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Protein

Cyclin-dependent kinase 2

Gene

Cdk2

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Serine/threonine-protein kinase involved in the control of the cell cycle; essential for meiosis, but dispensable for mitosis. Phosphorylates CTNNB1, USP37, p53/TP53, NPM1, CDK7, RB1, BRCA2, MYC, NPAT, EZH2. Triggers duplication of centrosomes and DNA. Acts at the G1-S transition to promote the E2F transcriptional program and the initiation of DNA synthesis, and modulates G2 progression; controls the timing of entry into mitosis/meiosis by controlling the subsequent activation of cyclin B/CDK1 by phosphorylation, and coordinates the activation of cyclin B/CDK1 at the centrosome and in the nucleus. Crucial role in orchestrating a fine balance between cellular proliferation, cell death, and DNA repair in human embryonic stem cells (hESCs). Activity of CDK2 is maximal during S phase and G2; activated by interaction with cyclin E during the early stages of DNA synthesis to permit G1-S transition, and subsequently activated by cyclin A2 (cyclin A1 in germ cells) during the late stages of DNA replication to drive the transition from S phase to mitosis, the G2 phase. EZH2 phosphorylation promotes H3K27me3 maintenance and epigenetic gene silencing. Phosphorylates CABLES1 (By similarity). Cyclin E/CDK2 prevents oxidative stress-mediated Ras-induced senescence by phosphorylating MYC. Involved in G1-S phase DNA damage checkpoint that prevents cells with damaged DNA from initiating mitosis; regulates homologous recombination-dependent repair by phosphorylating BRCA2, this phosphorylation is low in S phase when recombination is active, but increases as cells progress towards mitosis. In response to DNA damage, double-strand break repair by homologous recombination a reduction of CDK2-mediated BRCA2 phosphorylation. Phosphorylation of RB1 disturbs its interaction with E2F1. NPM1 phosphorylation by cyclin E/CDK2 promotes its dissociates from unduplicated centrosomes, thus initiating centrosome duplication. Cyclin E/CDK2-mediated phosphorylation of NPAT at G1-S transition and until prophase stimulates the NPAT-mediated activation of histone gene transcription during S phase. Required for vitamin D-mediated growth inhibition by being itself inactivated. Involved in the nitric oxide- (NO) mediated signaling in a nitrosylation/activation-dependent manner. USP37 is activated by phosphorylation and thus triggers G1-S transition. CTNNB1 phosphorylation regulates insulin internalization. Phosphorylates FOXP3 and negatively regulates its transcriptional activity and protein stability (PubMed:23853094). Phosphorylates CDK2AP2 (By similarity).By similarity5 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.1 Publication

Cofactori

Mg2+By similarityNote: Binds 2 Mg2+ ions.By similarity

Activity regulationi

Phosphorylation at Thr-14 or Tyr-15 inactivates the enzyme, while phosphorylation at Thr-160 activates it. Stimulated by MYC. Inactivated by CDKN1A (p21) (By similarity).By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei9CDK7 bindingBy similarity1
Binding sitei33ATPPROSITE-ProRule annotation1
Binding sitei86ATPPROSITE-ProRule annotation1
Sitei88 – 89CDK7 bindingBy similarity2
Active sitei127Proton acceptorPROSITE-ProRule annotation1
Metal bindingi132MagnesiumBy similarity1
Metal bindingi145MagnesiumBy similarity1
Binding sitei145ATPPROSITE-ProRule annotation1
Sitei166CDK7 bindingBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi10 – 18ATPPROSITE-ProRule annotation9
Nucleotide bindingi81 – 83ATPPROSITE-ProRule annotation3
Nucleotide bindingi129 – 132ATPPROSITE-ProRule annotation4

