Affinage

CDK2

Cyclin-dependent kinase 2 · UniProt P24941

Length
298 aa
Mass
33.9 kDa
Annotated
2026-06-09
100 papers in source corpus 47 papers cited in narrative 47 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

CDK2 is a cyclin-dependent serine/threonine kinase that drives the G1-to-S transition and DNA replication in the mammalian cell cycle (PMID:8502482, PMID:7698977). Its activity requires association with cyclin E (in G1) or cyclin A (at S-phase entry) and is gated by phosphorylation: activating phosphorylation at Thr160 — installed by autophosphorylation or chaperone-assisted maturation as an Hsp90/Cdc37 client (PMID:17361108, PMID:16285732) — is required for catalysis, while inhibitory Thr14/Tyr15 phosphorylation suppresses it and is reversed by CDC25 phosphatase (PMID:1396589, PMID:1517236). Activation reflects allosteric coupling between T-loop phosphorylation and cyclin binding, with monomeric CDK2 sampling an active-like but inactive state until cyclin engagement strengthens this coupling (PMID:33526892). Once active, cyclin E/CDK2 phosphorylates the retinoblastoma protein to relieve E2F repression and phosphorylates p27Kip1 at Thr187 to trigger its degradation, coupling mitogenic signaling to S-phase commitment (PMID:1518810, PMID:9192873, PMID:1398067); CDK2 activity at the licensed origin is required for origin unwinding and primer synthesis (PMID:7698977, PMID:18256689). CDK2 activity is held in check by the CIP/KIP inhibitors p21 and p27, which can act either as tight-binding inhibitors or substrates depending on enzyme and ATP levels, and the level of CDK2 activity at mitotic exit — set by p21 — bifurcates cells into proliferation or quiescence (PMID:10393546, PMID:9192873, PMID:24075009). CDK2 is non-redundant for meiosis: kinase-dead knockin mice are sterile with intact mitosis, and CDK2 controls telomere–nuclear envelope attachment (phosphorylating SUN1) and meiotic crossover formation at late recombination nodules (PMID:27371320, PMID:25380821, PMID:33075054). Beyond the canonical cycle, CDK2 phosphorylates a range of substrates including FOXO1 (linking DNA damage to apoptotic control), c-Myc at Ser62, SMRT, NICD1, ING5 and CK1δ, and has cell-cycle-independent roles in neutrophil chemotaxis (PMID:17038621, PMID:31431461, PMID:18838553, PMID:31267714, PMID:31451657). CDK2 is largely dispensable for proliferation of many cancer cells because CDK1, CDK4/6, and cyclin A redundancy can compensate, a redundancy that also underlies adaptation to CDK2 inhibitors (PMID:12676582, PMID:16678773, PMID:37267950).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1992 High

    Established how CDK2 catalytic output is switched on and off, defining the dual phosphorylation logic that gates a cell-cycle kinase.

    Evidence Site-directed mutagenesis and in vitro phosphatase assays in human and Xenopus systems mapping activating Thr160 and inhibitory Thr14/Tyr15 sites reversed by CDC25

    PMID:1396589 PMID:1517236

    Open questions at the time
    • Did not identify the activating Thr160 kinase (CAK) in these experiments
    • Upstream control of CDC25 toward CDK2 not addressed
  2. 1992 High

    Connected CDK2 to the RB/E2F machinery and showed cyclin E versus cyclin A partner cyclins act in temporally distinct windows, placing CDK2 at the G1/S control point.

    Evidence In vitro kinase assays with purified CDK2 against RB and cell-cycle-staged immunoprecipitation of cyclin E/A complexes with E2F/p107

    PMID:1398067 PMID:1518810

    Open questions at the time
    • Causal requirement for CDK2 in vivo not yet demonstrated
    • Functional consequence of RB phosphorylation on E2F release not shown here
  3. 1993 High

    Demonstrated CDK2 is functionally required for entry into S phase, moving it from correlation to causation.

    Evidence Microinjection of anti-CDK2 antibodies into quiescent fibroblasts with antigen pre-adsorption rescue and kinase activity measurement

    PMID:8502482

    Open questions at the time
    • Does not distinguish cyclin E from cyclin A complex contributions
    • Critical S-phase substrates not identified
  4. 1995 High

    Defined the specific replication step requiring CDK2, showing it acts at origin unwinding/initiation rather than chromatin organization.

    Evidence CDK2 immunodepletion in Xenopus egg extracts with primer synthesis and RPA localization readouts

    PMID:7698977

    Open questions at the time
    • Direct replication-machinery substrates of CDK2 not identified
    • Relative contribution of CDK1 not addressed in this study
  5. 1997 High

    Resolved how CDK2 escapes its own inhibitor, establishing the feed-forward p27-Thr187 phosphodegron and the substrate-versus-inhibitor duality of CIP/KIP proteins.

    Evidence In vitro kinase assays with T187A mutagenesis, ATP-dependent kinetics, and expression in fibroblasts; Ras/Myc cooperation linked to p27 loss and CDK2 activation

    PMID:9163430 PMID:9192873

    Open questions at the time
    • E3 ligase mediating p27 degradation not characterized here
    • Mechanism of the ATP-dependent inhibitor-to-substrate switch left open
  6. 1999 High

    Quantified CDK2 substrate preference and inhibitor stoichiometry, and identified redundant inhibitors (p130, cyclin D1) that buffer CDK2 activity.

    Evidence In vitro kinetics with purified CAK-phosphorylated CDK2/cyclin E, p27 inhibition assays, p27/p21 double-knockout MEFs, and cyclin D1/PCNA co-IP

    PMID:10074425 PMID:10393546 PMID:9925749

    Open questions at the time
    • Physiological relevance of cyclin D1-CDK2-PCNA complex limited to senescent context
    • Redundancy hierarchy among inhibitors in normal cells unresolved
  7. 2001 High

    Revealed that CDK2 can be activated through a non-canonical, Thr160-independent route, expanding the modes of CDK2 control.

