CDK2 (cyclin dependent kinase 2)

2017-12-01   Anette Gjörloff Wingren , Barnabas Nyesiga 

Biomedical science, Health and society, Malmö University, Malmö, Sweden nyesigabarnabas@gmail.com; anette.gjorloff-wingren@mah.se

Identity

HGNC
LOCATION
12q13.2
IMAGE
Atlas Image
LEGEND
Figure 1. Mapping of CDK2 gene on chromosome 12q13 (from GeneCards CDK2 gene)
LOCUSID
ALIAS
CDKN2,p33(CDK2)

Abstract

Review on CDK2, with data on DNA, on the protein encoded, and where the gene is implicated.

DNA/RNA

Description

One of the two different human cDNAs that can complement cdc28 mutations of budding yeast Saccharomyces cerevisiae cloned by Ninomiya et al. corresponds to the CDK2 gene (Ninomiya 1991). Elledge et al. identified CDK2 as a second functional p34 homolog with the help of a human cDNA expression library to search for suppressors of cdc28 mutations in S. cerevisiae (Elledge 1991). CDK2 gene is mapped to 12q13 (Demetrick 1994) (Fig. 1). The cloning of approximately 2.4-kilobase pair genomic DNA fragment from the upstream region of the human CDK2 gene has been described (Shiffman 1996). The CDK2 gene fragment was found to contain 5 transcription initiation sites within a 72-bp stretch. A 200-bp subfragment that confers 70% of maximal basal promoter activity was shown to contain 2 synergistically acting Sp1 sites (Shiffman 1996). The intron-exon boundaries of 7 exons in this gene were also identified (Shiffman 1996). There are other reports of CDK2 gene expressed as a 2.1 kb transcript encoding a polypeptide of 298 amino acids and encodes the human homolog of the Xenopus Eg1 gene, sharing 89% amino acid identity (Elledge 1991).

Transcription

The presence of CDK2 mRNA was observed late in G1 or in early S phase, slightly before CDC2 mRNA, under growth stimulation in normal human fibroblast cells (Ninomiya 1991). CDK2 mRNA has also been shown to be induced by serum in several cultured cell types (Shiffman 1996).

Proteins

Description

The CDK2 protein was found to be highly homologous to p34CDC2 kinase (65% identical) and more significantly homologous to Xenopus Eg1 kinase (89% identical), suggesting that CDK2 is the human homolog of Eg1 (Ninomiya 1991). CDK2 protein has a biological activity closely related to the CDC28 and CDK1 (Cdc2, p34CDC2) kinases (Ninomiya 1991) and the protein retains nearly all of the amino acids highly conserved among previously identified p34 homologs from other species (Elledge 1991). CDK2 is a mammalian Ser/Thr kinase that plays a critical role in controlling the progression from G1 to S phase of the cell cycle (Morgan 1997) and is functionally homologous to the well-studied cdc28a S. cerevisae protein (Zhao 2011). Monomeric CDK2 lacks regulatory activity requiring to be aroused by its positive regulators, cyclins E and A, or catalytic segment phosphorylation (Yan 2015). CDK2 activation is a two-step process; step one requires its association with the regulatory subunit cyclins A or E and step two involves phosphorylation of the residue Thr160 (Marcos 2011, Morris 2002, Pavletich 1999).
The crystal structure of the human CDK2 apoenzyme and its Mg2+ATP complex have been determined to 2.4 Å resolution (De Bondt 1993) while the crystal structure of CDK2-ATP complex has been determined at 2.3 Å resolution (Jeffrey 1995). Monomeric CDK2 is made of 298 amino acids (PDB code: 1HCL, residues 1-298), and folds into a typical bilobal structure, composed of a smaller N-terminal lobe (residues 1-85) that consists of antiparallel five-strand β-sheet and a major C-helix, together with a larger C-terminal lobe primarily composed of α-helix (De Bondt 1993). The two terminal domains are linked by a single peptide strand (residues 81-83) which acts as a hinge linker making sure that the two lobes can rotate with respect to each other without disruption of the secondary structure of this kinase (Cox 1994). Three binding sites have been reported in the monomeric CDK2 structure; the adenosine triphosphate (ATP) binding site (Site I) and two non-competitive binding sites (Site II and III). An allosteric binding site (Site IV) is generated as a result of structural changes that yield a variation of the ATP binding site when the kinase is subjected to the cyclin binding process (Yan 2015). Competitive binding site (Site I) is the most well-known ATP binding site, situated deep at the junction of the N and C domains. It includes the pivotal catalytic residues with high sensitivity and linker region (residues 81-83), and consists of 136 consecutive amino acids (10-145) on the CDK2 (Knockaert 2002). There is no association between non-competitive binding sites (site II and III) and catalytic subunits (Li 2013). Site III is also known to accommodate short peptides that partially dissociate the CDK2/cyclin E complex, thus obstructing the enzymatic activity of CDK2 (Chen 2009). The allosteric binding site (site IV) also known as ANS fluorophore 8-anilino-1-naphthalene sulfonate) binding pocket is located in a region that is adjacent to the C-helix, away from the ATP site, approximately halfway of the ATP site and the C-helix (Yan 2015).

