Affinage

CDK16

Cyclin-dependent kinase 16 · UniProt Q00536

Length
496 aa
Mass
55.7 kDa
Annotated
2026-06-09
73 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDK16 (PCTAIRE1/PCTK1) is an atypical cyclin-dependent serine/threonine kinase that couples upstream signaling cues to cytoskeletal, secretory, mitotic, and autophagic programs across brain, testis, muscle, and cancer cells (PMID:1437147, PMID:22184064, PMID:25205104). Its catalytic domain carries a cysteine-for-serine substitution in the canonical PSTAIRE motif and is essentially inactive in isolation, becoming activated >100-fold upon binding cyclin Y, which CDK16 recognizes through both its cyclin box and an N-terminal extension of the kinase (PMID:1437147, PMID:22796189, PMID:41857027). Activation is gated by an integrated phosphorylation/adaptor logic: cyclin Y must itself be phosphorylated (S100/S326) to recruit 14-3-3, which remodels the cyclin Y CDK-binding surface and contacts the CDK16 activation segment to license activity, whereas PKA phosphorylation of CDK16 at S153 blocks cyclin Y binding and at S119 creates an inhibitory 14-3-3 site (PMID:12154078, PMID:22184064, PMID:26205494, PMID:41857027). CDK16 sits downstream of multiple kinases — Cdk5/p35 phosphorylates it at S95 to enhance activity in neuronal development, and AMPK phosphorylates cyclin Y at S326 to drive CDK16-dependent autophagy (PMID:12084709, PMID:21335063, PMID:32098961). Using a non-canonical substrate consensus (proline at +1, basic at +4), CDK16 phosphorylates a defined substrate set: NSF S569 to control oligomerization and exocytosis, p27 S10 to regulate its stability and mitosis, PRC1 T481 to govern spindle formation and cytokinesis, KAP0 S83 to direct integrin-dependent spindle orientation, and WIPI2B S395 to promote neuronal autophagosome biogenesis (PMID:16461345, PMID:22796189, PMID:25205104, PMID:25605337, PMID:30992425, PMID:41727099). Through these activities CDK16 localizes dynamically to centrosomes, spindle poles, and the midbody and is required for proper mitotic progression, p27 turnover, and tumor growth in NRAS/KRAS-mutant and triple-negative breast cancers (PMID:25205104, PMID:30992425, PMID:35044463, PMID:35449080). CDK16 also interacts with the COPII Sec23p subunit to support ER-to-Golgi cargo transport, and its protein level is stabilized in testis by the cyclin Y-like protein CCNYL1, loss of which — like loss of CDK16 itself — causes male infertility (PMID:16091426, PMID:22184064, PMID:26305884). Human CDK16 variants that abolish cyclin Y binding produce inactive enzyme and associate with intellectual disability (PMID:26205494).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1992 Medium

    Established CDK16 as a distinct cdc2-related kinase, raising the question of how a kinase with a degenerate PSTAIRE motif that fails to bind canonical CDK partners is regulated.

    Evidence in vitro transcription-translation with anti-cdc2 immunoprecipitation and p13suc1 binding assay

    PMID:1437147

    Open questions at the time
    • No activating partner identified
    • No substrate or cellular function defined
  2. 1997 Medium

    Identified the first physical partners (p11 and 14-3-3) and showed both termini, not just the catalytic core, mediate binding, hinting at regulatory rather than catalytic interactions.

    Evidence yeast two-hybrid of mouse brain library confirmed by recombinant protein binding

    PMID:9197417

    Open questions at the time
    • Functional consequence of p11/14-3-3 binding not defined
    • Did not establish whether these partners activate or inhibit the kinase
  3. 1999 Medium

    Localized CDK16 expression and activity to terminally differentiated neurons and spermatids and showed activity is cell-cycle modulated, framing it as a tissue-restricted, regulated kinase.

    Evidence endogenous immunoprecipitation-kinase assays (MBP), subcellular fractionation, IHC, and cell-cycle synchronization

    PMID:10099831 PMID:10511311

    Open questions at the time
    • Physiological substrates unknown
    • Mechanism linking tyrosine phosphorylation to activity not resolved
  4. 2002 High

    Defined upstream activating inputs: Cdk5/p35 phosphorylates CDK16 at S95 to enhance activity, while PKA phosphorylation (S153, S119) inhibits it and creates a 14-3-3 site, revealing phosphorylation as the activity switch.

    Evidence reciprocal Co-IP, in vitro kinase assays with site-directed mutagenesis, and Cdk5-null mouse analysis

    PMID:12084709 PMID:12154078

    Open questions at the time
    • The activating cyclin partner was still unidentified
    • How phosphorylation translates into substrate phosphorylation in vivo unclear
  5. 2005 High

    Connected CDK16 to membrane traffic by demonstrating it binds COPII Sec23p and is needed for early secretory cargo transport, extending its role beyond neuronal signaling.

    Evidence yeast two-hybrid, direct binding, Co-IP, kinase-dead dominant-negative and RNAi with cargo transport assays

    PMID:16091426

    Open questions at the time
    • No phosphorylated COPII substrate identified
    • Mechanism of Sec23p regulation not resolved
  6. 2006 High

    Identified NSF S569 as the first bona fide CDK16 substrate, linking the kinase to exocytosis via control of NSF oligomerization.

