Affinage

CDK10

Cyclin-dependent kinase 10 · UniProt Q15131

Length
360 aa
Mass
41.0 kDa
Annotated
2026-04-28
31 papers in source corpus 16 papers cited in narrative 16 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDK10 is a cyclin-dependent serine/threonine kinase that suppresses oncogenic signaling, regulates ciliogenesis, and restrains innate immune activation through phosphorylation of diverse substrates. Activated by Cyclin M (FAM58A/CCNQ), CDK10 phosphorylates ETS2 to promote its proteasomal degradation, thereby repressing ETS2-driven c-RAF/MAPK signaling; loss of CDK10 de-represses this axis, conferring tamoxifen resistance in breast cancer and promoting metastasis in lung adenocarcinoma (PMID:18242510, PMID:24218572, PMID:37737453). CDK10/Cyclin M also phosphorylates PKN2 at T121/T124 to stabilize RhoA and maintain actin architecture, suppressing primary cilia assembly (PMID:27104747), and phosphorylates DNMT1 and RAP80 to prevent accumulation of double-stranded RNA and R-loops that would otherwise trigger MDA5- and cGAS-dependent innate immune responses (PMID:41507536). Bi-allelic loss-of-function mutations in CDK10 cause Al Kaissi syndrome characterized by growth retardation and skeletal defects, while mutations in its activating cyclin cause STAR syndrome (PMID:28886341, PMID:24218572).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1995 Medium

    CDK10 (PISSLRE) was first shown to be required for cell proliferation and implicated at the G2/M transition, establishing it as a functional CDK with a role in cell cycle progression.

    Evidence Antisense and dominant-negative constructs in U2OS cells caused G2/M arrest

    PMID:7664269

    Open questions at the time
    • G2/M role was not confirmed in non-human cells and may reflect isoform-specific effects
    • No cyclin partner or substrate was identified
    • Antisense/dominant-negative approach lacks specificity of modern genetic tools
  2. 2000 Medium

    Discovery of multiple CDK10 isoforms with different subcellular distributions explained how alternative splicing of a nuclear localization signal generates functionally distinct kinase pools.

    Evidence RT-PCR isoform mapping and subcellular fractionation

    PMID:11006117

    Open questions at the time
    • Functional significance of individual isoforms was not tested
    • No kinase activity was demonstrated for any isoform
  3. 2001 High

    Identification of ETS2 as the first CDK10-interacting protein revealed a direct connection between this kinase and transcriptional regulation, showing CDK10 inhibits ETS2 transactivation via the Pointed domain.

    Evidence Yeast two-hybrid, in vitro binding, and mammalian transactivation assays

    PMID:11313931

    Open questions at the time
    • Phosphorylation of ETS2 by CDK10 was not demonstrated
    • No activating cyclin was known
  4. 2008 High

    A functional RNAi screen established CDK10 as a tumor suppressor whose silencing activates ETS2-driven c-RAF transcription and the MAPK pathway, directly explaining tamoxifen resistance in breast cancer.

    Evidence RNAi screen with reporter and MAPK pathway activation measurement in breast cancer cells

    PMID:18242510

    Open questions at the time
    • The kinase activity responsible for ETS2 suppression was not reconstituted
    • Activating cyclin still unknown
  5. 2013 High

    Identification of Cyclin M (FAM58A) as the activating cyclin for CDK10 resolved a long-standing gap, and reconstitution of CDK10/CycM kinase activity on ETS2 showed that phosphorylation drives ETS2 proteasomal degradation; STAR syndrome mutations disrupt this complex.

    Evidence Co-IP, in vitro kinase assay, proteasome inhibitor experiments, genetic complementation with STAR-associated CycM mutants

    PMID:24218572

    Open questions at the time
    • Specific ETS2 phosphosites were not mapped
    • Structural basis of CDK10/CycM interaction unknown
  6. 2016 High

    Discovery that CDK10/CycM phosphorylates PKN2 at T121/T124 to stabilize RhoA and suppress ciliogenesis revealed the mechanistic basis for ciliary defects in STAR syndrome, expanding CDK10 substrates beyond transcription factors.

