":"PMC_15060143","title":"Failure to proliferate and mitotic arrest of CDK11(p110/p58)-null mutant mice at the blastocyst stage of embryonic cell development.","date":"2004","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15060143","citation_count":75,"is_preprint":false},{"pmid":"17606997","id":"PMC_17606997","title":"CDK11(p58) is required for the maintenance of sister chromatid cohesion.","date":"2007","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/17606997","citation_count":70,"is_preprint":false},{"pmid":"25990212","id":"PMC_25990212","title":"Cyclin-dependent kinase 11(p110) (CDK11(p110)) is crucial for human breast cancer cell proliferation and growth.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/25990212","citation_count":53,"is_preprint":false},{"pmid":"9750192","id":"PMC_9750192","title":"Duplication of a genomic region containing the Cdc2L1-2 and MMP21-22 genes on human chromosome 1p36.3 and their linkage to D1Z2.","date":"1998","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/9750192","citation_count":51,"is_preprint":false},{"pmid":"33309857","id":"PMC_33309857","title":"Galactosyltransferase B4GALT1 confers chemoresistance in pancreatic ductal adenocarcinomas by upregulating N-linked glycosylation of CDK11p110.","date":"2020","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/33309857","citation_count":40,"is_preprint":false},{"pmid":"21297952","id":"PMC_21297952","title":"CDK11(p58) is required for centriole duplication and Plk4 recruitment to mitotic centrosomes.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21297952","citation_count":30,"is_preprint":false},{"pmid":"23178491","id":"PMC_23178491","title":"CHK2 kinase promotes pre-mRNA splicing via phosphorylating CDK11(p110).","date":"2012","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/23178491","citation_count":26,"is_preprint":false},{"pmid":"15629159","id":"PMC_15629159","title":"Downregulation of beta1,4-galactosyltransferase 1 inhibits CDK11(p58)-mediated apoptosis induced by cycloheximide.","date":"2005","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/15629159","citation_count":24,"is_preprint":false},{"pmid":"22037210","id":"PMC_22037210","title":"Polypyrimidine tract-binding protein regulates the cell cycle through IRES-dependent translation of CDK11(p58) in mouse embryonic stem cells.","date":"2011","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/22037210","citation_count":22,"is_preprint":false},{"pmid":"30722725","id":"PMC_30722725","title":"CDK11p110 plays a critical role in the tumorigenicity of esophageal squamous cell carcinoma cells and is a potential drug target.","date":"2019","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/30722725","citation_count":18,"is_preprint":false},{"pmid":"21078675","id":"PMC_21078675","title":"Thr-370 is responsible for CDK11(p58) autophosphorylation, dimerization, and kinase activity.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21078675","citation_count":17,"is_preprint":false},{"pmid":"24436071","id":"PMC_24436071","title":"CDK11(p58) kinase activity is required to protect sister chromatid cohesion at centromeres in mitosis.","date":"2014","source":"Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology","url":"https://pubmed.ncbi.nlm.nih.gov/24436071","citation_count":16,"is_preprint":false},{"pmid":"29204684","id":"PMC_29204684","title":"DNA methylation of the CDC2L1 gene promoter region decreases the expression of the CDK11p58 protein and reduces apoptosis in keloid fibroblasts.","date":"2017","source":"Archives of dermatological research","url":"https://pubmed.ncbi.nlm.nih.gov/29204684","citation_count":16,"is_preprint":false},{"pmid":"26470709","id":"PMC_26470709","title":"Critical role of CDK11(p58) in human breast cancer growth and angiogenesis.","date":"2015","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/26470709","citation_count":15,"is_preprint":false},{"pmid":"17516030","id":"PMC_17516030","title":"CDK11(p58) protein kinase activity is associated with Bcl-2 down-regulation in pro-apoptosis pathway.","date":"2007","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17516030","citation_count":15,"is_preprint":false},{"pmid":"31610798","id":"PMC_31610798","title":"Transcriptional activation of CBFβ by CDK11p110 is necessary to promote osteosarcoma cell proliferation.","date":"2019","source":"Cell communication and signaling : 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pathway.","date":"2013","source":"Cellular and molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/23703121","citation_count":9,"is_preprint":false},{"pmid":"22120654","id":"PMC_22120654","title":"CDK11(p58) promotes rat astrocyte inflammatory response via activating p38 and JNK pathways induced by