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P97377

- CDK2_MOUSE

UniProt

P97377 - CDK2_MOUSE

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Protein

Cyclin-dependent kinase 2

Gene

Cdk2

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- 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. Interacts with cyclins A, B1, B3, D, or E. 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.By similarity4 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Enzyme 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)LengthDescriptionGraphical viewFeature identifierActions
Sitei9 – 91CDK7 bindingBy similarity
Binding sitei33 – 331ATPPROSITE-ProRule annotation
Binding sitei86 – 861ATPPROSITE-ProRule annotation
Sitei88 – 892CDK7 bindingBy similarity
Active sitei127 – 1271Proton acceptorPROSITE-ProRule annotation
Metal bindingi132 – 1321Magnesium; catalyticBy similarity
Metal bindingi145 – 1451Magnesium; catalyticBy similarity
Binding sitei145 – 1451ATPPROSITE-ProRule annotation
Sitei166 – 1661CDK7 bindingBy similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi10 – 189ATPPROSITE-ProRule annotation
Nucleotide bindingi81 – 833ATPPROSITE-ProRule annotation
Nucleotide bindingi129 – 1324ATPPROSITE-ProRule annotation

GO - Molecular functioni

  1. ATP binding Source: UniProtKB-KW
  2. cyclin binding Source: MGI
  3. cyclin-dependent protein serine/threonine kinase activity Source: MGI
  4. histone kinase activity Source: Ensembl
  5. kinase activity Source: MGI
  6. metal ion binding Source: UniProtKB-KW
  7. protein kinase activity Source: MGI

GO - Biological processi

  1. DNA repair Source: UniProtKB-KW
  2. G1/S transition of mitotic cell cycle Source: MGI
  3. meiotic nuclear division Source: UniProtKB-KW
  4. mitotic nuclear division Source: UniProtKB-KW
  5. positive regulation of cell proliferation Source: Ensembl
  6. positive regulation of DNA-dependent DNA replication initiation Source: MGI
  7. positive regulation of transcription, DNA-templated Source: MGI
  8. potassium ion transport Source: MGI
  9. protein phosphorylation Source: MGI
  10. Ras protein signal transduction Source: Ensembl
  11. regulation of cell cycle Source: GOC
  12. regulation of gene silencing Source: Ensembl
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

Cell cycle, Cell division, DNA damage, DNA repair, Meiosis, Mitosis

Keywords - Ligandi

ATP-binding, Magnesium, Metal-binding, Nucleotide-binding

Enzyme and pathway databases

ReactomeiREACT_188819. DNA Damage/Telomere Stress Induced Senescence.
REACT_198629. Meiotic recombination.
REACT_198649. Factors involved in megakaryocyte development and platelet production.
REACT_199110. G0 and Early G1.
REACT_206033. Senescence-Associated Secretory Phenotype (SASP).
REACT_206803. Cyclin A/B1 associated events during G2/M transition.
REACT_219010. Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexes.
REACT_220647. SCF(Skp2)-mediated degradation of p27/p21.
REACT_223647. Cyclin A:Cdk2-associated events at S phase entry.
REACT_227891. G2 Phase.
REACT_27235. Meiotic Recombination.

Names & Taxonomyi

Protein namesi
Recommended name:
Cyclin-dependent kinase 2 (EC:2.7.11.22)
Alternative name(s):
Cell division protein kinase 2
Gene namesi
Name:Cdk2
Synonyms:Cdkn2
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589: Chromosome 10

Organism-specific databases

MGIiMGI:104772. Cdk2.

Subcellular locationi

Cytoplasmcytoskeletonmicrotubule organizing centercentrosome By similarity. NucleusCajal body By similarity. Cytoplasm By similarity. Endosome By similarity
Note: Localized at the centrosomes in late G2 phase after separation of the centrosomes but before the start of prophase. Nuclear-cytoplasmic trafficking is mediated during the inhibition by 1,25-(OH)2D3 By similarity.By similarity

GO - Cellular componenti

  1. Cajal body Source: Ensembl
  2. chromosome, telomeric region Source: MGI
  3. condensed chromosome Source: MGI
  4. cyclin-dependent protein kinase holoenzyme complex Source: MGI
  5. cytoskeleton Source: UniProtKB-KW
  6. endosome Source: UniProtKB-KW
  7. nucleoplasm Source: Reactome
  8. nucleus Source: UniProtKB
  9. transcription factor complex Source: MGI
  10. X chromosome Source: MGI
  11. Y chromosome Source: MGI
Complete GO annotation...