    Evidence In vitro reconstitution of RINGO/Speedy–CDK2 complexes with T-loop mutagenesis and p21 inhibition assays; later substrate profiling showed broad specificity and CAK independence

    PMID:11461916 PMID:16191191

    Open questions at the time
    • In vivo contexts where RINGO activation dominates not defined
    • Endogenous RINGO–CDK2 substrate set in cells not mapped
  8. 2003 High

    Genetic ablation overturned the view of CDK2 as essential for the mitotic cycle, revealing dispensability for proliferation but absolute requirement for meiosis.

    Evidence Cdk2 knockout mice and cancer-cell loss-of-function (dominant-negative, antisense, siRNA) with kinase and proliferation assays

    PMID:12676582 PMID:14561402

    Open questions at the time
    • Molecular basis of compensation not yet identified in 2003
    • Meiotic substrates of CDK2 not defined
  9. 2006 High

    Identified the compensating kinases and a DNA-damage-linked substrate, explaining CDK2 redundancy in mitosis and a non-canonical apoptotic role.

    Evidence Cdk2/Cdk4 double-knockout mice with RB phosphorylation and E2F readouts plus HPV-E7/p27 epistasis; in vitro and in vivo FOXO1-Ser249 phosphorylation with checkpoint epistasis

    PMID:16678773 PMID:17038621

    Open questions at the time
    • Quantitative apportioning of RB phosphorylation between CDK2 and CDK4 unclear
    • How Chk1/Chk2 suppress CDK2 toward FOXO1 mechanistically not detailed
  10. 2008 High

    Showed CDK2 controls replication origin activation frequency in concert with CDK1 and extended the substrate repertoire to transcriptional corepressors.

    Evidence Depletion and chemical inhibition in Xenopus egg extracts with origin spacing analysis; SMRT phosphorylation creating Pin1 docking sites by co-IP and mutagenesis

    PMID:18256689 PMID:18838553

    Open questions at the time
    • Direct origin-firing substrates of CDK2 not identified
    • Generality of SMRT regulation across cell types untested
  11. 2009 Medium

    Linked CDK2 T160 activation to genome-surveillance signals — DNA damage, origin licensing, and p53 — establishing checkpoint-coupled control of CDK2.

    Evidence CDK2-/- and Chk1-/- DT40 cells with T160A rescue (centrosome amplification); siRNA depletion of licensing factors with p53 epistasis and CDK2 kinase/fractionation readouts; CAC1 co-IP

    PMID:19440053 PMID:19829063 PMID:19838212

    Open questions at the time
    • CAC1-CDK2 activation mechanism is a single Co-IP without reconstitution
    • How licensing status is transduced to T160 phosphorylation not resolved
  12. 2011 Medium

    Distinguished catalytic from non-catalytic CDK2 functions and uncovered an endosomal signaling role, broadening CDK2 beyond a cell-cycle kinase.

    Evidence Analog-sensitive CDK2 allele with bulky adenine analogs for restriction-point passage and CDK1/cyclin A restriction; endosomal fractionation/Co-IP and knockdown for the SHP-1/β-catenin insulin-internalization axis

    PMID:21262353 PMID:21658603

    Open questions at the time
    • β-catenin substrate assignment rests on Co-IP and knockdown without in vitro reconstitution (Low-confidence endosomal arm)
    • Structural basis of the non-catalytic cyclin A/CDK1 restriction function unknown
  13. 2016 High

    Demonstrated that CDK2 catalytic activity, not the protein per se, drives meiosis and identified additional cell-cycle substrates.

    Evidence Kinase-dead (D145N, T160A) knockin mice with meiotic sterility but normal mitosis; in vitro/in-cell phosphorylation of ING5-Thr152 and CK1δ

    PMID:25860957 PMID:26464264 PMID:27371320

    Open questions at the time
    • Meiotic substrates accounting for sterility not fully enumerated
    • Physiological impact of ING5/CK1δ phosphorylation in normal tissues limited
  14. 2014 High

    Defined CDK2's role in the proliferation-quiescence decision and showed its loss, combined with cyclin A2, suppresses tumorigenesis.

    Evidence Live-cell CDK2 activity sensor with single-cell imaging and p21 manipulation; conditional Cdk2/cyclin A2 double knockout in oncogene-transformed MEF tumor assays

    PMID:24075009 PMID:24802190 PMID:26464264

    Open questions at the time
    • Upstream determinants of the bifurcation beyond p21 not fully mapped
    • Whether the quiescence decision involves the same substrates as proliferation unclear
  15. 2021 High

    Provided the biophysical mechanism of CDK2 activation and metabolic coupling, explaining how cyclin binding, T160 phosphorylation, and redox state converge on activity.

    Evidence Solution biophysics, NMR/EPR and thermodynamic modeling of allosteric T-loop/cyclin coupling; ROS/cysteine-oxidation interference with live-cell CDK2 reporters showing blockade of KAP phosphatase binding

    PMID:33526892 PMID:35809563

    Open questions at the time
    • In vivo significance of the allosteric hub divergence between CDK2/CDK4 not tested functionally
    • Source and timing of the S-phase ROS signal not fully defined
  16. 2022 Medium

    Expanded CDK2 into replication-stress, immune, and host-pathogen contexts and revealed its targetability through PPI disruption and degradation.

    Evidence WEE1/CDK2/DNA2 epistasis by DNA fiber assays; CDK2-RB-E2F-DNMT1-ERV-IFN pathway via genetic/pharmacological loss; CDK2 phosphorylation of SARS-CoV-2 nsp12-Thr20; HHT-induced Trim21-mediated autophagic CDK2 degradation; c-Myc-Ser62/miR-571 axis

    PMID:31431461 PMID:35045293 PMID:35181784 PMID:35595767 PMID:36575184

    Open questions at the time
    • Several substrate/pathway assignments derive from single labs without reciprocal validation
    • Direct fork-protection substrate downstream of CDK2 not identified
  17. 2023 High

    Resolved how cells adapt to CDK2 inhibition and validated allosteric, cyclin-cooperative inhibitors with CDK2 selectivity.