lipopolysaccharide.","date":"2011","source":"Neurochemical research","url":"https://pubmed.ncbi.nlm.nih.gov/22120654","citation_count":8,"is_preprint":false},{"pmid":"35962848","id":"PMC_35962848","title":"Mitochondrial ribosomal small subunit (MRPS) MRPS23 protein-protein interaction reveals phosphorylation by CDK11-p58 affecting cell proliferation and knockdown of MRPS23 sensitizes breast cancer cells to CDK1 inhibitors.","date":"2022","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/35962848","citation_count":6,"is_preprint":false},{"pmid":"15656972","id":"PMC_15656972","title":"Isolation and characterization of the human Cdc2L1 gene 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CCS","url":"https://pubmed.ncbi.nlm.nih.gov/31665012","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14595,"output_tokens":4465,"usd":0.05538},"stage2":{"model":"claude-opus-4-6","input_tokens":7962,"output_tokens":3288,"usd":0.183015},"total_usd":0.238395,"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\": 2004,\n      \"finding\": \"CDK11(p110/p58)-null mice die at the blastocyst stage (E3.5) due to apoptosis, with cells showing both proliferative defects and mitotic arrest, establishing that CDK11 kinases are essential for cellular viability and early embryonic development.\",\n      \"method\": \"Homologous recombination knockout in mice; phenotypic analysis of null embryos\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype, replicated across multiple embryos\",\n      \"pmids\": [\"15060143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CDK11(p110) is part of large-molecular-weight complexes containing RNA polymerase II, transcriptional elongation factors, and general pre-mRNA splicing factors, suggesting it couples transcription and pre-mRNA splicing.\",\n      \"method\": \"Biochemical complex purification/fractionation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — complex isolation described but detailed Co-IP/pulldown methods not elaborated in abstract\",\n      \"pmids\": [\"15060143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CDK11(p58) is required for sister chromatid cohesion and completion of mitosis; its depletion causes misaligned/lagging chromosomes, premature sister chromatid separation, altered Shugoshin 1 (Sgo1) localization, and premature dissociation of cohesin complexes. This severe phenotype was rescued by CDK11(p58) but not by co-depletion with Plk1 or Sgo1.\",\n      \"method\": \"Hypomorphic siRNA knockdown with epistasis rescue experiments; fluorescence microscopy of chromosome behavior\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cellular phenotype and epistasis rescue, multiple siRNA doses used\",\n      \"pmids\": [\"17606997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CDK11(p58) is required for centriole duplication; its depletion reduces centrosomal recruitment of Plk4 and Cep192 during mitosis. CDK11(p58) directly interacts with Plk4, and centrioles from CDK11-depleted cells cannot be over-duplicated following Plk4 overexpression.\",\n      \"method\": \"siRNA knockdown, Co-IP (CDK11(p58) with Plk4), immunofluorescence of centrosomal proteins, Plk4 overexpression rescue assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction demonstrated, functional rescue experiment, multiple cell lines\",\n      \"pmids\": [\"21297952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CHK2 kinase phosphorylates CDK11(p110) at serine 737 in vitro in a DNA damage-independent manner; this phosphorylation promotes CDK11(p110) homodimerization and is required for its splicing-activating activity. CHK2 overexpression promotes pre-mRNA splicing, and mutation of S737 to alanine abrogates CDK11(p110) splicing activity.\",\n      \"method\": \"Tandem affinity purification, in vitro kinase assay, site-directed mutagenesis (S737A), pre-mRNA splicing assay, CHK2 knockdown/overexpression\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay with mutagenesis plus functional splicing assay, multiple orthogonal methods\",\n      \"pmids\": [\"23178491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CDK11(p58) autophosphorylates at Thr-370, and this autophosphorylation is required for homodimerization and kinase activity. The kinase-dead mutant D224N fails to form homodimers. T370A mutant cannot dimerize or be phosphorylated by wild-type CDK11(p58), loses kinase activity, fails to repress androgen receptor transactivation, and cannot enhance apoptosis.