Affinage

CDK10

Cyclin-dependent kinase 10 · UniProt Q15131

Length
360 aa
Mass
41.0 kDa
Annotated
2026-06-09
31 papers in source corpus 19 papers cited in narrative 18 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1994 Medium

    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

    PMID:8084611 PMID:8208557

    Open questions at the time
    • No enzymatic activity demonstrated
    • Cognate cyclin and substrates unknown at this stage
  2. 1995 Medium

    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

    PMID:7664269

    Open questions at the time
    • No molecular substrate identified
    • G2/M role not confirmed in other systems (later contradicted in murine cells)
  3. 2001 High

    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

    PMID:11313931

    Open questions at the time
    • Did not show ETS2 is a direct phosphosubstrate
    • Cyclin partner still unknown
  4. 2008 High

    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

    PMID:18242510

    Open questions at the time
    • Mechanism of ETS2 regulation (phosphorylation vs. binding) not resolved
    • Activating cyclin not yet identified
  5. 2013 High

    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

    PMID:24218572

    Open questions at the time
    • Did not map ETS2 phosphosites
    • Full substrate range beyond ETS2 unknown
  6. 2016 High

    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

    PMID:27104747

    Open questions at the time
    • In vivo significance of RhoA stabilization not tested at organismal level here
    • Link between cilia and developmental phenotypes not yet established
  7. 2017 High

    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

    PMID:28886341

    Open questions at the time
    • Direct substrate driving developmental defects not pinpointed
    • Tissue-specific contributions not separated
  8. 2017 Medium

    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

    PMID:28663269

    Open questions at the time
    • Direct substrate connecting CDK10 to Bcl-2 not identified
    • Apparent pro-tumor role contrasts with tumor-suppressive MAPK findings
  9. 2020 Medium

    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

    PMID:32175313

    Open questions at the time
    • No CDK10-selective inhibitor identified
    • No structural or cellular validation of inhibitor specificity
  10. 2021 High

    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

    PMID:35291876

    Open questions at the time
    • Cellular significance of most identified phosphosites untested
    • Functional consequence of CDK1/CDK5 phosphorylation of CDK10 unknown
  11. 2021 Medium

    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

    PMID:34369103

    Open questions at the time
    • Patient-tissue confirmation limited
    • Quantitative residual activity of variants in vivo unclear
  12. 2023 Medium

    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

    PMID:37737453

    Open questions at the time
    • ETS2 phosphosite not mapped in this context
    • Single lab
  13. 2024 Medium

    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

    PMID:38376606

    Open questions at the time
    • Ubiquitination site on CDK10 not mapped
    • Signals controlling RNF115 activity unknown
  14. 2024 Medium

    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

    PMID:38919013

    Open questions at the time
    • Direct substrate linking CDK10 to JNK/c-Jun not identified
    • Single context
  15. 2026 High

    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

    PMID:41507536

    Open questions at the time
    • Phosphosites on DNMT1/RAP80 not detailed
    • Relative contribution of dsRNA vs. R-loop suppression unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016740 transferase activity 3 GO:0140110 transcription regulator activity 2
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 2 R-HSA-1640170 Cell Cycle 2 R-HSA-168256 Immune System 1
Complex memberships
CDK10/Cyclin M (CDK10/CycM, CDK10/CycQ)

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 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. PCR-based cDNA cloning and amino acid sequence analysis Oncogene Medium 8084611 8208557
1995 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. Antisense and dominant-negative mutant overexpression in U2OS cells with cell cycle analysis Cancer research Medium 7664269
2000 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. RT-PCR isoform analysis, subcellular fractionation Biochemical and biophysical research communications Medium 11006117
2001 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. Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation in mammalian cells, transactivation reporter assay Oncogene High 11313931
2006 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. In vitro binding assay, cell proliferation analysis Journal of cellular biochemistry Medium 16741970
2008 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. RNAi screen, gene silencing, reporter assays, MAPK pathway analysis Cancer cell High 18242510
2013 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. Co-immunoprecipitation, in vitro kinase assay with recombinant proteins, proteasome inhibitor experiments, genetic complementation, cell-based ETS2 protein level measurement in STAR patient cells Proceedings of the National Academy of Sciences of the United States of America High 24218572
2016 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. Unbiased kinase substrate screen, in vitro kinase assay with phosphosite mapping, co-immunoprecipitation, RhoA rescue experiments, cilia length/number measurements, patient kidney tissue analysis Cell cycle (Georgetown, Tex.) High 27104747
2017 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. Conditional knockout mouse generation, MEF cilia length measurements, transcriptomic analysis American journal of human genetics High 28886341
2017 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. Kinase-defective mutant expression, apoptosis assays, in vivo xenograft model with siRNA Molecular cancer therapeutics Medium 28663269
2020 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. In vitro kinase assay with peptide substrate optimization, inhibitor profiling Frontiers in chemistry Medium 32175313
2021 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. Recombinant protein in vitro kinase assay, analogue-sensitive kinase approach with mass spectrometry phosphoproteomics Open biology High 35291876
2021 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. Recombinant protein expression in insect cells, in vitro kinase assay, yeast two-hybrid, proteasome inhibitor treatment in human cells Molecular genetics & genomic medicine Medium 34369103
2023 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. Co-immunoprecipitation, protein degradation assays, MAPK pathway analysis, xenograft mouse model Molecular carcinogenesis Medium 37737453
2024 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. Ubiquitination assay, co-immunoprecipitation, overexpression/knockdown experiments, in vivo tumor model Cell biology and toxicology Medium 38376606
2024 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. CDK10 siRNA knockdown, pathway inhibition (c-Jun depletion), cell proliferation and radioresistance assays BMB reports Medium 38919013
2026 CDK10 can partially compensate for the transcriptional function of CDK11 in RNA Polymerase II elongation regulation in metazoans. Functional genetic complementation experiments (context from CDK11 inhibition studies) bioRxivpreprint Low bio_10.1101_2025.09.27.678947
2026 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. In vivo kinome CRISPR screen, phosphorylation assays, kinase inhibitor screens (NVP-AST487, ponatinib identified as CDK10 inhibitors), mouse tumor models Nature cancer High 41507536