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase
Biological processCell cycle, Cell division, DNA damage, DNA repair, Meiosis, Mitosis
LigandATP-binding, Magnesium, Metal-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.11.22 3474
ReactomeiR-MMU-1538133 G0 and Early G1
R-MMU-176187 Activation of ATR in response to replication stress
R-MMU-176408 Regulation of APC/C activators between G1/S and early anaphase
R-MMU-187577 SCF(Skp2)-mediated degradation of p27/p21
R-MMU-2559582 Senescence-Associated Secretory Phenotype (SASP)
R-MMU-2559586 DNA Damage/Telomere Stress Induced Senescence
R-MMU-5693607 Processing of DNA double-strand break ends
R-MMU-6804116 TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest
R-MMU-6804756 Regulation of TP53 Activity through Phosphorylation
R-MMU-6804757 Regulation of TP53 Degradation
R-MMU-68911 G2 Phase
R-MMU-68949 Orc1 removal from chromatin
R-MMU-68962 Activation of the pre-replicative complex
R-MMU-69017 CDK-mediated phosphorylation and removal of Cdc6
R-MMU-69200 Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexes
R-MMU-69202 Cyclin E associated events during G1/S transition
R-MMU-69273 Cyclin A/B1/B2 associated events during G2/M transition
R-MMU-69563 p53-Dependent G1 DNA Damage Response
R-MMU-69656 Cyclin A:Cdk2-associated events at S phase entry
R-MMU-8849470 PTK6 Regulates Cell Cycle

Names & Taxonomyi

Protein namesi
Recommended name:
Cyclin-dependent kinase 2 (EC:2.7.11.221 Publication)
Alternative name(s):
Cell division protein kinase 2
Gene namesi
Name:Cdk2
Synonyms:Cdkn2
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 10

Organism-specific databases

MGIiMGI:104772 Cdk2

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Cytoskeleton, Endosome, Nucleus

Pathology & Biotechi

Disruption phenotypei

Reduced body size and impaired neural progenitor cell proliferation. Sterility due to defective meiosis; no effect on mitotic cells. Premature translocation of CDK1 from the cytoplasm to the nucleus compensating CDK2 loss. Prolonged and impaired DNA repair activity upon DNA damage by gamma-irradiation.3 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi15Y → F: Loss of tyrosine phosphorylation by WEE1 and CABLES1. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000857711 – 346Cyclin-dependent kinase 2Add BLAST346

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei1N-acetylmethionineBy similarity1
Modified residuei6N6-acetyllysineBy similarity1
Modified residuei14PhosphothreonineBy similarity1
Modified residuei15Phosphotyrosine; by WEE11 Publication1
Modified residuei19PhosphotyrosineBy similarity1
Modified residuei160Phosphothreonine; by CAK and CCRKBy similarity1
Modified residuei218PhosphoserineCombined sources1

Post-translational modificationi

Phosphorylated at Thr-160 by CDK7 in a CAK complex. Phosphorylation at Thr-160 promotes kinase activity, whereas phosphorylation at Tyr-15 by WEE1 reduces slightly kinase activity. Phosphorylated on Thr-14 and Tyr-15 during S and G2 phases before being dephosphorylated by CDC25A.By similarity
Nitrosylated after treatment with nitric oxide (DETA-NO).By similarity

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

PaxDbiP97377
PeptideAtlasiP97377
PRIDEiP97377

PTM databases

iPTMnetiP97377
PhosphoSitePlusiP97377
SwissPalmiP97377

Expressioni

Gene expression databases

BgeeiENSMUSG00000025358 Expressed in 248 organ(s), highest expression level in bone marrow
CleanExiMM_CDK2
ExpressionAtlasiP97377 baseline and differential
GenevisibleiP97377 MM

Interactioni

Subunit structurei

Found in a complex with CABLES1, CCNA1 and CCNE1. Interacts with CABLES1 (PubMed:11585773). Interacts with UHRF2. Part of a complex consisting of UHRF2, CDK2 and CCNE1. Interacts with the Speedy/Ringo proteins SPDYA and SPDYC. Interaction with SPDYA promotes kinase activation via a conformation change that alleviates obstruction of the substrate-binding cleft by the T-loop. Found in a complex with both SPDYA and CDKN1B/KIP1. Binds to RB1 and CDK7. Binding to CDKN1A (p21) leads to CDK2/cyclin E inactivation at the G1-S phase DNA damage checkpoint, thereby arresting cells at the G1-S transition during DNA repair. Associated with PTPN6 and beta-catenin/CTNNB1. Interacts with CACUL1. May interact with CEP63. Interacts with ANKRD17 (By similarity). Interacts with CEBPA (when phosphorylated) (PubMed:15107404). Forms a ternary complex with CCNA2 and CDKN1B; CDKN1B inhibits the kinase activity of CDK2 through conformational rearrangements. Interacts with cyclins A, B1, B3, D, or E. Interacts with CDK2AP2 (By similarity).By similarity2 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi198644, 30 interactors
ComplexPortaliCPX-2065 Cyclin A1-CDK2 complex
CPX-2066 Cyclin A2-CDK2 complex
CPX-2071 Cyclin B3-CDK2 complex
CPX-2081 Cyclin E1-CDK2 complex
CPX-2082 Cyclin E2-CDK2 complex
CORUMiP97377
DIPiDIP-24176N
ELMiP97377
IntActiP97377, 7 interactors
MINTiP97377
STRINGi10090.ENSMUSP00000026416