    Evidence Unbiased phosphorylation screen, in vitro kinase assay, phosphosite mutagenesis, RhoA rescue, cilia imaging in STAR patient tissue

    PMID:27104747

    Open questions at the time
    • Whether CDK10 regulates cilia disassembly versus assembly was not resolved
    • Direct structural basis of PKN2 phosphorylation unknown
  7. 2017 High

    Human genetic and mouse knockout studies confirmed that bi-allelic CDK10 loss causes Al Kaissi syndrome with growth retardation, skeletal defects, and elongated cilia, validating CDK10 as essential for developmental signaling through primary cilia.

    Evidence Homozygosity mapping/exome sequencing in affected families, conditional Cdk10 knockout mice, MEF cilia measurement

    PMID:28886341

    Open questions at the time
    • Specific developmental signaling pathways (Hedgehog, Wnt) affected by CDK10 loss were not fully characterized
    • Tissue-specific requirements for CDK10 remain unclear
  8. 2021 High

    Chemical genetic phosphoproteomics with an analogue-sensitive CDK10 mutant identified 89 phosphosites on 66 cellular proteins, vastly expanding the substrate repertoire to include RNA Pol II CTD, c-MYC, and RB1, and revealing CDK10 participation in cell cycle, translation, and transcription.

    Evidence Analogue-sensitive kinase chemical genetics in HEK cells with mass spectrometry phosphoproteomics, in vitro kinase assays on recombinant substrates

    PMID:35291876

    Open questions at the time
    • Most identified substrates lack functional validation
    • Relative importance of individual substrates to CDK10 biology is unknown
    • CDK10 regulation by CDK1/CDK5 phosphorylation was shown in vitro but functional consequences not determined
  9. 2021 Medium

    Biochemical analysis of Al Kaissi and STAR syndrome-associated truncated CDK10 and CycM variants showed they retain heterodimerization capacity but are degraded by the proteasome, explaining loss of function through protein instability rather than failure to form the complex.

    Evidence Recombinant expression, in vitro kinase assay, yeast two-hybrid, proteasome inhibitor treatment

    PMID:34369103

    Open questions at the time
    • In vivo protein stability of truncated variants was not measured in patient cells
    • Whether proteasome-mediated degradation is the sole pathogenic mechanism is unresolved
  10. 2024 Medium

    Identification of RNF115 as an E3 ligase that ubiquitinates CDK10 for proteasomal degradation defined a mechanism for CDK10 protein turnover and linked CDK10 loss to Raf-1 pathway activation in thyroid carcinoma.

    Evidence Co-IP, ubiquitination assay, rescue overexpression, in vivo tumor model

    PMID:38376606

    Open questions at the time
    • Specific ubiquitination sites on CDK10 not mapped
    • Whether RNF115-mediated degradation is tissue-specific is unknown
  11. 2024 Medium

    CDK10 silencing was shown to activate JNK/c-Jun signaling and confer radioresistance, expanding CDK10's tumor-suppressive role to a MAPK-independent axis.

    Evidence siRNA knockdown with pathway inhibitor/rescue experiments and radioresistance assays in lung cancer cells

    PMID:38919013

    Open questions at the time
    • Direct substrate linking CDK10 to JNK suppression not identified
    • Single lab, not independently replicated
  12. 2026 High

    An in vivo kinome CRISPR screen revealed CDK10 as a suppressor of innate immune activation, mechanistically through phosphorylation of DNMT1 and RAP80 to prevent dsRNA and R-loop accumulation and consequent MDA5/cGAS pathway engagement; pharmacological CDK10 inhibition enhanced antitumor immunity.