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis (T370A, T370D, D224N), Co-IP for dimerization, transactivation assay, apoptosis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay with mutagenesis plus multiple functional readouts\",\n      \"pmids\": [\"21078675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CDK11(p58) kinase activity is required to protect sister chromatid cohesion at centromeres during mitosis. CDK11 depletion prevents Bub1 and Shugoshin 1 recruitment to centromeres; a kinase-dead version of CDK11(p58) fails to rescue CDK11 depletion-induced sister chromatid separation. Loss of cohesion occurs in mitosis but not G2.\",\n      \"method\": \"siRNA depletion, kinase-dead mutant rescue, immunofluorescence of Bub1, Sgo1, and histone H3K4me2\",\n      \"journal\": \"Chromosome research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — kinase-dead rescue distinguishes catalytic requirement; multiple chromatin markers assessed\",\n      \"pmids\": [\"24436071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CDK11p58 forms a complex with cyclin L1β during late cytokinesis and localizes to the stem body (intercellular bridge). CDK11p58 kinase activity is required for ESCRT-III filament formation at the abscission site and for completion of abscission; this activity opposes Aurora B kinase to enable abscission.\",\n      \"method\": \"Co-immunoprecipitation, live-cell imaging/immunofluorescence, siRNA depletion, kinase-dead rescue, Aurora B inhibitor epistasis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, functional rescue with kinase-dead, epistasis with Aurora B inhibitor\",\n      \"pmids\": [\"31653703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CDK11/p58 phosphorylates eIF3F (a subunit of the eIF3 translation initiation complex) during M phase, repressing cap-dependent translation. Knockdown of CDK11/p58 abolishes M phase translational repression; alanine substitution of CDK11/p58 target sites in eIF3F nullifies cell cycle-dependent translational regulation.\",\n      \"method\": \"Ectopic expression/knockdown of CDK11/p58, in vitro phosphorylation assay, site-directed mutagenesis of eIF3F phosphorylation sites, cap-dependent translation reporter assay\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay with mutagenesis plus functional translation assay, mechanistically thorough\",\n      \"pmids\": [\"32030451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"B4GALT1 (beta-1,4-galactosyltransferase 1) interacts with and stabilizes CDK11p110 via N-linked glycosylation, promoting cancer progression and chemoresistance. Elevated NF-κB p65 activity transcriptionally upregulates B4GALT1, forming a p65-B4GALT1-CDK11p110 signaling axis.\",\n      \"method\": \"Co-IP, glycosylation inhibition assay, genetic knockdown/overexpression, orthotopic PDAC xenograft model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus functional model, but N-glycosylation site not mapped by mutagenesis\",\n      \"pmids\": [\"33309857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CDK11(p58)-mediated apoptosis (enhanced by cycloheximide treatment) involves cytochrome c release, caspase-3 activation, and subsequent caspase-3 cleavage of CDK11(p58) itself. Beta-1,4-galactosyltransferase 1 (beta1,4-GT1) promotes this apoptotic pathway, and its knockdown inhibits it.\",\n      \"method\": \"siRNA knockdown of beta1,4-GT1, caspase-3 cleavage assay, cytochrome c release assay, flow cytometry\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — functional assays with specific molecular readouts in single study\",\n      \"pmids\": [\"15629159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CDK11(p58) down-regulates Bcl-2 expression and its Ser70/Ser87 phosphorylation during cycloheximide-induced apoptosis; overexpression of Bcl-2 counteracts CDK11(p58) pro-apoptotic activity. Kinase activity of CDK11(p58) is essential for Bcl-2 down-regulation and apoptosis induction.\",\n      \"method\": \"Ectopic overexpression, kinase-dead mutant, western blot, apoptosis assay\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — kinase-dead mutant distinguishes catalytic requirement; single lab with defined molecular readout\",\n      \"pmids\": [\"17516030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Cyclin D3 interacts with CDK11(p58), and the cyclin D3/CDK11(p58) complex localizes primarily to the nucleus, where it represses Schwann cell proliferation and induces apoptosis. Silencing cyclin D3 reverses CDK11(p58)-mediated proliferation repression.\",\n      \"method\": \"Co-IP, immunofluorescence localization, siRNA silencing, overexpression, proliferation/apoptosis assays\",\n      \"journal\": \"Inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP with functional knockdown, single study\",\n      \"pmids\": [\"20066559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Polypyrimidine tract-binding protein (PTB) directly binds to the IRES region of CDK11(p58) mRNA and represses its IRES-dependent translation in embryonic stem cells. Loss of PTB leads to elevated CDK11(p58) protein and prolonged G2/M phase.