    Evidence yeast two-hybrid, direct binding, Co-IP, in vitro kinase assay with phosphosite mutagenesis, and growth hormone secretion assay in PC12 cells

    PMID:16461345

    Open questions at the time
    • In vivo contribution to neurotransmission not directly tested
    • Did not define the activating cyclin context
  7. 2011 High

    Resolved the activating partner by showing membrane-associated cyclin Y binds and activates CDK16 (blocked by PKA-S153 phosphorylation), and linked the kinase to spermatogenesis through conditional knockout-induced male infertility.

    Evidence Co-IP, GFP live imaging, pharmacological PKA manipulation, endogenous testis kinase assay, and conditional knockout phenotyping

    PMID:21335063 PMID:22184064

    Open questions at the time
    • Testis substrates underlying infertility not defined
    • Whether cyclin Y is the only relevant cyclin not addressed
  8. 2012 High

    Defined CDK16's non-canonical substrate consensus and quantified >100-fold activation by cyclin Y, providing the biochemical framework for substrate discovery and revealing additional regulatory inputs via BRSK2 (S12) in insulin secretion.

    Evidence positional scanning peptide library, in vitro reconstituted kinase assays, cyclin Y mutagenesis, and BRSK2 binding/kinase/GSIS assays

    PMID:22796189 PMID:22798068

    Open questions at the time
    • Endogenous substrates matching the consensus not yet enumerated
    • BRSK2-CDK16 axis tested only in beta-cell models
  9. 2014 High

    Established a pro-tumorigenic mitotic function by identifying p27 S10 as a substrate whose phosphorylation drives p27 degradation, mitotic progression, and tumor growth selectively in cancer cells.

    Evidence in vitro kinase assay, RNAi with p27-rescue epistasis, FACS cell-cycle analysis, and xenograft models

    PMID:25205104

    Open questions at the time
    • Why dependence is cancer-selective not fully explained
    • Direct link between p27 phosphorylation and centrosome defects not dissected
  10. 2015 High

    Defined the full activation logic — phospho-cyclin Y plus 14-3-3 — and expanded substrate scope to KAP0 S83 (integrin-dependent spindle orientation) and the CCNYL1-dependent stabilization required for fertility, while tying disease variants to loss of cyclin Y binding.

    Evidence cell-free reconstitution with cyclin Y phosphosite mutagenesis, phosphoproteomics/RNAi screens, Co-IP, knockout mice, and patient-variant functional assays

    PMID:25605337 PMID:26205494 PMID:26305884

    Open questions at the time
    • Tissue specificity of CCNY versus CCNYL1 activation not mechanistically resolved
    • Spectrum of intellectual-disability variants not exhaustively characterized
  11. 2017 High

    Provided structural and pharmacological insight, showing the isolated kinase domain is conformationally plastic and unstable without a cyclin and is druggable by type I and type II inhibitors, including dabrafenib, which acts on CDK16 to inhibit Rb phosphorylation and stabilize p27.

    Evidence X-ray co-crystal structures with inhibitors, cell-free kinase assays, and chemical proteomics with KD functional readouts

    PMID:28057719 PMID:29112787

    Open questions at the time
    • Structure of the full activated CDK16/cyclin Y/14-3-3 complex not yet resolved at this stage
    • On-target versus off-target inhibitor effects in cells incompletely separated
  12. 2019 High

    Identified PRC1 T481 as a mitotic substrate controlling cytokinesis and expanded the neuronal substrate set (AAK1, dynamin 1, synaptojanin 1), connecting CDK16 to spindle/midbody regulation and synaptic vesicle endocytosis.

    Evidence analog-sensitive CRISPR-engineered CDK16, MS proteomics, epistasis, and chemical-genetic screening in brain extracts

    PMID:30880224 PMID:30992425

    Open questions at the time
    • In vivo neuronal consequences of AAK1/dynamin/synaptojanin phosphorylation not established
    • How CDK16 is locally activated at the midbody unclear
  13. 2020 High

    Placed CDK16 downstream of AMPK in autophagy by showing AMPK phosphorylates cyclin Y at S326 to drive CDK16-dependent autophagosome formation, integrating CDK16 into energy-stress signaling.

    Evidence protein microarray substrate screen, in vitro kinase assay, Co-IP, and gain/loss-of-function autophagy assays with epistasis

    PMID:32098961

    Open questions at the time
    • Direct autophagy substrate of CDK16 not identified in this study
    • Generality across cell types not fully tested
  14. 2021 Medium

    Mapped CDK16 protein-stability control to AKT1 (stabilizing) versus LKB1 and BRCA1 (destabilizing) and resolved its dynamic mitotic localization to centrosomes, spindle poles, and midbody required for accurate division.

    Evidence Co-IP and stability assays; immunofluorescence across cell-cycle stages with siRNA spindle/segregation analysis

    PMID:33932497 PMID:35044463

    Open questions at the time
    • Stability interactions reported without phosphosite-level mechanism (Low-confidence interactions lacking reciprocal validation)
    • Recruitment mechanism to centrosome/midbody not defined
  15. 2022 Medium

    Translated the PRC1 axis to therapy, showing CDK16 promotes TNBC progression and metastasis through PRC1 phosphorylation and is targetable with rebastinib in vivo.