    Evidence In vivo CRISPR screen, in vitro kinase assay on DNMT1/RAP80, pharmacological inhibition (NVP-AST487, ponatinib), dsRNA/R-loop quantification, mouse tumor immunotherapy models

    PMID:41507536

    Open questions at the time
    • Specific phosphosites on DNMT1 and RAP80 responsible for immune suppression not fully mapped
    • Therapeutic window for CDK10 inhibition in immunotherapy not established
    • Partial functional compensation between CDK10 and CDK11 noted but not delineated mechanistically

Open questions

Synthesis pass · forward-looking unresolved questions
  • A comprehensive structural model of the CDK10/Cyclin M holoenzyme, the full spectrum of physiologically relevant substrates among the 66+ candidates, and the mechanistic basis for CDK10/CDK11 functional overlap remain to be established.
  • No crystal or cryo-EM structure of CDK10/CycM complex
  • Functional validation of most phosphoproteomic substrates is lacking
  • Tissue-specific and developmental stage-specific roles of CDK10 are incompletely characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0140110 transcription regulator activity 3
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-1640170 Cell Cycle 2 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-168256 Immune System 1
Partners
DNMT1ETS2FAM58APKN2RAP80RHOARNF115
Complex memberships
CDK10/Cyclin M (CycM/CCNQ)