    Evidence Multiple CDK2 inhibitors with substrate phosphoproteomics showing CDK4/6 backstopping; crystal structures of type II, covalent, and type III allosteric inhibitors with cooperativity measurements and testicular-explant phenotyping

    PMID:26158339 PMID:26320860 PMID:37267950 PMID:37270540

    Open questions at the time
    • Durability of combination CDK2/CDK4/6 inhibition in vivo not fully established
    • Selectivity determinants against CDK1 only partially mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • The full set of physiological CDK2 substrates underlying its non-redundant meiotic function and its cell-cycle-independent roles (e.g., neutrophil migration) remains to be defined.
  • Meiotic crossover and telomere-attachment substrates beyond SUN1 not enumerated
  • Mechanism by which CDK2 controls neutrophil polarity/FPR signaling unknown
  • How context selects canonical versus non-canonical CDK2 substrate sets unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 9 GO:0016740 transferase activity 4 GO:0140657 ATP-dependent activity 2 GO:0098772 molecular function regulator activity 1
Localization
GO:0005634 nucleus 2 GO:0000228 nuclear chromosome 1 GO:0005768 endosome 1
Pathway
R-HSA-1474165 Reproduction 3 R-HSA-1640170 Cell Cycle 3 R-HSA-69306 DNA Replication 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-73894 DNA Repair 2
Partners
CCNA2CCNE1CDC25CDC37CDKN1ACDKN1BHSP90RB1
Complex memberships
Hsp90/Cdc37 chaperone complexcyclin A/CDK2cyclin E/CDK2