    Evidence siRNA, rebastinib inhibition, xenograft/PDX and metastasis models, and PRC1 phosphorylation immunoblotting

    PMID:35449080

    Open questions at the time
    • Rebastinib specificity for CDK16 in vivo not fully isolated
    • Contribution of other CDK16 substrates to TNBC not assessed
  16. 2026 High

    Achieved atomic-resolution understanding of activation, showing 14-3-3 remodels the cyclin Y CDK-binding surface and contacts the CDK16 activation segment, while cyclin Y engages the CDK16 N-terminal extension, and defined WIPI2B S395 as a CDK16 substrate counterbalanced by PP2A in neuronal autophagy.

    Evidence cryo-EM and HDX-MS of the activation complex; in vitro reconstitution with purified CDK16/PP2A, C. elegans epistasis, and neuronal imaging (WIPI2B finding preprint)

    PMID:41727099 PMID:41857027

    Open questions at the time
    • Structural basis of substrate selection still unresolved
    • WIPI2B/autophagy finding is a preprint awaiting peer review

Open questions

Synthesis pass · forward-looking unresolved questions
  • How distinct upstream cues (Cdk5, AMPK, PKA, copper, cyclin Y versus CCNYL1) are integrated to select among CDK16's many substrates in a tissue- and cell-cycle-specific manner remains unresolved.
  • No unifying model for substrate selection across contexts
  • Copper-binding and CDK16-JAK1 activation reported in a single low-confidence study
  • Spatial/temporal coordination of activation and localization not mechanistically defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016740 transferase activity 4 GO:0098772 molecular function regulator activity 3 GO:0140657 ATP-dependent activity 1
Localization
GO:0005829 cytosol 3 GO:0005730 nucleolus 1 GO:0005815 microtubule organizing center 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 3 R-HSA-1474165 Reproduction 2 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-9612973 Autophagy 2
Partners
BRSK2CCNYCCNYL1CDK5R1JAK1S100A10SEC23AYWHAZ
Complex memberships
CDK16-cyclin Y-14-3-3 complex