\",\n      \"method\": \"RNA immunoprecipitation, IRES reporter assay, PTB knockout ES cells, proliferation analysis\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct RNA binding demonstrated plus functional consequence; single lab\",\n      \"pmids\": [\"22037210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CDK11p110 (but not CDK11p58) directly binds the CBFβ gene promoter and transcriptionally activates CBFβ expression in osteosarcoma cells. CDK11p110-dependent CBFβ upregulation promotes osteosarcoma cell proliferation.\",\n      \"method\": \"Promoter luciferase assay, chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA/Gel Shift), gene array\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal methods (ChIP + EMSA + luciferase) confirming direct promoter binding in single study\",\n      \"pmids\": [\"31610798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CDK11B promotes ubiquitin-proteasome-mediated degradation of the transcription factor SPDEF in hepatocellular carcinoma stem cells. SPDEF degradation relieves its suppression of miR-448, which in turn represses DOT1L, promoting HCC stem cell self-renewal.\",\n      \"method\": \"Co-IP, ubiquitination-IP, ChIP assay, sphere/colony formation assay, in vivo xenograft\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and ubiquitination-IP demonstrate interaction and modification; pathway validated in vivo\",\n      \"pmids\": [\"33328586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CDK11-p58 (referred to as CDK11A isoform in this study but confirmed as CDK11 p58 isoform) phosphorylates MRPS23 at serine 11, as shown by in vitro kinase assay and MALDI-ToF/ToF analysis. MRPS23 S11 phosphorylation activates PI3K-AKT and anti-apoptotic pathways to promote breast cancer cell proliferation.\",\n      \"method\": \"Co-IP, phosphoprotein enrichment, in vitro kinase assay with CDK11/cyclin D3, MALDI-ToF/ToF mass spectrometry, site-directed mutagenesis (S11A/S11G)\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay with mass spectrometry identification of phosphosite and mutagenesis; single study\",\n      \"pmids\": [\"35962848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CDK11(p58) activates p38 and JNK MAPK pathways in astrocytes upon LPS stimulation, promoting inflammatory response. CDK11(p58) knockdown reduces LPS-induced inflammatory response, and overexpression enhances it.\",\n      \"method\": \"siRNA knockdown, overexpression, western blot of p38 and JNK phosphorylation, LPS stimulation assay\",\n      \"journal\": \"Neurochemical research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, pathway phosphorylation assay without direct substrate identification\",\n      \"pmids\": [\"22120654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CDK11(p58) inhibits VEGF transcription and promoter activity in breast cancer cells in a kinase-activity-dependent manner, thereby suppressing angiogenesis both in vitro and in vivo in nude mice. Kinase-dead CDK11(p58) fails to inhibit VEGF mRNA or promoter activity.\",\n      \"method\": \"Dual-luciferase reporter for VEGF promoter, real-time PCR, kinase-dead mutant, xenograft tumor model, immunohistochemistry\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — kinase-dead mutant distinguishes catalytic requirement, in vivo validation; single lab\",\n      \"pmids\": [\"26470709\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDK11B encodes two major isoforms—CDK11(p110), expressed throughout the cell cycle in complexes with RNA pol II and splicing factors to couple transcription and pre-mRNA splicing (phosphorylated by CHK2 at S737 to promote dimerization and splicing activity), and CDK11(p58), translated specifically in G2/M via an IRES and required for centrosome maturation, centriole duplication (via direct interaction with Plk4), sister chromatid cohesion (by recruiting Bub1 and Shugoshin 1), abscission (forming a complex with cyclin L1β to promote ESCRT-III assembly opposing Aurora B), and global translational repression during mitosis (by phosphorylating eIF3F), with its autophosphorylation at Thr-370 being essential for dimerization and all downstream kinase-dependent functions.