Localisation

The nuclear translocation of CDK2/cyclin E and cyclin E binding are needed for CDK2 enzymatic activation and substrate targeting because the CDK2 activating enzyme (CAK) and many of the CDK2 targets reside in the nucleus (Blanchard 2000, Dietrich 1997, Keenan 2001). Intracellular trafficking of CDK2 is unclear though some studies suggest that cyclins may play a role in the translocation of the cyclin/CDK complex via the classical importin α/β pathway (Moore 1999, Moore 2002). It is suggested that importin α binds to the nuclear localization signal on cyclins whereas importin β binds to nuclear transport machinery proteins as well as to cyclin-bound importin α. Translocation of the cyclin/CDK/importin α/β complex into the nucleus then occurs via an energy-dependent process (Flores 2010). Other studies have demonstrated consistent concentration of CDK2/cyclin E in the nucleus in both Drosophila embryos and cultured human cells (Knoblich 1994, Ohtsubo 1995), whereas CDK1 (Cdc2)/ CCNB1 (cyclin B1) is retained in the cytoplasm in interphase, entering the nucleus at the earliest stages of mitosis (Lehner and OFarrell 1990, Pines and Hunter, 1994).  Other studies using egg extracts have shown how accumulation of CDK2/cyclin E in the nucleus is needed both for initiating DNA replication (Chevalier 1996) and preventing re-replication (Hua 1997, Walter 1998). There are indications that CDK2 nuclear translocation is associated with the formation of molecular complexes containing active MAP Kinase and is dependent on MAP Kinase activation (Blanchard 2000).