Evidence

Reading pass · 47 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 CDK2 activity is regulated by phosphorylation: Thr160 phosphorylation is required for kinase activity (T160A abolishes activity), while Tyr15 and Thr14 phosphorylation are inhibitory (mutation of Y15/T14 stimulates activity). CDC25 phosphatase activates CDK2 by dephosphorylating Y15/T14 in vitro. Site-directed mutagenesis, transient transfection in COS cells, in vitro phosphatase assay, cell cycle synchronization The EMBO journal High 1396589
1992 CDK2 phosphorylates the retinoblastoma protein (RB) in vitro at sites phosphorylated in vivo, and CDK2 forms a complex with RB in vitro. The timing of CDK2 activation correlates with onset of RB phosphorylation in the cell cycle. In vitro kinase assay with purified CDK2, co-precipitation/complex formation assay Proceedings of the National Academy of Sciences of the United States of America High 1518810
1992 Cyclin E and cyclin A each associate with CDK2 in a temporally distinct manner during the cell cycle: cyclin E/CDK2 appears in G1 and associates with E2F and p107, while cyclin A/CDK2 association with E2F becomes detectable as cells enter S phase. Immunoprecipitation with cyclin-specific antisera, cell cycle synchronization Genes & development High 1398067
1992 In Xenopus, CDK2 is regulated by periodic phosphorylation on tyrosine and serine residues during the cell cycle; CDC25 phosphatase dephosphorylates CDK2 at the major in vivo phosphorylation site and activates it in vitro. Phosphopeptide mapping, in vitro CDC25 dephosphorylation assay, immunoprecipitation The Journal of biological chemistry High 1517236
1993 CDK2 is required for the G1-to-S phase transition in mammalian cells; microinjection of anti-CDK2 antibodies blocked cells from entering S phase, and the effect was abrogated by pre-adsorption with CDK2 protein. Cyclin E/CDK2 complex accounts for the majority of histone H1 kinase activity in late G1. Antibody microinjection into serum-stimulated quiescent human fibroblasts, immunoprecipitation/kinase assay Oncogene High 8502482
1995 CDK2 kinase is required for activating the origin unwinding step of DNA replication; in CDK2-depleted Xenopus egg extracts, primer synthesis does not occur and RPA remains tightly associated with replication foci. Organization of chromatin into replication foci is CDK2-independent and precedes CDK2 activation. Cell-free Xenopus egg extract replication system, CDK2 immunodepletion, primer synthesis assay, RPA localization The Journal of cell biology High 7698977
1997 Cyclin E/CDK2 directly phosphorylates p27Kip1 at Thr187 in vitro and in vivo, leading to p27 elimination from the cell and allowing G1-to-S progression. Mutation of T187 to alanine creates a p27 resistant to cyclin E-driven degradation. p27 interacts with cyclin E/CDK2 in two ways: as a tight inhibitor (at low ATP) or as a substrate (at physiological ATP), governed by ATP binding to CDK2. In vitro kinase assay, mutagenesis (T187A), transient expression in murine fibroblasts, cell cycle analysis Genes & development High 9192873
1997 Ras and Myc cooperate to induce accumulation of active cyclin E-dependent CDK2 kinase activity and E2F target gene expression; this cooperative activation is associated with loss of the p27 CDK inhibitor. Ras alone is insufficient to induce cyclin E-CDK2 activity. Ras inhibition (dominant negative), Myc/Ras co-expression, CDK kinase assays, cell cycle analysis in Rb+/+ and Rb-/- fibroblasts Nature Medium 9163430
1999 p27 acts as a tight-binding inhibitor of CDK2/Cyclin E; CDK2/Cyclin E has ~60-fold higher specificity for pRb than histone H1. The CDK2/Cyclin E/p27 ternary complex is kinetically inactive as a kinase but serves as a substrate for CDK2/Cyclin E. p27 can be phosphorylated by CDK2/Cyclin E only at high enzyme concentrations. In vitro kinase assay with purified recombinant proteins (CAK-phosphorylated CDK2/Cyclin E, p27), kcat/Km determination, inhibition kinetics Biochemistry High 10393546
1999 p130 (Rb family member) directly substitutes for p27 and p21 as a CDK2 inhibitor in mitogen-starved fibroblasts; cyclin E-CDK2 kinase activity cannot be inhibited by mitogen starvation in cells lacking both p27 and p130. MEFs from p27/p21 double knockout mice, CDK2 activity assays, p130 identification as titratable CDK2 inhibitor Current biology : CB Medium 10074425
1999 Cyclin D1 forms complexes with PCNA and CDK2 in senescent cells; excess cyclin D1 inhibits CDK2 kinase activity and represses DNA replication in vitro. Overexpression of CDK2 or PCNA rescues the cyclin D1-mediated inhibition of DNA synthesis. Co-immunoprecipitation, in vitro kinase assay (GST-cyclin D1), in vitro DNA replication assay, rescue by CDK2/PCNA overexpression Experimental cell research Medium 9925749
2000 PKCη associates with the cyclin E/CDK2/p21 complex in keratinocytes, phosphorylates p21 within the complex, and inhibits CDK2 kinase activity (measured by Rb phosphorylation). This is accompanied by dephosphorylation of Thr160 on CDK2. Co-immunoprecipitation, in vitro kinase assay, dominant-negative PKCη, immunofluorescence colocalization Oncogene Medium 11175348
2001 RINGO (Speedy) activates CDK2 independently of Thr160 phosphorylation; CDK2-RINGO complexes are less susceptible to inhibition by p21 than cyclin-bound CDK2. RINGO can bind and stimulate CDK2 kinase activity without the T-loop phosphorylation required for cyclin-activated CDK2. In vitro kinase assays with RINGO-CDK2 complexes, T161A mutagenesis, p21 inhibition assays The Journal of biological chemistry High 11461916
2003 CDK2 knockout mice are viable but sterile; Cdk2 is required for germ cell development and meiosis. In Cdk2-/- cells, cyclin E1 immunoprecipitates show no kinase activity toward histone H1. CDK2 loss affects the timing of S phase entry but does not prevent cell proliferation, with cyclin A2 complexes maintaining activity. Gene knockout mice, immunoprecipitation/kinase assay, cell cycle analysis, MEF proliferation assays, ectopic CDK2 re-expression rescue Current biology : CB High 14561402
2003 CDK2 is dispensable for proliferation in multiple cancer cell types (colon cancer, osteosarcoma, Rb-negative cervical cancers); inhibition of CDK2 by dominant-negative CDK2, antisense oligonucleotides, or siRNA did not prevent cell proliferation in these cells. Dominant-negative CDK2 expression, antisense oligonucleotides, siRNA knockdown, cell proliferation assays Cancer cell Medium 12676582
2005 CDK2 is a genuine client of the Hsp90/Cdc37 chaperone complex; disruption of helix αC of CDK2 disrupts Hsp90 and Cdc37 binding. The G-box motif of CDK2 is critical for Cdc37 binding, while helix αC and stabilization of helix αE are required for Hsp90 binding. Pull-down assays, Hsp90 inhibitor (geldanamycin) treatment, deletion mutagenesis, molybdate stabilization Biochemistry Medium 16285732