Structurei

3D structure databases

ProteinModelPortaliP97377
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini4 – 334Protein kinasePROSITE-ProRule annotationAdd BLAST331

Sequence similaritiesi

Phylogenomic databases

eggNOGiKOG0594 Eukaryota
ENOG410XPP3 LUCA
GeneTreeiENSGT00910000144030
HOGENOMiHOG000233024
HOVERGENiHBG014652
InParanoidiP97377
KOiK02206
OMAiRHTNETI
OrthoDBiEOG091G0CH0
PhylomeDBiP97377
TreeFamiTF101021

Family and domain databases

InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR008271 Ser/Thr_kinase_AS
PfamiView protein in Pfam
PF00069 Pkinase, 2 hits
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SUPFAMiSSF56112 SSF56112, 2 hits
PROSITEiView protein in PROSITE
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket
Isoform CDK2-beta (identifier: P97377-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide
        10         20         30         40         50
MENFQKVEKI GEGTYGVVYK AKNKLTGEVV ALKKIRLDTE TEGVPSTAIR
60 70 80 90 100
EISLLKELNH PNIVKLLDVI HTENKLYLVF EFLHQDLKKF MDASALTGIP
110 120 130 140 150
LPLIKSYLFQ LLQGLAFCHS HRVLHRDLKP QNLLINAEGS IKLADFGLAR
160 170 180 190 200
AFGVPVRTYT HEVVTLWYRA PEILLGCKYY STAVDIWSLG CIFAEMHLVC
210 220 230 240 250
TQHHAKCCGE HRRNGRHSLC PLCSYLEVAA SQGGGMTAVS APHPVTRRAL
260 270 280 290 300
FPGDSEIDQL FRIFRTLGTP DEVVWPGVTS MPDYKPSFPK WARQDFSKVV
310 320 330 340
PPLDEDGRSL LSQMLHYDPN KRISAKAALA HPFFQDVTKP VPHLRL
Length:346
Mass (Da):38,978
Last modified:May 30, 2000 - v2
Checksum:iD806BC2F150AEDFC
GO
Isoform CDK2-alpha (identifier: P97377-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     197-244: Missing.

Show »
Length:298
Mass (Da):33,887
Checksum:iFB28DBD8BA587BDA
GO

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_004800197 – 244Missing in isoform CDK2-alpha. 1 PublicationAdd BLAST48

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U63337 mRNA Translation: AAB37128.1
AJ223732 mRNA Translation: CAA11533.1
AJ223733 Genomic DNA Translation: CAA11534.1
AJ223733 Genomic DNA Translation: CAA11535.1
BC005654 mRNA Translation: AAH05654.1
CCDSiCCDS24288.1 [P97377-2]
CCDS24289.1 [P97377-1]
RefSeqiNP_058036.1, NM_016756.4 [P97377-2]
NP_904326.1, NM_183417.3 [P97377-1]
UniGeneiMm.111326

Genome annotation databases

EnsembliENSMUST00000026415; ENSMUSP00000026415; ENSMUSG00000025358 [P97377-2]
ENSMUST00000026416; ENSMUSP00000026416; ENSMUSG00000025358 [P97377-1]
GeneIDi12566
KEGGimmu:12566
UCSCiuc007hny.2 mouse [P97377-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U63337 mRNA Translation: AAB37128.1
AJ223732 mRNA Translation: CAA11533.1
AJ223733 Genomic DNA Translation: CAA11534.1
AJ223733 Genomic DNA Translation: CAA11535.1
BC005654 mRNA Translation: AAH05654.1
CCDSiCCDS24288.1 [P97377-2]
CCDS24289.1 [P97377-1]
RefSeqiNP_058036.1, NM_016756.4 [P97377-2]
NP_904326.1, NM_183417.3 [P97377-1]
UniGeneiMm.111326