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 PCTAIRE-1 (CDK16) encodes a putative serine/threonine kinase with a kinase domain ~50-55% homologous to cdc2/CDC28 family members, containing a cysteine-for-serine substitution in the conserved PSTAIRE motif. The translated product failed to bind p13suc1 but was precipitated by antibodies to Schizosaccharomyces pombe p34cdc2 or the human PSTAIRE motif, establishing it as a novel cdc2-related kinase subfamily member. In vitro transcription-translation, immunoprecipitation with anti-cdc2 antibodies, p13suc1 binding assay Oncogene Medium 1437147
1997 PCTAIRE-1 associates with p11 (calpactin I light chain) and 14-3-3 isoforms (eta, theta/tau, zeta) in mouse brain. Both interactions were identified by yeast two-hybrid screening and confirmed by direct binding with pure recombinant proteins. Interaction with p11 and 14-3-3 requires both the N-terminal and C-terminal ends of PCTAIRE-1, not just the catalytic core. Yeast two-hybrid screening of mouse brain cDNA library, direct binding assay with recombinant proteins Molecular & general genetics : MGG Medium 9197417
1998 Brain PCTAIRE-1 purified via p11 or 14-3-3 affinity resins followed by immunoprecipitation displayed significant kinase activity, confirming it is an active kinase in brain. Full interaction with p11 and 14-3-3 requires both N- and C-terminal domains of PCTAIRE-1. Affinity purification with p11/14-3-3 resins, immunoprecipitation, kinase activity assay European journal of biochemistry Medium 9799109
1999 Pctaire1 is expressed as two major proteins (~62 kDa and ~68 kDa) predominantly in testis and brain, localizing to the cytoplasm of terminally differentiated pyramidal neurons and elongated spermatids. Immunoprecipitation from adult testis and brain demonstrated kinase activity toward myelin basic protein, and this activity was potentially regulated through association with regulatory partner(s). Immunoprecipitation, kinase assay (MBP substrate), subcellular fractionation, immunohistochemistry Cell growth & differentiation Medium 10099831
1999 PCTAIRE-1 exhibits cytoplasmic distribution throughout the cell cycle and does not colocalize with cytoskeleton components or endoplasmic reticulum. Endogenous PCTAIRE-1 kinase activity (using MBP substrate) is cell cycle-dependent, peaking in S and G2 phases, and low kinase activity until S phase onset correlates with elevated tyrosine phosphorylation of the molecule. Indirect immunofluorescence, confocal microscopy, immunoprecipitation-kinase assay, cell cycle synchronization Cell growth & differentiation Medium 10511311
2000 PCTAIRE-1 localizes to multiple subcellular compartments in brain: diffuse distribution in most regions and spot-like localization in nucleoli of large neurons (Purkinje cells, hippocampal pyramidal cells), identified by colocalization with nucleolar marker B23. Immunolabeling with PCTAIRE-1-specific antibody, colocalization with B23 nucleolar marker, confocal microscopy Molecular and cellular neurosciences Medium 11085876
2002 Pctaire1 interacts with p35 (the Cdk5 activator) both in vitro and in vivo in muscle and brain. Pctaire1 is phosphorylated by Cdk5/p25 at Ser95 as the major site. In Cdk5 null mice, Pctaire1 kinase activity is significantly reduced, and phosphorylation by Cdk5/p25 complex enhances Pctaire1 kinase activity. In vitro binding assay, co-immunoprecipitation, in vitro kinase assay, Cdk5 knockout mice analysis The Journal of biological chemistry High 12084709
2002 Bacterially expressed PCTAIRE-1 is completely inactive but is a good PKA substrate; PKA phosphorylates four N-terminal sites. Phosphorylation of Ser119 creates a functional 14-3-3 binding site in vitro and in vivo. Mutation of PKA site Ser153 to Ala generates an activated kinase in transfected mammalian cells, with activity comparable to CDK5/p21. Gel filtration of brain extracts suggested monomeric PCTAIRE-1 may be the active species. In vitro kinase assay (PKA phosphorylation), site-directed mutagenesis, 14-3-3 binding assay, gel filtration of brain extracts, mammalian cell transfection Journal of cell science High 12154078
2005 PCTAIRE kinases interact directly with the Sec23p subunit of the COPII complex, as shown by yeast two-hybrid, direct binding, and co-immunoprecipitation. Inhibition of PCTAIRE kinase activity (kinase-dead mutant expression) or siRNA-mediated depletion causes defects in early secretory pathway cargo transport, VTC formation, and Golgi localization. Yeast two-hybrid, direct binding assay, co-immunoprecipitation, kinase-dead dominant-negative expression, RNAi knockdown, secretory cargo transport assays Journal of cell science High 16091426
2006 Pctaire1 phosphorylates NSF (N-ethylmaleimide-sensitive fusion protein) at Ser569 on its D2 domain, which is required for NSF oligomerization. The S569A mutation augments NSF self-association. Inhibition of Pctaire1 (kinase-dead mutant) enhances NSF self-association in COS-7 cells. Expression of Pctaire1-KD or NSF-S569A in PC12 cells significantly increases high K+-stimulated growth hormone release, revealing a role for Pctaire1 in regulating exocytosis through NSF hexamerization control. Yeast two-hybrid, direct binding assay, co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, growth hormone secretion assay in PC12 cells The Journal of biological chemistry High 16461345
2010 MRTF-A/MRTF-B (Mkl1/Mkl2) transcription factors regulate Pctaire1 (Cdk16) expression. Conditional deletion of MRTFs in mice leads to dysregulation of Pctaire1, which cooperates with Cdk5 to initiate a kinase cascade governing cytoskeletal rearrangements essential for neuronal migration and neurite outgrowth. Epistatic analysis places Pctaire1 downstream of the MRTF/SRF transcriptional partnership in brain development. Conditional gene knockout in mice, genetic epistasis analysis, brain structure analysis Development Medium 20534669