2005 Biochemical characterization of CDK2-Speedy/Ringo A2 shows it has broad substrate specificity (unlike the canonical (S/T)PX(K/R) preference of CDK2-cyclin A), phosphorylates Cdc25 proteins nearly as well as CDK2-cyclin A at non-canonical sites, and its activity and substrate recognition are not significantly affected by Thr160 phosphorylation. CDK2-Speedy/Ringo A2 is not a substrate for metazoan CAK. In vitro kinase assays with purified proteins, phosphopeptide mapping, CAK phosphorylation assay, Thr160A mutagenesis BMC biochemistry High 16191191
2006 Cdk2 and Cdk4 cooperate to phosphorylate Rb in vivo; Cdk2-/-Cdk4-/- double knockout mice die embryonically (~E15) with progressive reduction of Rb phosphorylation and reduced E2F-target gene expression. HPV-E7 inactivation of Rb rescues DKO MEF phenotypes (senescence, proliferation), but p27 loss does not. Double knockout mice, western blot for Rb phosphorylation, MEF proliferation/senescence assays, genetic epistasis with HPV-E7 and p27 knockout Developmental cell High 16678773
2006 CDK2 directly phosphorylates FOXO1 at Ser249 in vitro and in vivo, causing cytoplasmic localization and inhibition of FOXO1. This phosphorylation is abrogated upon DNA damage through the Chk1/Chk2 checkpoint pathway. CDK2-mediated inhibition of FOXO1 regulates apoptotic cell death after DNA strand breakage. In vitro kinase assay, in vivo phosphorylation, siRNA knockdown, subcellular localization assays, checkpoint kinase inhibition Science (New York, N.Y.) High 17038621
2007 CDK2 is capable of autophosphorylation at Thr160; bacterially expressed monomeric CDK2 is phosphorylated at Thr160 and exhibits kinase activity toward histone H1 that is stimulated by cyclin E or A. Pharmacological CDK2 inhibition or co-expression of p21/p27 inhibits Thr160 phosphorylation in human cells. Bacterial expression/purification, mass spectrometry phosphopeptide mapping, mutagenesis (K33R, T160A), lambda phosphatase treatment, CDK2 inhibitor treatment in cells Cell cycle (Georgetown, Tex.) High 17361108
2008 CDK2 phosphorylates SMRT transcriptional corepressor at multiple sites, creating a phosphorylation-dependent binding site for the Pin1 prolyl isomerase, which decreases SMRT protein stability and affects SMRT-dependent transcriptional repression. Her2/Neu/ErbB2 signaling functions upstream of both Pin1 and CDK2 to regulate SMRT stability. Co-immunoprecipitation (in vitro and in mammalian cells), mutagenesis of phosphorylation sites, protein stability assays The Journal of cell biology Medium 18838553
2008 Both Cdk1 and Cdk2 are necessary for efficient DNA replication in Xenopus egg extracts by controlling origin activation frequency; Cdk2/cyclin E contributes more to origin cluster efficiency than Cdk1/cyclin A. CDK activity controls the pre-replication complex to pre-initiation complex transition at low activity levels. Protein depletion and selective chemical inhibition in Xenopus egg extracts, DNA replication and origin spacing analysis The EMBO journal High 18256689
2009 DNA damage induces Chk1-dependent activating T160 phosphorylation of CDK2 and increases CDK2 activity; this CDK2 upregulation promotes centrosome amplification after ionizing radiation. CDK1 can substitute for CDK2 in IR-induced centrosome amplification. T160A mutation blocks CDK2-mediated rescue of centrosome amplification. CDK2-/- and Chk1-/- DT40 cells, kinase activity assays, immunofluorescence, CDK2 T160A mutagenesis, rescue experiments Oncogene High 19838212
2009 Depletion of origin licensing factors (Cdc6 or Cdt1) inhibits cyclin E/CDK2 activity in normal cells through reduction of activating T160 phosphorylation and delayed nuclear CDK2 accumulation; this Cdk2 inhibition requires p53. CDK2 activity is uncoupled from origin licensing in p53-deficient cancer cells. siRNA depletion, CDK2 kinase assay, T160 phosphorylation western blot, CDK2 subcellular fractionation, p53 co-depletion epistasis Cell cycle (Georgetown, Tex.) Medium 19440053
2011 CDK2 has a non-catalytic function in restricting assembly of cyclin A with CDK1; a sensitizing mutation in CDK2 impaired this function, which could be corrected by both inhibitory and non-inhibitory bulky adenine analogs. Chemical-genetic approach revealed CDK2 activity is required for restriction point passage and S phase entry in human cells. Chemical genetics with analog-sensitive CDK2 allele, bulky adenine analog inhibition and rescue, cell cycle analysis Molecular cell High 21658603
2013 CDK2 activity bifurcates at mitotic exit to control the proliferation-quiescence decision: cells either immediately build up CDK2 activity (commit to next cycle) or suppress CDK2 activity and enter transient quiescence (G0-like state). This bifurcation is directly controlled by the CDK inhibitor p21, and regulated by mitogens during a restriction window at the end of the previous cell cycle. Live-cell CDK2 activity sensor, single-cell imaging, p21 manipulation Cell High 24075009
2014 CDK2 ablation combined with cyclin A2 loss strongly suppresses tumor formation in oncogene-transformed MEFs, associated with decreased proliferation, premature senescence, and failure of compensatory Cdk1 activity increase (which occurs with cyclin A2 loss alone). Conditional double knockout mice, oncogene-transformed MEF tumor formation assays, Cdk1 kinase activity measurement Cancer research Medium 24802190
2014 CDK2 is required for nuclear envelope dynamics and telomere attachment during mouse meiotic prophase I; CDK2 ablation causes abnormal distribution of SUN1, KASH5, and lamin C2 in spermatocytes, and some telomeres fail to attach to the nuclear envelope. Mouse testis CDK2 phosphorylates SUN1 in vitro. Immunofluorescence and electron microscopy of Cdk2-/- spermatocytes, in vitro kinase assay with SUN1 substrate Journal of cell science Medium 25380821
2015 Wild-type CDK2 can bind type II inhibitors that target the DFG-out (inactive) conformation; type II inhibitors compete with binding of activating cyclins to CDK2. Key residues distant from the ATP-binding pocket modulate the energetics of the DFG-out transition. Site-directed mutagenesis, protein crystallography (first CDK2/type II inhibitor co-crystal structure), biochemical/biophysical inhibitor binding assays ACS chemical biology High 26158339
2015 An irreversible CDK2 inhibitor (NU6300) binds covalently to CDK2, confirmed by co-complex crystal structure. Acute treatment produced durable inhibition of Rb phosphorylation in cells, consistent with irreversible CDK2 inhibition. Crystal structure of CDK2/NU6300 covalent complex, cell-based Rb phosphorylation assay Chemistry & biology High 26320860
2016 CDK2 catalytic activity is essential for meiotic cell division in vivo; kinase-dead CDK2 knockin mice (D145N or T160A) are sterile with defective meiosis, identical to Cdk2 knockout mice. These point mutant mice show normal mitotic cell cycle progression, demonstrating the meiotic function is specifically kinase-activity-dependent. Knockin mouse generation (D145N, T160A point mutations), phenotypic analysis, cell cycle analysis in MEFs, reproductive organ analysis The Biochemical journal High 27371320