Function

CDK2 activity has been indicated to be regulated by protein CDNK1B (p27KIP1) which inhibits CDK2 kinase activity in G0 and early G1 phase and leads to cell-cycle arrest (Polyak 1994). Once combined with its positive regulatory subunits, CDK2 fosters the transition of the well-established G1/S phase boundary and drives the cell cycle through S interval (Shapiro 2006, Sherr 1994, Pines 1991). CDK2/cyclin A is a necessity for orderly S-phase progression (Sherr 1994), while phosphorylation of retinoblastoma protein ( RB1) to facilitate the G1/S transition is mediated by CDK2/cyclin E complex (Pines 1991). CDK2/cyclin E phosphorylates Rb leading to the release and activation of E2F transcription factors required to promote transcription of genes that encode proteins required for G1 to S phase progression (Dyson 1998, Nevins 1998). CDK2 associates with both inactive and activated MAP Kinase and its activation is linked to formation of CDK2/ MAP Kinase complexes (Blanchard 2000). CDK2 is one of the most essential regulators for the transition and progression in a cell-division cycle and plays a crucial role in regulating multiple events of cell division cycle including centrosome duplication, DNA synthesis, G1-S transition, and modulation of G2 progression (Chohan 2015, De Boer 2008, Fiset 2011, Omar 2010). CDK2 is a requirement for robust DNA damage checkpoint signalling and loss of CDK2 was observed to cause a marked deficiency in the G2/M arrest which is a basic response to DNA damage in cells that were also nullizygous for P53 (Chung and Bunz, 2010). CDK2 plays a critical role in facilitating robust DNA damage checkpoint control by the ATR- CHEK1- CDC25A pathway. CDK2 seems to promote the formation of active ATR complexes by ATRIP phosphorylation and by CDC6 stabilization (Chung and Bunz, 2010). There is a possibility of CDK2 also controlling checkpoint signaling via additional mechanisms such as the recently described CDK2 interacting protein ( CINP) which facilitates robust ATR signalling (Lovejoy 2009). In addition, loss of CDK2 was demonstrated to alter the regulation of several proteins that are known to regulate S-phase progression, but also control mitotic entry, including CDC25A, CHK1, CDC6 and ATRIP (Donzelli and Draetta, 2003, Borlado and Mendez 2008, Cimprich and Cortez, 2008). Expression of CCNE1-CDK2 at physiologic levels of ATP results in phosphorylation of CDKN1B at thr187, leading to elimination of CDKN1B from the cell and progression of the cell cycle from G1 to S phase (Sheaff 1997). At low ATP levels, the inhibitory functions of CDKN1B are enhanced, thereby arresting cell proliferation (Sheaff 1997). Apoptosis of human endothelial cells after growth factor deprivation is associated with rapid and dramatic upregulation of cyclin A-associated CDK2 activity (Levkau 1998).  In apoptotic cells, the carboxyl-termini of the CDK inhibitors CDKN1A and CDKN1B are truncated by specific cleavage aided by CASP3 and/or a CASP3-like caspase. After cleavage, CDKN1A loses its nuclear localization sequence and exits the nucleus. Cleavage of CDKN1A and CDKN1B resulted in a substantial reduction in their association with nuclear cyclin-CDK2 complexes, leading to a dramatic induction of CDK2 activity. Dominant-negative CDK2, as well as a mutant CDKN1A resistant to caspase cleavage, partially suppressed apoptosis. CDK2 activation, through caspase-mediated cleavage of CDK inhibitors, may be instrumental in the execution of apoptosis following caspase activation (Levkau 1998). Forkhead box O (FOXO) are key regulators of cell survival and CDK2 is known to specifically phosphorylate FOXO1 at ser249 in vitro and in vivo resulting into cytoplasmic localization and inhibition of FOXO1 (Huang 2006).  Functional interaction between CDK2 and FOXO1 provides a mechanism that regulates apoptotic cell death after DNA strand breakage (Huang 2006). Proto-oncogenes such as MYC and RAS promote normal cell growth, fuel tumor development when deregulated and if over-activated can trigger intrinsic tumor suppressor mechanisms leading to apoptosis and senescence (Hydbring and Larsson, 2010). Ras is known to suppress Myc-induced apoptosis while Myc was recently discovered to repress Ras-induced senescence. The ability of Myc to suppress senescence is dependent on its phosphorylation at Ser 62 by CDK2. Using CDK2 as a cofactor, Myc is able to directly control major genes involved in senescence. Selective pharmacological inhibition of CDK2 was observed to force Myc/Ras expressing cells into cellular senescence, an indication that CDK2 is a potential therapeutic target for treatment of tumors driven by Myc or Ras (Hydbring and Larsson, 2010).