2011 CDK16 is activated by membrane-associated cyclin Y (CCNY). Binding of CCNY to CDK16 requires a region upstream of the kinase domain. Phosphorylation of Ser153 on CDK16 (a PKA site) inhibits CCNY binding. Treatment with PKA activator forskolin blocks, while kinase inhibition promotes, CCNY-dependent membrane targeting of CDK16-GFP. CDK16 from murine testis was unphosphorylated, interacted with CCNY, and exhibited kinase activity. Conditional CDK16 knockout mice develop normally but male mice are infertile with spermatozoa showing thinned annulus, bent shape, impaired motility, and malformed heads. Co-immunoprecipitation, GFP live-cell imaging, pharmacological manipulation (forskolin/kinase inhibitors), immunoprecipitation-kinase assay from testis, conditional knockout mouse generation and phenotypic analysis Molecular and cellular biology High 22184064
2011 Cdk5-dependent phosphorylation of Pctaire1 at Ser95 is required for dendrite development. Pctaire1 localizes along neurites and at growth cones in early hippocampal neurons, and as puncta colocalized with synaptic markers in dendrites of mature neurons. Knockdown of Pctaire1 abolishes dendrite development, and a Ser95-phosphorylation-deficient mutant also reduces dendrite complexity. siRNA knockdown, site-directed mutagenesis (S95A), immunocytochemistry, live-cell imaging in hippocampal neurons Neuroscience Medium 21335063
2012 BRSK2 interacts with PCTAIRE1 (CDK16) and phosphorylates it at Ser12. BRSK2 and PCTAIRE1 co-localize in the cytoplasm of MIN6 β-cells. Phosphorylation of PCTAIRE1 at Ser12 by BRSK2 reduces glucose-stimulated insulin secretion (GSIS) in MIN6 cells. Conversely, siRNA knockdown of BRSK2 increases serum insulin levels in mice. Yeast two-hybrid, GST pulldown, co-immunoprecipitation, immunofluorescence colocalization, in vitro kinase assay, siRNA knockdown, glucose-stimulated insulin secretion assay, in vivo mouse studies The Journal of biological chemistry High 22798068
2012 PCTAIRE-1 has a unique substrate consensus motif: requires proline at +1 and a basic residue at +4 (but not +3) relative to the phosphorylation site, distinct from conventional CDKs. A peptide substrate (PCTAIRE-tide) based on this motif dramatically improved kinase assay sensitivity. Cyclin Y binding to PCTAIRE-1 increases kinase activity >100-fold toward PCTAIRE-tide; point mutations in cyclin Y predicted to disrupt PCTAIRE-1 binding prevented complex formation and activation. Positional scanning peptide library, in vitro kinase assay, peptide substrate optimization, site-directed mutagenesis of cyclin Y, co-immunoprecipitation Cellular signalling High 22796189
2014 PCTAIRE1 phosphorylates tumor suppressor p27 at Ser10 in vitro. PCTAIRE1 silencing reduces Ser10 phosphorylation on p27 and leads to p27 accumulation in cancer cells but not nontransformed cells. Epistasis analysis showed that p27 silencing rescues mitotic arrest caused by PCTAIRE1 silencing. In xenograft mouse models, conditional PCTAIRE1 silencing restores p27 protein levels and suppresses tumor growth. PCTAIRE1 silencing causes centrosome dynamics defects and aberrant mitosis in cancer cells. Yeast two-hybrid, in vitro kinase assay, RNAi, FACS cell cycle analysis, xenograft mouse model, genetic epistasis (p27 rescue of PCTAIRE1 KD phenotype) Cancer research High 25205104
2014 Pctaire1/Cdk16 promotes skeletal myoblast migration and fusion during myogenesis. Overexpression promotes myogenic differentiation and fusion; knockdown inhibits these processes, establishing a functional role in skeletal muscle development based on cytoskeletal regulation mechanisms. Overexpression, siRNA knockdown, myogenic differentiation assays, cell migration assays FEBS letters Medium 24931367
2015 CCNYL1 (cyclin Y-like 1), but not CCNY, is required for male fertility in mice. CCNYL1 interacts with CDK16, and this interaction mutually stabilizes both proteins and increases CDK16 kinase activity. N-terminal phosphorylation sites on CDK16 identified by mass spectrometry are required for CCNYL1 binding and modulation of CDK16 kinase activity. In Ccnyl1-/- mice, CDK16 protein (but not mRNA) levels decrease in testis. Knockout mouse generation, co-immunoprecipitation, in vitro kinase assay, mass spectrometry phosphorylation site mapping, site-directed mutagenesis PLoS genetics High 26305884
2015 PCTK1 (CDK16) regulates integrin-dependent spindle orientation through phosphorylation of Ser83 on KAP0 (regulatory subunit of PKA). Phospho-Ser83 on KAP0 is dispensable for KAP0 dimerization and PKA binding but required for interaction with myosin X, a spindle orientation regulator. KAP0 binds the FERM domain of myosin X and enhances myosin X-FERM association with β1 integrin, linking ECM to spindle orientation. Phosphoproteomic analysis, RNAi screen, in vitro kinase assay, site-directed mutagenesis (KAP0 S83), co-immunoprecipitation, spindle orientation assays Molecular and cellular biology High 25605337
2015 Phosphorylated cyclin Y (pSer100/pSer326) in complex with 14-3-3 proteins activates PCTAIRE-1/CDK16. Recombinant wild-type cyclin Y (prepared in COS-1 cells) co-purified with 14-3-3 and activated bacterially expressed PCTAIRE-1 in cell-free assays, while S100A/S326A cyclin Y mutant failed to bind 14-3-3 and failed to activate PCTAIRE-1. CDK16 variants associated with intellectual disability in patients were unable to interact with cyclin Y and were inactive enzymes. Mass spectrometry phosphosite identification, site-directed mutagenesis, recombinant protein purification, cell-free kinase activation assay, co-immunoprecipitation The Biochemical journal High 26205494
2017 Crystal structures of CDK16 kinase domain were determined in complex with inhibitors indirubin E804 (active conformation) and rebastinib (DFG-out/inactive conformation). The structures revealed conformational plasticity of the CDK16 kinase domain and that the ATP-binding pocket can accommodate both type I and type II inhibitors. Dabrafenib and rebastinib were identified as the most potent CDK16 inhibitors. The structures suggest the isolated kinase domain is relatively unstable without a cyclin partner. X-ray crystallography (co-crystal structures with inhibitors), cell-free kinase assay, cell-based inhibitor assays The Biochemical journal High 28057719