2019 CDK2 has a non-canonical role in regulating neutrophil migration and cell polarity, independent of its cell cycle functions; CDK2 inhibition or knockdown disrupts neutrophil chemotaxis and polarization without inducing cell death, and alters downstream formyl peptide receptor signaling in terminally differentiated neutrophils. miRNA screen in zebrafish, CDK2 inhibition and siRNA knockdown in zebrafish and human neutrophil-like cells, chemotaxis assay, cell polarity imaging Proceedings of the National Academy of Sciences of the United States of America Medium 31451657
2019 CDK1 and CDK2 phosphorylate Notch intracellular domain (NICD1) in a domain required for SCF E3 ligase recognition; inhibiting CDK1 or CDK2 increases NICD1 levels in vitro and in vivo and delays segmentation clock oscillation period. In vitro kinase assay with CDK1 and CDK2, CDK inhibitor treatment in vivo, NICD1 protein level measurement, clock period analysis EMBO reports Medium 31267714
2020 CDK2 localizes to late recombination nodules (LRNs) at meiotic crossover sites; elevated CDK2 activity increases MLH1 focus numbers at LRNs but not crossover numbers, while reduced CDK2 activity abolishes crossover formation entirely during meiotic prophase I. CDK2 activity point mutant knockin mice (elevated/reduced activity), immunofluorescence of LRN proteins, crossover analysis PLoS biology Medium 33075054
2021 Allosteric coupling between CDK2 regulatory phosphorylation (Thr160) and cyclin binding explains CDK2 activation; monomeric CDK2 samples an active-like state but lacks activity; T-loop phosphorylation enhances allosteric coupling with cyclin. An allosteric hub diverged between CDK2 and CDK4 governs the strength of allosteric coupling and differential inhibitor recognition. Solution biophysics, thermodynamic modeling, NMR/EPR spectroscopy, functional assays Nature chemical biology High 33526892
2022 Mitochondrial ROS promote CDK2 T-loop (Thr160) phosphorylation and full CDK2 activation during S phase by oxidizing a conserved cysteine residue near the T-loop, which prevents binding of the T-loop phosphatase KAP, thereby coupling mitochondrial metabolism to DNA replication via CDK2. Chemical/metabolic ROS interference, live-cell CDK2 activity reporters, phosphorylation assays, cysteine mutagenesis Developmental cell High 35809563
2022 Disrupting the CDK2/Cyclin A protein-protein interaction (PPI) with homoharringtonine (HHT) induces autophagic degradation of CDK2 via Trim21 E3 ubiquitin ligase in cancer cells, confirmed in a leukemia mouse model. In silico PPI pocket screening, protein interaction disruption assay, CDK2 degradation assay, Trim21 identification, leukemia mouse model Nature communications Medium 35595767
2022 CDK2 inhibition reduces RB phosphorylation, decreases E2F-mediated DNMT1 transcription, and increases endogenous retroviral RNA expression and type I IFN response, enhancing antitumor immunity through increased antigen presentation and CD8+ T-cell infiltration. CDK2 small molecule inhibitors, genetic Cdk2 deficiency in murine tumor models, IFN response measurement, T-cell infiltration analysis Cancer immunology research Medium 35181784
2022 WEE1 kinase protects stalled DNA replication forks by suppressing CDK2 activity; CDK2 suppression is the major WEE1-dependent activity counteracting fork degradation, and DNA2 nuclease is responsible for excessive fork degradation in WEE1-inhibited cells. WEE1 inhibition, CDK2 inhibition, DNA fiber assays, DNA2 knockdown epistasis Cell reports Medium 35045293
2022 SARS-CoV-2 nsp12 (RdRp) interacts with host CDK2; CDK2 phosphorylates nsp12 at Thr20, facilitating assembly of the RdRp complex (nsp12/nsp7/nsp8) and promoting viral RNA synthesis. CDK2 inhibitors impair viral RNA synthesis and SARS-CoV-2 infection. Mass spectrometry-based proteomics, Co-IP, in vitro phosphorylation assay, CDK2 inhibitor treatment, viral RNA measurement Signal transduction and targeted therapy Medium 36575184
2023 Upon acute CDK2 inhibition, CDK4/6 activity backstops CDK2 by maintaining Rb1 hyperphosphorylation, active E2F transcription, and cyclin A2 expression, enabling re-activation of CDK2 in the presence of drug. CDK1 does not compensate for acute CDK2 inhibition (unlike in Cdk2-/- mice). Co-inhibition of CDK2 and CDK4/6 is required to suppress adaptation. Multiple CDK2 inhibitors, phosphoproteomics of CDK2 substrates, cell cycle analysis, combination drug treatment Cell High 37267950
2023 Type III allosteric CDK2 inhibitors (anthranilic acid series) bind CDK2 with nanomolar affinity and exhibit strong negative cooperativity with cyclin binding, providing CDK2 selectivity over CDK1. These inhibitors recapitulate Cdk2-/- meiotic phenotypes in testicular explants. Crystal structure, biophysical binding assays, cellular CDK2 activity assays, mouse testicular explant phenotypic assay Nature communications High 37270540
2011 Endosomal CDK2 associates with SHP-1 phosphatase and β-catenin in hepatic endosome fractions; CDK2 phosphorylates β-catenin (but not CEACAM1), and partial CDK2 downmodulation increases insulin internalization rate, placing CDK2 in a Cdk2/SHP-1/β-catenin/CEACAM1 axis regulating insulin internalization. Subcellular fractionation, Triton X-100 resistance assay, co-immunoprecipitation, CDK2 knockdown, insulin internalization assay Cellular signalling Low 21262353
2009 CAC1 (Cdk-Associated Cullin1), a novel cullin-domain protein, physically associates with CDK2 and promotes CDK2 kinase activity; CAC1 knockdown by RNAi inhibits cell proliferation and induces G1/S arrest. Co-immunoprecipitation, CDK2 kinase activity assay after CAC1 knockdown, RNAi, cell cycle analysis Cell cycle (Georgetown, Tex.) Low 19829063
2016 CDK2/Cyclin E and CDK2/Cyclin A phosphorylate ING5 at Thr152 in vitro; this phosphorylation occurs in cells in a cell cycle-dependent manner, and is enhanced by cyclin E/CDK2 overexpression and repressed by p27KIP1. In vitro kinase assay, phosphosite mutagenesis, cell cycle-dependent phosphorylation analysis, CDK2/cyclin overexpression and p27 inhibition PloS one Medium 25860957
2016 CDK2/Cyclin E phosphorylates CK1δ at its C-terminal domain, and this phosphorylation reduces CK1δ activity in vitro; pre-incubation of CK1δ with CDK2/E reduces CK1δ activity, and CDK inhibition with dinaciclib increases CK1δ activity in pancreatic cancer cells. In vitro kinase assay, CK1δ activity assay after CDK2/E phosphorylation, CDK inhibitor treatment in cells Amino acids Medium 26464264
2019 CDK2 phosphorylates c-Myc at Serine 62 at the beginning of S phase, promoting c-Myc association with the miR-571 promoter and suppressing miR-571 expression to prevent aberrant DNA rereplication; this Cdk2-c-Myc-miR-571 axis regulates DNA replication and genomic stability. ChIP assay, c-Myc phospho-Ser62 detection, miR-571 promoter reporter, CDK2 inhibition and overexpression Cancer research Medium 31431461