Implicated in

Top note
Among all the CDKs, CDK2 is known to be an important kinase in tumorigenesis and proliferation in many cancer types including lung cancer, liver cancer, colon cancer and breast cancer (Opyrchal 2014, Shi 2015, Lim 2014). There is strong evidence showing that CDK2 is functionally linked with hyper proliferation in multiple cancer cells and is a potential therapeutic target for cancer therapy (Chohan 2015).
Entity name
Prostate cancer
Note
CDK2 has been found to play a pivotal role in cell proliferation of prostate cancer (Omar 2010).
Entity name
Breast cancer
Note
CDK2 is also crucial for malignant transformation of breast epithelial cells. Suppression of CDK2 activity can effectively inhibit the proliferation of human breast cancer cells (Ali 2009). Active CDK2 in the form of a cyclin D1/CDK2 fusion protein induces tumors that contain an invasive component that exhibits multiple features in common with human basal-like tumors and tumor-derived cell lines (Corsino 2008). Cyclin D1/CDK2 complexes were detected in human breast cancer cell lines (Sweeney 1998), and the levels of these complexes correlated well with the degree of cyclin D1 overexpression.
Entity name
Ovarian cancer
Note
The role of cyclin E and its associated kinase CDK2 in ovarian cancer has been investigated by screening primary, metastatic, recurrent and benign ovarian tumors. Using gene amplification, Cyclin E was shown to be amplified in 21% and CDK2 in 6.4% of the cases analyzed. Additionally, Cyclin E RNA was overexpressed in 29.5% and CDK2 in 6.5% of ovarian tumors tested. Cyclin E and CDK2 were overexpressed mostly in primary ovarian cancers (32% and 10%, respectively) compared to metastatic and recurrent diseases (Marone 1998).
Entity name
Glioblastoma
Note
Wang et al. identified CDK2 expression to be significantly elevated in glioma tumor especially in Glioblastoma Multiforme (GBM) and was functionally required for GBM cell proliferation and tumorigenesis (Wang 2016). CDK2 expression was identified to be significantly enriched in GBM tumors and functionally required for tumor proliferation both in vitro and in vivo. Additionally, high CDK2 expression was associated to poor prognosis in GBM patients. Radio resistance is a major factor of poor clinical prognosis and tumor recurrence in GBM patients. CDK2 was found to be one of the most up-regulated kinase encoding genes in GBM after radio treatment. CDK2-dependent radio resistance is indispensable for GBM tumorigenesis and recurrence after therapeutic treatment (Wang 2016).
Entity name
Cholangiocarcinoma
Note
Elevated levels of CDK2 expression have been observed in human cholangiocarcinoma tissues where apoptosis-related protein-1 dependent suppression of CDK2 induced cell cycle arrest and restrained tumor growth (Zheng 2016).
Entity name
Oral squamous cell carcinoma (SCC)
Note
CDK2 overexpression in oral squamous cell carcinoma (SCC) may elevate pRB phosphorylation and permit more rapid entry of the cancer cells into S phase. In a clinicopathological survey of oral SCC, incidence of CDK2 expression was high in the poorly differentiated lesions, and was associated with the mode of tumor invasion, lymph node involvement and survival, an indication that change in CDK2 expression is associated with oral cancer progression (Mihara 2001). CDK2 expression was significantly correlated with lymph node involvement, tumor differentiation, mode of tumor invasion, and shorter survival period. Increased expression of CDK2 is both a critical factor in oral cancer progression and a negative predictive marker of the patients prognosis (Mihara 2001).
Entity name
Lung cancer
Note
CDK2 has been found to play a pivotal role in cell proliferation of non-small cell lung cancer (Kawana 1998).
Entity name
Pemphigus vulgaris (PV)
Disease
Pemphigus vulgaris (PV) is an autoimmune blistering disease that affects skin and mucous membranes. CDK2 appeared to have a role in the development of PV lesions (Lanza 2008). Exposing of synchronized human keratinocytes to PV serum increased the proportion of cells in S phase, caused cell rounding and cell-cell detachment, elevated CDK2 expression in a dose-dependent manner, and altered the expression of over 500 genes especially those that are involved in cell communication and cell- cell junction formation. Small interfering RNA against CDK2 reversed PV serum-induced CDK2 overexpression and reduced cell-cell detachment. By utilizing a neonatal mouse model in which PV lesions were induced by a single intraperitoneal injection of whole serum obtained from a PV patient, it was shown that pre-treatment of mice with a pharmacologic CDK2 inhibitor prevented skin lesion development and PV serum-induced changes in gene expression. Histochemical analysis of PV patient skin revealed CDK2 overexpression around the site of the acantholytic cleft and along suprabasal layers in perilesional sites. It was finally concluded that activation of CDK2-mediated signaling is an essential event in the development of PV lesions (Lanza 2008).