2017 CDK16 knockdown inhibits phosphorylation of the Rb protein at S780 and increases expression of p27 in NRAS- and KRAS-mutant cancer cells, phenocopied by dabrafenib treatment. Mass spectrometry-based chemical proteomics identified CDK16 as a unique direct target of dabrafenib (but not vemurafenib). Mass spectrometry-based chemical proteomics, siRNA knockdown, immunoblotting for pRb-S780 and p27 Molecular oncology Medium 29112787
2019 CDK16/CCNY complex phosphorylates PRC1 (protein regulator of cytokinesis 1) at Thr481. Using analog-sensitive CDK16 generated by CRISPR-Cas9, specific CDK16 inhibition induces PRC1 dephosphorylation at Thr481 and PRC1 delocalization to the nucleus during interphase. CDK16 inhibition and PRC1 downregulation exhibit epistatic effects on cell viability, placing them in the same pathway. Analog-sensitive CDK16 generated by CRISPR-Cas9, mass spectrometry proteomics for substrate identification, immunoblotting for PRC1 phosphorylation, genetic epistasis (CDK16 inhibition + PRC1 KD) Experimental & molecular medicine High 30992425
2019 Chemical genetic screen using engineered PCTAIRE-1/cyclin Y complex in mouse brain extracts identified AAK1 (AP2-Associated Kinase 1), dynamin 1, and synaptojanin 1 as novel CDK16 substrates involved in receptor endocytosis and synaptic transmission control. PCTAIRE-1-regulated phosphorylation sites on AAK1 were identified by MS and validated in cellular studies and brain tissue lysates. Chemical genetic screen (engineered kinase + thiophosphate labeling), mass spectrometry phosphosite identification, cellular validation, brain tissue lysate validation Cellular signalling Medium 30880224
2020 AMPK phosphorylates cyclin Y at Ser326. This phosphorylation promotes cyclin Y interaction with CDK16, stimulating CDK16 catalytic activity. The CCNY/CDK16 complex is sufficient to promote autophagy when expressed in cells, and is necessary for efficient AMPK-dependent autophagy activation. This places CDK16 downstream of AMPK in the autophagy induction pathway. Protein microarray (AMPK substrate screen), in vitro kinase assay, co-immunoprecipitation, autophagy assays (autophagosome formation), genetic loss-of-function, epistasis Nature communications High 32098961
2021 AKT1 interacts with and stabilizes PCTAIRE1 protein. LKB1 interacts with PCTAIRE1 and promotes its degradation. BRCA1 also interacts with PCTAIRE1 and promotes its degradation. These interactions place CDK16 protein stability at the intersection of PI3K/AKT and energy-sensing/tumor suppressor pathways. Co-immunoprecipitation, protein stability assays (cycloheximide chase implied), immunoblotting Cellular signalling Low 33932497
2021 CDK16 (PCTAIRE1) localizes to centrosomes during G2, to spindle poles as cells enter mitosis, and to the midbody during cytokinesis. CDK16 protein levels and phosphorylation peak at mitosis. Knockdown of PCTAIRE1 results in aberrant mitosis with defects in spindle assembly and chromosome segregation. PCTAIRE1 was also identified among candidates promoting resistance to mitotic arrest induced by polyomavirus small T expression. Library screening, immunofluorescence localization across cell cycle stages, siRNA knockdown with spindle assembly and chromosome segregation analysis, cell cycle-dependent protein level/phosphorylation analysis Journal of cell science Medium 35044463
2022 CDK16 phosphorylates PRC1 (protein regulator of cytokinesis 1) to regulate spindle formation during mitosis in TNBC cells. Genetic knockdown and pharmacological inhibition (rebastinib) of CDK16 suppress TNBC tumor progression and metastasis in vitro and in vivo, and this function is mediated through PRC1 phosphorylation. siRNA knockdown, pharmacological inhibition (rebastinib), xenograft and patient-derived organoid/xenograft models, lung/systemic metastasis mouse models, transcriptomic analysis, immunoblotting for PRC1 phosphorylation Journal of experimental & clinical cancer research : CR Medium 35449080
2025 Copper directly binds to CDK16 kinase and activates it, which in turn enhances CDK16 binding to and activation of JAK1 kinase, upregulating c-Myc and cyclin D1 transcription in TNBC cells. STEAP3 overexpression increases intracellular copper, promoting this cascade. In vitro and in vivo experiments with copper chelation (tetrathiomolybdate), co-immunoprecipitation, xenograft models, gain/loss-of-function studies Cancer letters Low 41338444
2026 Cryo-EM structure and hydrogen/deuterium exchange mass spectrometry revealed that 14-3-3 binding modulates the conformation of the CDK binding surface of cyclin Y, enabling CDK16 activation. CDK16 interacts with the cyclin box of CCNY; 14-3-3 provides additional contacts including with the activation segment of CDK16. CDK16 activation also requires interactions of CCNY with the N-terminal extension of CDK16. Cryo-EM structural analysis, hydrogen/deuterium exchange mass spectrometry (HDX-MS), biophysical characterization Nature communications High 41857027
2026 CDK16 phosphorylates WIPI2B at Ser395 to regulate neuronal autophagosome biogenesis. PP2A antagonistically dephosphorylates WIPI2B at S395. Purified mammalian PP2A and CDK16 directly modified WIPI2B S395 phosphorylation in vitro. In C. elegans, PP2A and CDK16 regulate neuronal autophagy through the same genetic pathway as WIPI2B. In primary murine neurons, PP2A and CDK16 colocalize with WIPI2B at autophagosomes, and manipulation of their expression altered WIPI2B puncta formation and autophagosome biogenesis rates. In vitro kinase/phosphatase assays with purified proteins, C. elegans genetic epistasis, primary murine neuron imaging, colocalization by immunofluorescence, gain/loss-of-function autophagosome biogenesis assays bioRxivpreprint High 41727099