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CDK11B encodes a cyclin-dependent kinase that produces two major isoforms—CDK11(p110) and CDK11(p58)—with distinct roles in transcription-coupled splicing, mitotic progression, and translational control. CDK11(p110) resides in complexes with RNA polymerase II and splicing factors to couple transcription with pre-mRNA splicing, an activity regulated by CHK2-mediated phosphorylation at S737 that promotes homodimerization [PMID:15060143, PMID:23178491]; CDK11(p110) also directly binds gene promoters such as CBFβ to activate transcription [PMID:31610798]. The mitotic isoform CDK11(p58), translated via an IRES element repressed by PTB [PMID:22037210], autophosphorylates at Thr-370 to enable dimerization and kinase activity [PMID:21078675], and executes multiple mitotic functions: it recruits Bub1 and Shugoshin 1 to protect centromeric cohesion [PMID:17606997, PMID:24436071], interacts with Plk4 to drive centriole duplication [PMID:21297952], forms a complex with cyclin L1β to promote ESCRT-III–dependent abscission opposing Aurora B [PMID:31653703], and phosphorylates eIF3F to repress cap-dependent translation during M phase [PMID:32030451]. CDK11-null mice die at the blastocyst stage from proliferative failure and mitotic arrest, establishing the essential requirement for these kinases in cell viability [PMID:15060143].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing that CDK11 is essential for viability resolved whether the two paralogous CDK11 loci are redundant: knockout of CDK11(p110/p58) causes blastocyst-stage lethality with mitotic arrest and apoptosis, demonstrating a non-redundant requirement in cell proliferation and survival.\",\n      \"evidence\": \"Homologous recombination knockout in mice with phenotypic analysis of null embryos\",\n      \"pmids\": [\"15060143\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CDK11A can partially compensate for CDK11B loss was not tested\", \"Specific mitotic substrates responsible for arrest not identified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Biochemical isolation of CDK11(p110) in complexes with RNA pol II and splicing factors established a molecular framework for how this isoform couples transcription to pre-mRNA splicing.\",\n      \"evidence\": \"Biochemical complex purification and fractionation from mammalian cells\",\n      \"pmids\": [\"15060143\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrates within the spliceosome not identified\", \"No reconstitution of splicing stimulation with purified components\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating that CDK11(p58) depletion causes premature sister chromatid separation with altered Shugoshin 1 localization established its role as a protector of centromeric cohesion during mitosis, a function not rescued by co-depletion of Plk1 or Sgo1.\",\n      \"evidence\": \"Hypomorphic siRNA knockdown with epistasis rescue experiments; fluorescence microscopy in human cells\",\n      \"pmids\": [\"17606997\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CDK11(p58) directly phosphorylates Sgo1 or Bub1 was not determined\", \"Cyclin partner for cohesion function not identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identification of Thr-370 autophosphorylation as the switch for CDK11(p58) homodimerization and catalytic activation resolved how the kinase is activated, since T370A mutants lost all downstream functions including apoptosis induction and transcriptional repression.\",\n      \"evidence\": \"In vitro kinase assay with T370A/T370D/D224N site-directed mutants, Co-IP for dimerization, functional assays\",\n      \"pmids\": [\"21078675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of dimerization interface unknown\", \"Whether Thr-370 phosphorylation is regulated by an upstream signal in vivo not established\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showing that CDK11(p58) interacts with Plk4 and is required for centrosomal recruitment of Plk4 and Cep192 extended its mitotic role to centriole duplication, a function upstream of Plk4-driven centriole biogenesis.\",\n      \"evidence\": \"Co-IP of CDK11(p58) with Plk4, siRNA depletion, Plk4 overexpression rescue in multiple cell lines\",\n      \"pmids\": [\"21297952\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CDK11(p58) phosphorylates Plk4 directly not tested\", \"Temporal regulation of the CDK11–Plk4 interaction during the cell cycle not mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovery that PTB directly binds the CDK11(p58) IRES and represses its translation in ES cells provided the first trans-acting regulator of isoform-specific CDK11(p58) production, explaining how CDK11(p58) levels are restricted to G2/M.\",\n      \"evidence\": \"RNA immunoprecipitation, IRES reporter assay, PTB knockout embryonic stem cells\",\n      \"pmids\": [\"22037210\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PTB regulation operates in somatic mitotic cells not confirmed\", \"Other IRES trans-acting factors not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of CHK2 as the kinase that phosphorylates CDK11(p110) at S737 to promote dimerization and splicing activity resolved how the transcription-coupled splicing function of the p110 isoform is regulated, independently of DNA damage.