Bibliography

Pubmed IDLast YearTitleAuthors
196385872009The development of a selective cyclin-dependent kinase inhibitor that shows antitumor activity.Ali S et al
215657022011Briefly bound to activate: transient binding of a second catalytic magnesium activates the structure and dynamics of CDK2 kinase for catalysis.Bao ZQ et al
109625812000Cdk2 associates with MAP kinase in vivo and its nuclear translocation is dependent on MAP kinase activation in IL-2-dependent Kit 225 T lymphocytes.Blanchard DA et al
180483872008CDC6: from DNA replication to cell cycle checkpoints and oncogenesis.Borlado LR et al
186157132009A novel binding pocket of cyclin-dependent kinase 2.Chen H et al
87998081996Xenopus cyclin E, a nuclear phosphoprotein, accumulates when oocytes gain the ability to initiate DNA replication.Chevalier S et al
253868242015Cyclin-dependent kinase-2 as a target for cancer therapy: progress in the development of CDK2 inhibitors as anti-cancer agents.Chohan TA et al
201955062010Cdk2 is required for p53-independent G2/M checkpoint control.Chung JH et al
185945632008ATR: an essential regulator of genome integrity.Cimprich KA et al
77122931994Domain movements in protein kinases.Cox S et al
183729192008Cyclin A/cdk2 coordinates centrosomal and nuclear mitotic events.De Boer L et al
85107511993Crystal structure of cyclin-dependent kinase 2.De Bondt HL et al
82757151994Chromosomal mapping of human CDK2, CDK4, and CDK5 cell cycle kinase genes.Demetrick DJ et al
91416231997Translocation of cdk2 to the nucleus during G1-phase in PDGF-stimulated human fibroblasts.Dietrich C et al
128357542003Regulating mammalian checkpoints through Cdc25 inactivation.Donzelli M et al
96947911998The regulation of E2F by pRB-family proteins.Dyson N et al
212623532011Compartmentalized CDK2 is connected with SHP-1 and β-catenin and regulates insulin internalization.Fiset A et al
201475222010Nuclear targeting of cyclin-dependent kinase 2 reveals essential roles of cyclin-dependent kinase 2 localization and cyclin E in vitamin D-mediated growth inhibition.Flores O et al
91050461997A role for Cdk2 kinase in negatively regulating DNA replication during S phase of the cell cycle.Hua XH et al
204452242010Cdk2: a key regulator of the senescence control function of Myc.Hydbring P et al
76303971995Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex.Jeffrey PD et al
113045352001Cyclin-dependent kinase 2 nucleocytoplasmic translocation is regulated by extracellular regulated kinase.Keenan SM et al
81565871994Cyclin E controls S phase progression and its down-regulation during Drosophila embryogenesis is required for the arrest of cell proliferation.Knoblich JA et al
181997522008Evidence of key role of Cdk2 overexpression in pemphigus vulgaris.Lanza A et al
21398051990The roles of Drosophila cyclins A and B in mitotic control.Lehner CF et al
96609391998Cleavage of p21Cip1/Waf1 and p27Kip1 mediates apoptosis in endothelial cells through activation of Cdk2: role of a caspase cascade.Levkau B et al
238641052013An in silico exploration of the interaction mechanism of pyrazolo[1,5-a]pyrimidine type CDK2 inhibitors.Li Y et al
259189372015Insights on Structural Characteristics and Ligand Binding Mechanisms of CDK2.Li Y et al
245501432014Curcumin suppresses proliferation of colon cancer cells by targeting CDK2.Lim TG et al
198899792009Functional genomic screens identify CINP as a genome maintenance protein.Lovejoy CA et al
217427932011Physiological relevance of cell cycle kinases.Malumbres M et al
94266871998Analysis of cyclin E and CDK2 in ovarian cancer: gene amplification and RNA overexpression.Marone M et al
112679472001Overexpression of CDK2 is a prognostic indicator of oral cancer progression.Mihara M et al
124759602002Identification of the nuclear localization signal in Xenopus cyclin E and analysis of its role in replication and mitosis.Moore JD et al
99224491999Nuclear import of Cdk/cyclin complexes: identification of distinct mechanisms for import of Cdk2/cyclin E and Cdc2/cyclin B1.Moore JD et al
94428751997Cyclin-dependent kinases: engines, clocks, and microprocessors.Morgan DO et al
119598502002Kinetic mechanism of activation of the Cdk2/cyclin A complex. Key role of the C-lobe of the Cdk.Morris MC et al
97161761998Toward an understanding of the functional complexity of the E2F and retinoblastoma families.Nevins JR et al
17179941991Cloning of a human cDNA encoding a CDC2-related kinase by complementation of a budding yeast cdc28 mutation.Ninomiya-Tsuji J et al
77395421995Human cyclin E, a nuclear protein essential for the G1-to-S phase transition.Ohtsubo M et al
249706532014Inhibition of Cdk2 kinase activity selectively targets the CD44⁺/CD24⁻/Low stem-like subpopulation and restores chemosensitivity of SUM149PT triple-negative breast cancer cells.Opyrchal M et al
12237151975Status asthmaticus.Partana JS et al
102221911999Mechanisms of cyclin-dependent kinase regulation: structures of Cdks, their cyclin activators, and Cip and INK4 inhibitors.Pavletich NP et al
16483791991Cyclins: wheels within wheels.Pines J et al
80704051994The differential localization of human cyclins A and B is due to a cytoplasmic retention signal in cyclin B.Pines J et al
80332121994Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals.Polyak K et al
17038621990[The effect of endo-beta-galactosidase on lactosamine sialoantigens Gd, Fl, Vo, Li].Roelcke D et al
166037192006Cyclin-dependent kinase pathways as targets for cancer treatment.Shapiro GI et al
91928731997Cyclin E-CDK2 is a regulator of p27Kip1.Sheaff RJ et al
79548211994G1 phase progression: cycling on cue.Sherr CJ et al
261478972015In Silico Identification and In Vitro and In Vivo Validation of Anti-Psychotic Drug Fluspirilene as a Potential CDK2 Inhibitor and a Candidate Anti-Cancer Drug.Shi XN et al
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Other Information