Source papers

Stage 0 corpus · 73 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Myocardin-related transcription factors regulate the Cdk5/Pctaire1 kinase cascade to control neurite outgrowth, neuronal migration and brain development. Development (Cambridge, England) 104 20534669
1992 PCTAIRE-1 and PCTAIRE-3, two members of a novel cdc2/CDC28-related protein kinase gene family. Oncogene 103 1437147
2011 Cyclin-dependent kinase 16/PCTAIRE kinase 1 is activated by cyclin Y and is essential for spermatogenesis. Molecular and cellular biology 99 22184064
2005 PCTAIRE protein kinases interact directly with the COPII complex and modulate secretory cargo transport. Journal of cell science 84 16091426
1996 X inactivation analysis and DNA methylation studies of the ubiquitin activating enzyme E1 and PCTAIRE-1 genes in human and mouse. Human molecular genetics 72 8852665
2002 Regulation of the CDK-related protein kinase PCTAIRE-1 and its possible role in neurite outgrowth in Neuro-2A cells. Journal of cell science 68 12154078
2006 Pctaire1 phosphorylates N-ethylmaleimide-sensitive fusion protein: implications in the regulation of its hexamerization and exocytosis. The Journal of biological chemistry 58 16461345
2002 Pctaire1 interacts with p35 and is a novel substrate for Cdk5/p35. The Journal of biological chemistry 53 12084709
2014 PCTAIRE1 phosphorylates p27 and regulates mitosis in cancer cells. Cancer research 52 25205104
2018 Fisetin decreases TET1 activity and CCNY/CDK16 promoter 5hmC levels to inhibit the proliferation and invasion of renal cancer stem cell. Journal of cellular and molecular medicine 47 30411496
2016 Lipid Nanoparticle-mediated siRNA Transfer Against PCTAIRE1/PCTK1/Cdk16 Inhibits In Vivo Cancer Growth. Molecular therapy. Nucleic acids 47 27351680
2015 CCNYL1, but Not CCNY, Cooperates with CDK16 to Regulate Spermatogenesis in Mouse. PLoS genetics 46 26305884
1999 The cellular distribution and kinase activity of the Cdk family member Pctaire1 in the adult mouse brain and testis suggest functions in differentiation. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 45 10099831
1997 PCTAIRE 2, a Cdc2-related serine/threonine kinase, is predominantly expressed in terminally differentiated neurons. European journal of biochemistry 43 9370357
2012 Brain-selective kinase 2 (BRSK2) phosphorylation on PCTAIRE1 negatively regulates glucose-stimulated insulin secretion in pancreatic β-cells. The Journal of biological chemistry 40 22798068
1999 PCTAIRE-1: characterization, subcellular distribution, and cell cycle-dependent kinase activity. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 40 10511311
2022 CDK16 promotes the progression and metastasis of triple-negative breast cancer by phosphorylating PRC1. Journal of experimental & clinical cancer research : CR 39 35449080
2017 Dabrafenib inhibits the growth of BRAF-WT cancers through CDK16 and NEK9 inhibition. Molecular oncology 39 29112787
2017 Structure and inhibitor specificity of the PCTAIRE-family kinase CDK16. The Biochemical journal 38 28057719
2020 AMPK-dependent activation of the Cyclin Y/CDK16 complex controls autophagy. Nature communications 35 32098961
1997 The Cdk-like protein PCTAIRE-1 from mouse brain associates with p11 and 14-3-3 proteins. Molecular & general genetics : MGG 35 9197417
2000 Identification of tudor repeat associator with PCTAIRE 2 (Trap). A novel protein that interacts with the N-terminal domain of PCTAIRE 2 in rat brain. European journal of biochemistry 34 10727952
2016 Potential role of PCTAIRE-2, PCTAIRE-3 and P-Histone H4 in amyloid precursor protein-dependent Alzheimer pathology. Oncotarget 28 26885753
2017 PCTAIRE1/CDK16/PCTK1 is overexpressed in cutaneous squamous cell carcinoma and regulates p27 stability and cell cycle. Journal of dermatological science 27 28274513
2019 Phosphoregulation of the oncogenic protein regulator of cytokinesis 1 (PRC1) by the atypical CDK16/CCNY complex. Experimental & molecular medicine 26 30992425
1998 Characterization of brain PCTAIRE-1 kinase immunoreactivity and its interactions with p11 and 14-3-3 proteins. European journal of biochemistry 26 9799109
2015 PCTK1 regulates integrin-dependent spindle orientation via protein kinase A regulatory subunit KAP0 and myosin X. Molecular and cellular biology 25 25605337
2014 PCTAIRE kinase 3/cyclin-dependent kinase 18 is activated through association with cyclin A and/or phosphorylation by protein kinase A. The Journal of biological chemistry 25 24831015
2006 The regulation of tau phosphorylation by PCTAIRE 3: implications for the pathogenesis of Alzheimer's disease. Neurobiology of disease 25 16766195
1993 The isolation from a unicellular organism, Dictyostelium discoideum, of a highly-related cdc2 gene with characteristics of the PCTAIRE subfamily. Biochimica et biophysica acta 25 8218353
2014 Pctaire1/Cdk16 promotes skeletal myogenesis by inducing myoblast migration and fusion. FEBS letters 24 24931367
2011 Enhanced expression of Pctk1, Tcf12 and Ccnd1 in hippocampus of rats: Impact on cognitive function, synaptic plasticity and pathology. Neurobiology of learning and memory 24 21982980
2014 PCTAIRE1 regulates p27 stability, apoptosis and tumor growth in malignant melanoma. Oncoscience 22 25593992
2011 Cyclin-dependent kinase 5-dependent phosphorylation of Pctaire1 regulates dendrite development. Neuroscience 20 21335063
2000 Multiple subcellular localizations of PCTAIRE-1 in brain. Molecular and cellular neurosciences 20 11085876
2020 circRNA 001306 enhances hepatocellular carcinoma growth by up-regulating CDK16 expression via sponging miR-584-5p. Journal of cellular and molecular medicine 19 33135290