Source papers

Stage 0 corpus · 31 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Identification of CDK10 as an important determinant of resistance to endocrine therapy for breast cancer. Cancer cell 178 18242510
1995 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. Cancer research 125 7882308
2001 Cdk10, a Cdc2-related kinase, associates with the Ets2 transcription factor and modulates its transactivation activity. Oncogene 93 11313931
2013 CDK10/cyclin M is a protein kinase that controls ETS2 degradation and is deficient in STAR syndrome. Proceedings of the National Academy of Sciences of the United States of America 69 24218572
1995 The cdc-2-related kinase, PISSLRE, is essential for cell growth and acts in G2 phase of the cell cycle. Cancer research 56 7664269
1994 PISSLRE, a human novel CDC2-related protein kinase. Oncogene 55 8208557
1994 Molecular cloning of PISSLRE, a novel putative member of the cdk family of protein serine/threonine kinases. Oncogene 44 8084611
2011 CDK10 functions as a tumor suppressor gene and regulates survivability of biliary tract cancer cells. Oncology reports 38 22209942
1999 The PISSLRE gene: structure, exon skipping, and exclusion as tumor suppressor in breast cancer. Genomics 37 10036189
2016 STAR syndrome-associated CDK10/Cyclin M regulates actin network architecture and ciliogenesis. Cell cycle (Georgetown, Tex.) 35 27104747
2017 CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays. American journal of human genetics 33 28886341
2012 Clinical and biological significance of Cdk10 in hepatocellular carcinoma. Gene 31 22326270
2017 The awakening of the CDK10/Cyclin M protein kinase. Oncotarget 29 28178678
2017 A homozygous deleterious CDK10 mutation in a patient with agenesis of corpus callosum, retinopathy, and deafness. American journal of medical genetics. Part A 22 29130579
2013 Promoter hypermethylation contributes to the frequent suppression of the CDK10 gene in human nasopharyngeal carcinomas. Cellular oncology (Dordrecht, Netherlands) 22 23740091
2017 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. Molecular cancer therapeutics 18 28663269
2006 Identification of murine cdk10: association with Ets2 transcription factor and effects on the cell cycle. Journal of cellular biochemistry 18 16741970
2000 Human CDK10 gene isoforms. Biochemical and biophysical research communications 18 11006117
2021 CDK10 in Gastrointestinal Cancers: Dual Roles as a Tumor Suppressor and Oncogene. Frontiers in oncology 17 34277407
2020 Development of a CDK10/CycM in vitro Kinase Screening Assay and Identification of First Small-Molecule Inhibitors. Frontiers in chemistry 17 32175313
2022 Functional characterization of the human Cdk10/Cyclin Q complex. Open biology 16 35291876
2015 Elevated C1orf63 expression is correlated with CDK10 and predicts better outcome for advanced breast cancers: a retrospective study. BMC cancer 15 26209438
2009 CDK10 is not a target for aberrant DNA methylation in breast cancer. Anticancer research 12 19846932
2024 RNF115 aggravates tumor progression through regulation of CDK10 degradation in thyroid carcinoma. Cell biology and toxicology 9 38376606
2021 Integrative Analysis of Omics Data Reveals Regulatory Network of CDK10 in Vitiligo Risk. Frontiers in genetics 9 33679896
2023 CDK10 suppresses metastasis of lung adenocarcinoma through inhibition of the ETS2/c-Raf/p-MEK/p-ERK signaling loop. Molecular carcinogenesis 8 37737453
2021 Functional characterization of CDK10 and cyclin M truncated variants causing severe developmental disorders. Molecular genetics & genomic medicine 5 34369103
2024 Downregulated CDK10 promotes cancer progression and radioresistance in lung cancer through activating the JNK/c-Jun signaling pathway. BMB reports 4 38919013
2012 Effects of the cyclin-dependent kinase 10 (CDK10) on the tamoxifen sensitivity of keloid samples. Molecules (Basel, Switzerland) 2 22298115
2026 CDK10 suppresses nucleic acid sensors-mediated antitumor immunity. Nature cancer 1 41507536
2025 Two Siblings With Al Kaissi Syndrome: Clinical, Radiological, and Molecular Characterization of Compound Heterozygous CDK10 Variants. American journal of medical genetics. Part A 0 40960173

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