Locus ID:

NCBI: 1017
MIM: 116953
HGNC: 1771
Ensembl: ENSG00000123374

Variants:

dbSNP: 1017
ClinVar: 1017
TCGA: ENSG00000123374
COSMIC: CDK2

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000123374ENST00000266970P24941
ENSG00000123374ENST00000266970A0A024RB77
ENSG00000123374ENST00000354056P24941
ENSG00000123374ENST00000354056A0A024RB10
ENSG00000123374ENST00000440311E7ESI2
ENSG00000123374ENST00000553376G3V5T9
ENSG00000123374ENST00000555357G3V317
ENSG00000123374ENST00000555408G3V317

Expression (GTEx)

0
10
20
30
40
50
60
70

Pathways

PathwaySourceExternal ID
Cell cycleKEGGko04110
p53 signaling pathwayKEGGko04115
Progesterone-mediated oocyte maturationKEGGko04914
Prostate cancerKEGGko05215
Small cell lung cancerKEGGko05222
Cell cycleKEGGhsa04110
p53 signaling pathwayKEGGhsa04115
Pathways in cancerKEGGhsa05200
Prostate cancerKEGGhsa05215
Small cell lung cancerKEGGhsa05222
Progesterone-mediated oocyte maturationKEGGhsa04914
Oocyte meiosisKEGGko04114
Oocyte meiosisKEGGhsa04114
MeaslesKEGGko05162
MeaslesKEGGhsa05162
Herpes simplex infectionKEGGko05168
Herpes simplex infectionKEGGhsa05168
Epstein-Barr virus infectionKEGGhsa05169
Epstein-Barr virus infectionKEGGko05169
Viral carcinogenesisKEGGhsa05203
Viral carcinogenesisKEGGko05203
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
Hepatitis BKEGGhsa05161
FoxO signaling pathwayKEGGhsa04068
Cell cycle - G1/S transitionKEGGhsa_M00692
Cell cycle - G2/M transitionKEGGhsa_M00693
Cell cycle - G1/S transitionKEGGM00692
Cell cycle - G2/M transitionKEGGM00693
HemostasisREACTOMER-HSA-109582
Factors involved in megakaryocyte development and platelet productionREACTOMER-HSA-983231
Signal TransductionREACTOMER-HSA-162582
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
Cell CycleREACTOMER-HSA-1640170
Cell Cycle CheckpointsREACTOMER-HSA-69620
G1/S DNA Damage CheckpointsREACTOMER-HSA-69615
p53-Dependent G1/S DNA damage checkpointREACTOMER-HSA-69580
p53-Dependent G1 DNA Damage ResponseREACTOMER-HSA-69563
G2/M CheckpointsREACTOMER-HSA-69481
Activation of ATR in response to replication stressREACTOMER-HSA-176187
Cell Cycle, MitoticREACTOMER-HSA-69278
Mitotic G1-G1/S phasesREACTOMER-HSA-453279
G0 and Early G1REACTOMER-HSA-1538133
G1/S TransitionREACTOMER-HSA-69206
Cyclin E associated events during G1/S transitionREACTOMER-HSA-69202
SCF(Skp2)-mediated degradation of p27/p21REACTOMER-HSA-187577
Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexesREACTOMER-HSA-69200
Activation of the pre-replicative complexREACTOMER-HSA-68962
S PhaseREACTOMER-HSA-69242
Cyclin A:Cdk2-associated events at S phase entryREACTOMER-HSA-69656
Synthesis of DNAREACTOMER-HSA-69239
Switching of origins to a post-replicative stateREACTOMER-HSA-69052
Orc1 removal from chromatinREACTOMER-HSA-68949
CDK-mediated phosphorylation and removal of Cdc6REACTOMER-HSA-69017
Regulation of DNA replicationREACTOMER-HSA-69304