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 CDK10 interacts with the N-terminus of the ETS2 transcription factor (containing the Pointed domain and transactivation domain) and inhibits ETS2 transactivation activity in mammalian cells; this interaction requires an intact Pointed domain on ETS2 and is specific (CDK10 does not bind ETS1 in two-hybrid assay). Yeast two-hybrid, in vitro binding assay, mammalian cell transactivation assay Oncogene High 11313931
1995 CDK10 (PISSLRE) is essential for cell growth and acts at the G2/M phase of the cell cycle; antisense and dominant-negative PISSLRE constructs suppressed growth and arrested cells at G2/M in U2OS cells. Antisense and dominant-negative overexpression with cell cycle analysis Cancer research Medium 7664269
2000 CDK10 is expressed as multiple isoforms with different translation initiation sites that have different subcellular distributions due to an alternatively spliced nuclear localization signal. RT-PCR isoform characterization, subcellular fractionation Biochemical and biophysical research communications Medium 11006117
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 tamoxifen resistance. RNAi screen, reporter assay, pathway activation measurement (MAPK readout) Cancer cell High 18242510
2006 Murine CDK10 binds ETS2 transcription factors in vitro and does not directly regulate the G2/M transition in mouse cell lines, indicating species-specific or isoform-specific differences in function. In vitro binding assay, cell cycle analysis of murine CDK10 overexpression Journal of cellular biochemistry Medium 16741970
2013 Cyclin M (product of FAM58A) is an activating cyclin for CDK10; CDK10/cyclin M complex phosphorylates ETS2 in vitro and promotes ETS2 degradation by the proteasome in cells. STAR syndrome-associated cyclin M mutants are unable to interact with CDK10. Cyclin M silencing phenocopies CDK10 silencing in increasing c-Raf and conferring tamoxifen resistance. Co-immunoprecipitation, in vitro kinase assay, proteasome inhibitor experiments, genetic complementation with STAR mutants, cyclin M siRNA 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 maintains actin network architecture, thereby suppressing primary cilia assembly and elongation. Unbiased phosphorylation substrate screen, in vitro kinase assay, site-directed mutagenesis of PKN2, RhoA rescue experiment, cilia imaging, STAR patient kidney sections Cell cycle High 27104747
2017 Bi-allelic loss-of-function CDK10 mutations in humans and Cdk10-knockout mice cause severe growth retardation, skeletal defects, and abnormal elongated cilia in MEFs, consistent with CDK10 functioning in ciliogenesis and transducing signals from primary cilia during development. Homozygosity mapping/exome sequencing, conditional knockout mice, MEF primary cilia measurement, comparative transcriptomics American journal of human genetics High 28886341
2017 CDK10 kinase activity is required for its tumor-suppressive function in colorectal cancer; kinase-defective CDK10 mutant cell lines show exaggerated apoptosis and reduced proliferation, and CDK10 upregulates Bcl-2 expression to suppress apoptosis. Kinase-dead mutant expression, apoptosis assays, in vivo xenograft with siRNA lentivirus Molecular cancer therapeutics Medium 28663269
2020 CDK10/cyclin M (CycM) phosphorylates a defined peptide substrate; known pan-CDK inhibitors (SNS-032, riviciclib, flavopiridol, dinaciclib, AZD4573, AT7519) and the CDK9-selective inhibitor NVP-2 potently inhibit CDK10/CycM in vitro, establishing pharmacological inhibitor sensitivity of this kinase. In vitro homogeneous miniaturized kinase assay with optimized peptide substrate, inhibitor profiling Frontiers in chemistry Medium 32175313
2021 CDK10/Cyclin Q (CycM) phosphorylates RNA pol II CTD, c-MYC, and RB1 in vitro; using an analogue-sensitive mutant kinase in HEK cells, 89 phosphosites on 66 proteins were identified, implicating CDK10 in cell cycle, translation, stress response, growth signaling, and rRNA/mRNA transcriptional regulation. CDK10 is itself phosphorylated in vitro by CDK1 and CDK5 at multiple sites. Recombinant protein in vitro kinase assay, analogue-sensitive kinase chemical genetics in cells, mass spectrometry phosphoproteomics Open biology High 35291876
2021 Truncated CDK10 and cyclin M variants associated with Al Kaissi and STAR syndromes retain the ability to heterodimerize; the CycM truncation partially activates CDK10 in vitro while the CDK10 truncation is kinase-inactive; both truncated variants are degraded by the proteasome in human cells. Insect cell recombinant expression, in vitro kinase assay, yeast two-hybrid, proteasome inhibitor treatment in human cells Molecular genetics & genomic medicine Medium 34369103
2024 RNF115, an E3 ubiquitin ligase, ubiquitinates CDK10 and promotes its proteasomal degradation in thyroid carcinoma cells, thereby activating the Raf-1 pathway; CDK10 overexpression counteracts RNF115-driven malignant phenotypes. Co-immunoprecipitation, ubiquitination assay, rescue overexpression, in vivo tumor model Cell biology and toxicology Medium 38376606
2026 CDK10 phosphorylates DNMT1 and RAP80, reducing accumulation of double-stranded RNA and R-loops, thereby suppressing MDA5 and cGAS innate immune pathway activation; CDK10 inhibition (genetic or pharmacological with NVP-AST487 or ponatinib) activates these pathways and enhances antitumor immunity in mouse models. CDK10 can partially compensate for CDK11 function in transcription. In vivo kinome CRISPR screen, in vitro kinase assay, inhibitor screens, mouse tumor immunotherapy models, R-loop and dsRNA accumulation assays Nature cancer High 41507536
2023 CDK10 binds to and promotes proteasomal degradation of ETS2 in lung adenocarcinoma cells, thereby suppressing ETS2-driven transcription of c-RAF and MMP2/9, inactivating the c-Raf/p-MEK/p-ERK pathway, and inhibiting EMT and metastasis; p-MEK/p-ERK provides positive feedback on ETS2 expression. Co-immunoprecipitation, protein degradation assays, pathway activation measurement, siRNA knockdown, xenograft lung metastasis model Molecular carcinogenesis Medium 37737453
2024 Silencing CDK10 in lung cancer cells activates the JNK/c-Jun signaling pathway, promoting cell proliferation, migration, and radioresistance; c-Jun depletion reverses the effects of CDK10 knockdown, placing CDK10 upstream of JNK/c-Jun. siRNA knockdown, pathway inhibitor/rescue experiments, radioresistance assays BMB reports Medium 38919013

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 30 22326270
2017 The awakening of the CDK10/Cyclin M protein kinase. Oncotarget 28 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
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 15 35291876
2021 CDK10 in Gastrointestinal Cancers: Dual Roles as a Tumor Suppressor and Oncogene. Frontiers in oncology 15 34277407
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 8 38376606
2021 Integrative Analysis of Omics Data Reveals Regulatory Network of CDK10 in Vitiligo Risk. Frontiers in genetics 7 33679896
2023 CDK10 suppresses metastasis of lung adenocarcinoma through inhibition of the ETS2/c-Raf/p-MEK/p-ERK signaling loop. Molecular carcinogenesis 6 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 3 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