\",\n      \"evidence\": \"Tandem affinity purification, in vitro kinase assay, S737A mutagenesis, pre-mRNA splicing assay, CHK2 knockdown/overexpression\",\n      \"pmids\": [\"23178491\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo splicing targets affected by the CHK2–CDK11 axis not catalogued\", \"Physiological stimulus that activates this DNA damage-independent CHK2 pathway unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Kinase-dead rescue experiments established that CDK11(p58) catalytic activity—not merely its presence—is required for Bub1 and Sgo1 centromeric recruitment and cohesion protection specifically in mitosis, not G2.\",\n      \"evidence\": \"siRNA depletion with kinase-dead mutant rescue, immunofluorescence of Bub1, Sgo1, H3K4me2 in human cells\",\n      \"pmids\": [\"24436071\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct phosphorylation substrate linking CDK11 to Bub1/Sgo1 recruitment not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"ChIP and EMSA demonstration that CDK11(p110) directly binds the CBFβ promoter and activates its transcription revealed a direct transcription factor-like activity for CDK11, beyond its known kinase and splicing functions.\",\n      \"evidence\": \"ChIP, EMSA, luciferase promoter assay in osteosarcoma cells\",\n      \"pmids\": [\"31610798\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether promoter binding requires kinase activity or a cyclin partner not tested\", \"Genome-wide scope of CDK11(p110) promoter occupancy unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying a CDK11(p58)–cyclin L1β complex at the intercellular bridge that promotes ESCRT-III assembly for abscission, opposing Aurora B, revealed a new post-anaphase function for CDK11(p58) in cytokinesis completion.\",\n      \"evidence\": \"Co-IP, live-cell imaging, siRNA depletion, kinase-dead rescue, Aurora B inhibitor epistasis\",\n      \"pmids\": [\"31653703\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrate phosphorylated by CDK11(p58)–cyclin L1β to trigger ESCRT-III assembly not identified\", \"Whether this opposes the NoCut checkpoint directly unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstration that CDK11(p58) phosphorylates eIF3F during M phase to repress cap-dependent translation identified the first mechanism by which a CDK directly links mitotic entry to global translational repression.\",\n      \"evidence\": \"In vitro kinase assay, eIF3F phosphosite mutagenesis, cap-dependent translation reporter\",\n      \"pmids\": [\"32030451\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether eIF3F phosphorylation also affects IRES-dependent translation not addressed\", \"In vivo validation of specific phosphosites during endogenous mitosis not shown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of MRPS23 S11 as a CDK11/cyclin D3 phosphosite that activates PI3K-AKT signaling in breast cancer expanded the substrate repertoire of CDK11(p58) beyond canonical mitotic and splicing targets.\",\n      \"evidence\": \"In vitro kinase assay with CDK11/cyclin D3, MALDI-ToF/ToF mass spectrometry, S11A/S11G mutagenesis\",\n      \"pmids\": [\"35962848\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological context of MRPS23 phosphorylation during the cell cycle not established\", \"Mechanism connecting mitochondrial ribosomal protein phosphorylation to PI3K-AKT unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the direct substrates that mediate CDK11(p58)'s cohesion-protection and centriole-duplication functions, the structural basis of CDK11 dimerization, and the degree of functional overlap between CDK11A and CDK11B paralogs.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure of CDK11 or CDK11–cyclin complex available\", \"Direct phosphorylation targets for cohesion and centrosome functions unidentified\", \"CDK11A vs CDK11B paralog-specific functions not delineated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4, 5, 6, 8, 16]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [12, 14]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [2, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 2, 3, 6, 7, 8]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 10, 11]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"complexes\": [\n      \"RNA pol II / splicing factor complex\",\n      \"CDK11(p58)–cyclin L1β abscission complex\",\n      \"CDK11(p58)–cyclin D3 complex\"\n    ],\n    \"partners\": [\n      \"PLK4\",\n      \"CCNL1\",\n      \"CCND3\",\n      \"CHEK2\",\n      \"SGO1\",\n      \"BUB1\",\n      \"EIF3F\",\n      \"B4GALT1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}