3D structure databases

ProteinModelPortaliP97377
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi198644, 30 interactors
ComplexPortaliCPX-2065 Cyclin A1-CDK2 complex
CPX-2066 Cyclin A2-CDK2 complex
CPX-2071 Cyclin B3-CDK2 complex
CPX-2081 Cyclin E1-CDK2 complex
CPX-2082 Cyclin E2-CDK2 complex
CORUMiP97377
DIPiDIP-24176N
ELMiP97377
IntActiP97377, 7 interactors
MINTiP97377
STRINGi10090.ENSMUSP00000026416

PTM databases

iPTMnetiP97377
PhosphoSitePlusiP97377
SwissPalmiP97377

Proteomic databases

PaxDbiP97377
PeptideAtlasiP97377
PRIDEiP97377

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000026415; ENSMUSP00000026415; ENSMUSG00000025358 [P97377-2]
ENSMUST00000026416; ENSMUSP00000026416; ENSMUSG00000025358 [P97377-1]
GeneIDi12566
KEGGimmu:12566
UCSCiuc007hny.2 mouse [P97377-1]

Organism-specific databases

CTDi1017
MGIiMGI:104772 Cdk2

Phylogenomic databases

eggNOGiKOG0594 Eukaryota
ENOG410XPP3 LUCA
GeneTreeiENSGT00910000144030
HOGENOMiHOG000233024
HOVERGENiHBG014652
InParanoidiP97377
KOiK02206
OMAiRHTNETI
OrthoDBiEOG091G0CH0
PhylomeDBiP97377
TreeFamiTF101021

Enzyme and pathway databases

BRENDAi2.7.11.22 3474
ReactomeiR-MMU-1538133 G0 and Early G1
R-MMU-176187 Activation of ATR in response to replication stress
R-MMU-176408 Regulation of APC/C activators between G1/S and early anaphase
R-MMU-187577 SCF(Skp2)-mediated degradation of p27/p21
R-MMU-2559582 Senescence-Associated Secretory Phenotype (SASP)
R-MMU-2559586 DNA Damage/Telomere Stress Induced Senescence
R-MMU-5693607 Processing of DNA double-strand break ends
R-MMU-6804116 TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest
R-MMU-6804756 Regulation of TP53 Activity through Phosphorylation
R-MMU-6804757 Regulation of TP53 Degradation
R-MMU-68911 G2 Phase
R-MMU-68949 Orc1 removal from chromatin
R-MMU-68962 Activation of the pre-replicative complex
R-MMU-69017 CDK-mediated phosphorylation and removal of Cdc6
R-MMU-69200 Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexes
R-MMU-69202 Cyclin E associated events during G1/S transition
R-MMU-69273 Cyclin A/B1/B2 associated events during G2/M transition
R-MMU-69563 p53-Dependent G1 DNA Damage Response
R-MMU-69656 Cyclin A:Cdk2-associated events at S phase entry
R-MMU-8849470 PTK6 Regulates Cell Cycle

Miscellaneous databases

ChiTaRSiCdk2 mouse
PROiPR:P97377
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000025358 Expressed in 248 organ(s), highest expression level in bone marrow
CleanExiMM_CDK2
ExpressionAtlasiP97377 baseline and differential
GenevisibleiP97377 MM

Family and domain databases

InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR008271 Ser/Thr_kinase_AS
PfamiView protein in Pfam
PF00069 Pkinase, 2 hits
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SUPFAMiSSF56112 SSF56112, 2 hits
PROSITEiView protein in PROSITE
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiCDK2_MOUSE
AccessioniPrimary (citable) accession number: P97377
Secondary accession number(s): O55105
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 15, 1999
Last sequence update: May 30, 2000
Last modified: November 7, 2018
This is version 179 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  3. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

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