2015 PCTAIRE1-knockdown sensitizes cancer cells to TNF family cytokines. PloS one 19 25790448
2015 Cyclin Y phosphorylation- and 14-3-3-binding-dependent activation of PCTAIRE-1/CDK16. The Biochemical journal 19 26205494
2012 Analysis of substrate specificity and cyclin Y binding of PCTAIRE-1 kinase. Cellular signalling 19 22796189
2023 Baicalin Blocks Colon Cancer Cell Cycle and Inhibits Cell Proliferation through miR-139-3p Upregulation by Targeting CDK16. The American journal of Chinese medicine 18 36599649
2018 CDK16 overexpressed in non-small cell lung cancer and regulates cancer cell growth and apoptosis via a p27-dependent mechanism. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 18 29674275
2017 Up-regulation of CDK16 by multiple mechanisms in hepatocellular carcinoma promotes tumor progression. Journal of experimental & clinical cancer research : CR 18 28716136
2015 RNA interference screening identifies a novel role for PCTK1/CDK16 in medulloblastoma with c-Myc amplification. Oncotarget 18 25402633
1994 Cloning of genomic loci and chromosomal localization of the human PCTAIRE-1 and -3 protein kinase genes. Genomics 18 8088790
2021 Lung cancer cells expressing a shortened CDK16 3'UTR escape senescence through impaired miR-485-5p targeting. Molecular oncology 16 34687270
2020 Transcriptomic Analysis in Liquid Biopsy Identifies Circulating PCTAIRE-1 mRNA as a Biomarker in NSCLC. Cancer genomics & proteomics 16 31882554
2023 The roles, molecular interactions, and therapeutic value of CDK16 in human cancers. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 14 37236028
2021 Proteomic investigation of Cbl and Cbl-b in neuroblastoma cell differentiation highlights roles for SHP-2 and CDK16. iScience 12 33889818
2015 Upregulated CDK16 Expression in Serous Epithelial Ovarian Cancer Cells. Medical science monitor : international medical journal of experimental and clinical research 12 26546806
2016 miR-33a is downregulated in melanoma cells and modulates cell proliferation by targeting PCTAIRE1. Oncology letters 11 27073545
2019 Identification of novel PCTAIRE-1/CDK16 substrates using a chemical genetic screen. Cellular signalling 10 30880224
2013 Genetic variation in MKL2 and decreased downstream PCTAIRE1 expression in extreme, fatal primary human microcephaly. Clinical genetics 10 23692340
2004 Cloning and expression analysis of two novel PCTAIRE 3 transcripts from human brain. Gene 10 15019984
2022 LncRNA HCG18 facilitates melanoma progression by modulating miR-324-5p/CDK16 axis. American journal of translational research 9 35273726
2022 PCTAIRE1 promotes mitotic progression and resistance against antimitotic and apoptotic signals. Journal of cell science 8 35044463
2022 Discovery of 3-Amino-1H-pyrazole-Based Kinase Inhibitors to Illuminate the Understudied PCTAIRE Family. International journal of molecular sciences 8 36499165
2020 New tricks of an old autophagy regulator: AMPK-dependent regulation of autophagy through CCNY (cyclin Y)-CDK16. Autophagy 8 32401167
1996 Expression of alternatively spliced PCTAIRE-1 mRNA in PC12 cells and neonatal rat brain. Gene 8 8918260
1998 UHX1 and PCTK1: precise characterisation and localisation within a gene-rich region in Xp11.23 and evaluation as candidate genes for retinal diseases mapped to Xp21.1-p11.2. European journal of human genetics : EJHG 6 9801870
2021 Regulation of PCTAIRE1 protein stability by AKT1, LKB1 and BRCA1. Cellular signalling 5 33932497
1995 Physical linkage of the cdc2-related gene (PCTK1) and the ubiquitin-activating enzyme E1 gene (UBE1) on human Xp11.3. Cytogenetics and cell genetics 5 7656587
2021 Long non-coding RNA TPT1-AS1 alleviates cell injury and promotes the production of extracellular matrix by targeting the microRNA-324-5p/CDK16 axis in human dermal fibroblasts after thermal injury. Experimental and therapeutic medicine 4 34149889
2025 CDK16+ Luminal Progenitor Cell-Like Tumor Cells Interacted with POSTN+ Cancer-Associated Fibroblasts Associate with Chemo-Resistance In Breast Cancer. Small methods 2 39930931
2025 Copper orchestrates triple-negative breast cancer progression via the STEAP3-dependent CDK16-JAK1 activation. Cancer letters 1 41338444
2023 PCTAIRE Protein Kinase 1 (PCTK1) Suppresses Proliferation, Stemness, and Chemoresistance in Colorectal Cancer through the BMPR1B-Smad1/5/8 Signaling Pathway. International journal of molecular sciences 1 37373155
2019 Retraction Note: Up-regulation of CDK16 by multiple mechanisms in hepatocellular carcinoma promotes tumor progression. Journal of experimental & clinical cancer research : CR 1 31122280
2005 Generation and characterization of monoclonal antibodies to human PCTAIRE 3. Hybridoma (2005) 1 15857174
2026 Single-cell RNA-Seq reveals transcriptional heterogeneity in sepsis and down-regulation of SNHG5/miR-324-5p/CDK16 axis in T cells. Cell biology and toxicology 0 41673232
2026 PP2A and CDK16 antagonistically regulate WIPI2B phosphorylation and neuronal autophagosome biogenesis. bioRxiv : the preprint server for biology 0 41727099
2026 Structural basis of the cyclin Y/14-3-3 protein-mediated activation of CDK16. Nature communications 0 41857027
2026 Computer-aided discovery of CDK16 inhibitors: a docking-augmented machine learning regression modelling approach. Journal of computer-aided molecular design 0 41940903
2026 UBA1-CDK16: A female-specific chimeric RNA emerging through evolution and involved in immune regulation. Science advances 0 42213831
2024 UBA1-CDK16 : A Sex-Specific Chimeric RNA and Its Role in Immune Sexual Dimorphism. bioRxiv : the preprint server for biology 0 38405903

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