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2. Nucleic acids research 1370 26861625
1997 Cyclin E-CDK2 is a regulator of p27Kip1. Genes & development 802 9192873
1992 Cell cycle regulation of CDK2 activity by phosphorylation of Thr160 and Tyr15. The EMBO journal 627 1396589
2003 Cdk2 knockout mice are viable. Current biology : CB 572 14561402
2013 The proliferation-quiescence decision is controlled by a bifurcation in CDK2 activity at mitotic exit. Cell 561 24075009
1992 Cyclin E/cdk2 and cyclin A/cdk2 kinases associate with p107 and E2F in a temporally distinct manner. Genes & development 456 1398067
2003 Proliferation of cancer cells despite CDK2 inhibition. Cancer cell 424 12676582
1997 Myc and Ras collaborate in inducing accumulation of active cyclin E/Cdk2 and E2F. Nature 416 9163430
1993 The cdk2 kinase is required for the G1-to-S transition in mammalian cells. Oncogene 338 8502482
2006 CDK2-dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage. Science (New York, N.Y.) 293 17038621
2019 Targeting CDK2 in cancer: challenges and opportunities for therapy. Drug discovery today 248 31839441
1992 Phosphorylation of the retinoblastoma protein by cdk2. Proceedings of the National Academy of Sciences of the United States of America 227 1518810
2021 Cyclin E/CDK2: DNA Replication, Replication Stress and Genomic Instability. Frontiers in cell and developmental biology 210 34901021
2011 MicroRNA miR-885-5p targets CDK2 and MCM5, activates p53 and inhibits proliferation and survival. Cell death and differentiation 127 21233845
2006 Combined loss of Cdk2 and Cdk4 results in embryonic lethality and Rb hypophosphorylation. Developmental cell 126 16678773
2023 Rapid adaptation to CDK2 inhibition exposes intrinsic cell-cycle plasticity. Cell 119 37267950
2024 Lactylation-driven FTO targets CDK2 to aggravate microvascular anomalies in diabetic retinopathy. EMBO molecular medicine 114 38297099
1998 Analysis of cyclin E and CDK2 in ovarian cancer: gene amplification and RNA overexpression. International journal of cancer 114 9426687
2021 Discovery of a first-in-class CDK2 selective degrader for AML differentiation therapy. Nature chemical biology 112 33664520
2005 Cdk1 and Cdk2 complexes (cyclin dependent kinases) in apoptosis: a role beyond the cell cycle. Cancer letters 107 15617830
1999 A new pathway for mitogen-dependent cdk2 regulation uncovered in p27(Kip1)-deficient cells. Current biology : CB 105 10074425
2014 Loss of Cdk2 and cyclin A2 impairs cell proliferation and tumorigenesis. Cancer research 100 24802190
2007 Mice thrive without Cdk4 and Cdk2. Molecular oncology 97 19383288
2018 CDK2 inhibitors as candidate therapeutics for cisplatin- and noise-induced hearing loss. The Journal of experimental medicine 95 29514916
2022 Inhibition of the CDK2 and Cyclin A complex leads to autophagic degradation of CDK2 in cancer cells. Nature communications 89 35595767
2022 A ROS-dependent mechanism promotes CDK2 phosphorylation to drive progression through S phase. Developmental cell 87 35809563
2015 Identification and Characterization of an Irreversible Inhibitor of CDK2. Chemistry & biology 87 26320860
2015 Type II Inhibitors Targeting CDK2. ACS chemical biology 85 26158339
1996 p21 Disrupts the interaction between cdk2 and the E2F-p130 complex. Molecular and cellular biology 79 8622674
2005 Cell cycle sibling rivalry: Cdc2 vs. Cdk2. Cell cycle (Georgetown, Tex.) 77 16258277
2001 Differential regulation of Cdc2 and Cdk2 by RINGO and cyclins. The Journal of biological chemistry 75 11461916
2017 MYC Modulation around the CDK2/p27/SKP2 Axis. Genes 73 28665315
2011 Switching Cdk2 on or off with small molecules to reveal requirements in human cell proliferation. Molecular cell 73 21658603
2006 Discovery and evaluation of dual CDK1 and CDK2 inhibitors. Cancer research 72 16618755
2004 Bioluminescent imaging of Cdk2 inhibition in vivo. Nature medicine 72 15122251
2018 Combined BET bromodomain and CDK2 inhibition in MYC-driven medulloblastoma. Oncogene 71 29511348
1995 An analysis of the regulation of DNA synthesis by cdk2, Cip1, and licensing factor. The Journal of cell biology 70 7698977
2020 Development of CDK2 and CDK5 Dual Degrader TMX-2172. Angewandte Chemie (International ed. in English) 63 32415712
2017 Cdk2 strengthens the intra-S checkpoint and counteracts cell cycle exit induced by DNA damage. Scientific reports 63 29044141
2009 A dual role of Cdk2 in DNA damage response. Cell division 61 19445729
2014 CDK2 regulates nuclear envelope protein dynamics and telomere attachment in mouse meiotic prophase. Journal of cell science 59 25380821
2009 Origin licensing and p53 status regulate Cdk2 activity during G(1). Cell cycle (Georgetown, Tex.) 59 19440053
1999 Cyclin D1 inhibits cell proliferation through binding to PCNA and cdk2. Experimental cell research 59 9925749
2024 Cyclin-dependent kinase 2 (CDK2) inhibitors and others novel CDK inhibitors (CDKi) in breast cancer: clinical trials, current impact, and future directions. Critical reviews in oncology/hematology 58 38462150
2015 Insights on Structural Characteristics and Ligand Binding Mechanisms of CDK2. International journal of molecular sciences 57 25918937
1995 Coexpression of cdk2/cdc2 and retinoblastoma gene products in colorectal cancer. British journal of cancer 56 7779716
2018 Targeting CDK2 overcomes melanoma resistance against BRAF and Hsp90 inhibitors. Molecular systems biology 55 29507054
2019 SKA3 Promotes tumor growth by regulating CDK2/P53 phosphorylation in hepatocellular carcinoma. Cell death & disease 54 31804459
2010 Cdk2: a key regulator of the senescence control function of Myc. Aging 54 20445224
2008 Cdk1 and Cdk2 activity levels determine the efficiency of replication origin firing in Xenopus. The EMBO journal 54 18256689
2000 PKCeta associates with cyclin E/cdk2/p21 complex, phosphorylates p21 and inhibits cdk2 kinase in keratinocytes. Oncogene 54 11175348