Removal of licensing factors from originsREACTOMER-HSA-69300
Mitotic G2-G2/M phasesREACTOMER-HSA-453274
G2 PhaseREACTOMER-HSA-68911
G2/M TransitionREACTOMER-HSA-69275
Cyclin A/B1 associated events during G2/M transitionREACTOMER-HSA-69273
M/G1 TransitionREACTOMER-HSA-68874
DNA Replication Pre-InitiationREACTOMER-HSA-69002
Regulation of mitotic cell cycleREACTOMER-HSA-453276
APC/C-mediated degradation of cell cycle proteinsREACTOMER-HSA-174143
Regulation of APC/C activators between G1/S and early anaphaseREACTOMER-HSA-176408
MeiosisREACTOMER-HSA-1500620
Meiotic recombinationREACTOMER-HSA-912446
DNA ReplicationREACTOMER-HSA-69306
DNA RepairREACTOMER-HSA-73894
Cellular responses to stressREACTOMER-HSA-2262752
Cellular SenescenceREACTOMER-HSA-2559583
DNA Damage/Telomere Stress Induced SenescenceREACTOMER-HSA-2559586
Senescence-Associated Secretory Phenotype (SASP)REACTOMER-HSA-2559582
DNA Double-Strand Break RepairREACTOMER-HSA-5693532
Homology Directed RepairREACTOMER-HSA-5693538
HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)REACTOMER-HSA-5693567
Processing of DNA double-strand break endsREACTOMER-HSA-5693607
Signaling by PTK6REACTOMER-HSA-8848021
PTK6 Regulates Cell CycleREACTOMER-HSA-8849470
TP53 Regulates Transcription of Cell Cycle GenesREACTOMER-HSA-6791312
TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle ArrestREACTOMER-HSA-6804116
Regulation of TP53 ActivityREACTOMER-HSA-5633007
Regulation of TP53 Expression and DegradationREACTOMER-HSA-6806003
Regulation of TP53 DegradationREACTOMER-HSA-6804757
Regulation of TP53 Activity through PhosphorylationREACTOMER-HSA-6804756

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
200682312010Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis.568
268616252016Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2.349
240750092013The proliferation-quiescence decision is controlled by a bifurcation in CDK2 activity at mitotic exit.154
145360782003Multisite phosphorylation by Cdk2 and GSK3 controls cyclin E degradation.146
170386212006CDK2-dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage.128
156079612004Critical role of CDK2 for melanoma growth linked to its melanocyte-specific transcriptional regulation by MITF.123
126765822003Proliferation of cancer cells despite CDK2 inhibition.110
150243852004p27 binds cyclin-CDK complexes through a sequential mechanism involving binding-induced protein folding.110
209356352010Cyclin-dependent kinases regulate epigenetic gene silencing through phosphorylation of EZH2.108
173862612007Requirements for Cdk7 in the assembly of Cdk1/cyclin B and activation of Cdk2 revealed by chemical genetics in human cells.102

Citation

Anette Gjörloff Wingren ; Barnabas Nyesiga

CDK2 (cyclin dependent kinase 2)

Atlas Genet Cytogenet Oncol Haematol. 2017-12-01

Online version: http://atlasgeneticsoncology.org/gene/40031/cdk2-(cyclin-dependent-kinase-2)