1992 Cdc25 regulates the phosphorylation and activity of the Xenopus cdk2 protein kinase complex. The Journal of biological chemistry 54 1517236
2008 Cdk2 and Pin1 negatively regulate the transcriptional corepressor SMRT. The Journal of cell biology 53 18838553
2006 Protein phosphatase 2A antagonizes ATM and ATR in a Cdk2- and Cdc7-independent DNA damage checkpoint. Molecular and cellular biology 52 16479016
2022 WEE1 kinase protects the stability of stalled DNA replication forks by limiting CDK2 activity. Cell reports 49 35045293
2005 Cdk2: a genuine protein kinase client of Hsp90 and Cdc37. Biochemistry 49 16285732
2019 Phenotypical microRNA screen reveals a noncanonical role of CDK2 in regulating neutrophil migration. Proceedings of the National Academy of Sciences of the United States of America 48 31451657
2014 Hexokinase 2 regulates G1/S checkpoint through CDK2 in cancer-associated fibroblasts. Cellular signalling 46 24780297
2017 Next-Generation CDK2/9 Inhibitors and Anaphase Catastrophe in Lung Cancer. Journal of the National Cancer Institute 43 28376145
1994 Chromosomal mapping of human CDK2, CDK4, and CDK5 cell cycle kinase genes. Cytogenetics and cell genetics 43 8275715
2018 Identification of CDK2 as a novel target in treatment of prostate cancer. Future oncology (London, England) 41 29323532
2014 Mammalian E-type cyclins control chromosome pairing, telomere stability and CDK2 localization in male meiosis. PLoS genetics 41 24586195
2018 Long Noncoding RNA LINC00958 Accelerates Gliomagenesis Through Regulating miR-203/CDK2. DNA and cell biology 39 29570358
2010 Tipping the balance: Cdk2 enables Myc to suppress senescence. Cancer research 39 20713526
2023 Development of allosteric and selective CDK2 inhibitors for contraception with negative cooperativity to cyclin binding. Nature communications 38 37270540
2015 miR-200c Targets CDK2 and Suppresses Tumorigenesis in Renal Cell Carcinoma. Molecular cancer research : MCR 38 26248649
2009 DNA damage induces Chk1-dependent threonine-160 phosphorylation and activation of Cdk2. Oncogene 38 19838212
2004 Cdk2 as a master of S phase entry: fact or fake? Cell cycle (Georgetown, Tex.) 38 14657662
1999 Functional interactions between herpesvirus oncoprotein MEQ and cell cycle regulator CDK2. Journal of virology 38 10196317
2021 Allostery governs Cdk2 activation and differential recognition of CDK inhibitors. Nature chemical biology 36 33526892
2005 CDK2 translational down-regulation during endothelial senescence. Experimental cell research 36 15922732
1999 Mechanism of Cdk2/Cyclin E inhibition by p27 and p27 phosphorylation. Biochemistry 36 10393546
2006 Cdk2 and Cdk4 cooperatively control the expression of Cdc2. Cell division 35 16759374
2022 SLCO4A1-AS1 promotes colorectal tumourigenesis by regulating Cdk2/c-Myc signalling. Journal of biomedical science 34 35039060
2001 Perspectives for cancer therapies with cdk2 inhibitors. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 34 12030783
2016 A CDK2 activity signature predicts outcome in CDK2-low cancers. Oncogene 33 27819669
2024 CDK2 and CDK4: Cell Cycle Functions Evolve Distinct, Catalysis-Competent Conformations, Offering Drug Targets. JACS Au 31 38818077
2018 Molecular profiling and combinatorial activity of CCT068127: a potent CDK2 and CDK9 inhibitor. Molecular oncology 31 29063678
2007 Autocatalytic phosphorylation of CDK2 at the activating Thr160. Cell cycle (Georgetown, Tex.) 31 17361108
2019 CDK1 and CDK2 regulate NICD1 turnover and the periodicity of the segmentation clock. EMBO reports 30 31267714
2016 miR-302b regulates cell cycles by targeting CDK2 via ERK signaling pathway in gastric cancer. Cancer medicine 30 27465546
2013 SMG-1 suppresses CDK2 and tumor growth by regulating both the p53 and Cdc25A signaling pathways. Cell cycle (Georgetown, Tex.) 30 24107632
2002 p27, cyclin E, and CDK2 expression in normal and cancerous endometrium. International journal of oncology 30 12239611
2021 Non-metabolic function of MTHFD2 activates CDK2 in bladder cancer. Cancer science 29 34632667
2017 NEUROG1 Regulates CDK2 to Promote Proliferation in Otic Progenitors. Stem cell reports 29 29033307
2016 Cdk2 catalytic activity is essential for meiotic cell division in vivo. The Biochemical journal 29 27371320
2022 CDK2 Inhibition Enhances Antitumor Immunity by Increasing IFN Response to Endogenous Retroviruses. Cancer immunology research 27 35181784
2020 Protein Dynamics Enables Phosphorylation of Buried Residues in Cdk2/Cyclin-A-Bound p27. Biophysical journal 27 33147476
2014 KAP regulates ROCK2 and Cdk2 in an RNA-activated glioblastoma invasion pathway. Oncogene 27 24704824
2003 Chemical and biological profile of dual Cdk1 and Cdk2 inhibitors. Current medicinal chemistry. Anti-cancer agents 27 12678910
2025 Discrete vulnerability to pharmacological CDK2 inhibition is governed by heterogeneity of the cancer cell cycle. Nature communications 25 39924553
2005 Biochemical characterization of Cdk2-Speedy/Ringo A2. BMC biochemistry 25 16191191
2009 Identification and characterization of CAC1 as a novel CDK2-associated cullin. Cell cycle (Georgetown, Tex.) 24 19829063
2019 The Cdk2-c-Myc-miR-571 Axis Regulates DNA Replication and Genomic Stability by Targeting Geminin. Cancer research 23 31431461
2016 CK1δ activity is modulated by CDK2/E- and CDK5/p35-mediated phosphorylation. Amino acids 23 26464264
2015 ING5 is phosphorylated by CDK2 and controls cell proliferation independently of p53. PloS one 23 25860957
2007 CDK2 and FOXO1: a fork in the road for cell fate decisions. Cell cycle (Georgetown, Tex.) 23 17457058
2020 A novel function for CDK2 activity at meiotic crossover sites. PLoS biology 22 33075054
2022 SARS-CoV-2 hijacks cellular kinase CDK2 to promote viral RNA synthesis. Signal transduction and targeted therapy 21 36575184
2011 Compartmentalized CDK2 is connected with SHP-1 and β-catenin and regulates insulin internalization. Cellular signalling 21 21262353

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