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)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi15 – 151Y → F: Loss of tyrosine phosphorylation by WEE1 and CABLES1. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 346346Cyclin-dependent kinase 2PRO_0000085771Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei1 – 11N-acetylmethionineBy similarity
Modified residuei6 – 61N6-acetyllysineBy similarity
Modified residuei14 – 141PhosphothreonineBy similarity
Modified residuei15 – 151Phosphotyrosine; by WEE11 Publication
Modified residuei19 – 191PhosphotyrosineBy similarity
Modified residuei160 – 1601Phosphothreonine; by CAK and CCRKBy similarity

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.By similarity
Nitrosylated after treatment with nitric oxide (DETA-NO).By similarity

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

MaxQBiP97377.
PaxDbiP97377.
PRIDEiP97377.

PTM databases

PhosphoSiteiP97377.

Expressioni

Gene expression databases

BgeeiP97377.
CleanExiMM_CDK2.
ExpressionAtlasiP97377. baseline and differential.
GenevestigatoriP97377.

Interactioni

Subunit structurei

Found in a complex with CABLES1, CCNA1 and CCNE1. Interacts with CABLES1 By similarity. Interacts with UHRF2. Part of a complex consisting of UHRF2, CDK2 and CCNE1. Interacts with the Speedy/Ringo proteins SPDYA and SPDYC. 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 By similarity. May interact with CEP63 By similarity.By similarity

Binary interactionsi

WithEntry#Exp.IntActNotes
Ccna2P519433EBI-847048,EBI-846980
Ccne1Q614573EBI-847048,EBI-643090

Protein-protein interaction databases

BioGridi198644. 27 interactions.
DIPiDIP-24176N.
IntActiP97377. 5 interactions.
MINTiMINT-4090366.

Structurei

3D structure databases

ProteinModelPortaliP97377.
SMRiP97377. Positions 1-346.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini4 – 334331Protein kinasePROSITE-ProRule annotationAdd
BLAST

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiCOG0515.
HOGENOMiHOG000233024.
HOVERGENiHBG014652.
InParanoidiP97377.
KOiK02206.
OMAiLVHRFFR.
OrthoDBiEOG7966H8.
PhylomeDBiP97377.
TreeFamiTF101021.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 2 hits.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 2 hits.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. Align

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)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei197 – 24448Missing in isoform CDK2-alpha. 1 PublicationVSP_004800Add
BLAST

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
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

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
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 .
CCDSi CCDS24288.1. [P97377-2 ]
CCDS24289.1. [P97377-1 ]
RefSeqi NP_058036.1. NM_016756.4. [P97377-2 ]
NP_904326.1. NM_183417.3. [P97377-1 ]
UniGenei Mm.111326.

3D structure databases

ProteinModelPortali P97377.
SMRi P97377. Positions 1-346.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 198644. 27 interactions.
DIPi DIP-24176N.
IntActi P97377. 5 interactions.
MINTi MINT-4090366.

PTM databases

PhosphoSitei P97377.

Proteomic databases

MaxQBi P97377.
PaxDbi P97377.
PRIDEi P97377.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSMUST00000026415 ; ENSMUSP00000026415 ; ENSMUSG00000025358 . [P97377-2 ]
ENSMUST00000026416 ; ENSMUSP00000026416 ; ENSMUSG00000025358 . [P97377-1 ]
GeneIDi 12566.
KEGGi mmu:12566.
UCSCi uc007hny.2. mouse. [P97377-1 ]

Organism-specific databases

CTDi 1017.
MGIi MGI:104772. Cdk2.

Phylogenomic databases

eggNOGi COG0515.
HOGENOMi HOG000233024.
HOVERGENi HBG014652.
InParanoidi P97377.
KOi K02206.
OMAi LVHRFFR.
OrthoDBi EOG7966H8.
PhylomeDBi P97377.
TreeFami TF101021.

Enzyme and pathway databases

Reactomei REACT_188819. DNA Damage/Telomere Stress Induced Senescence.
REACT_198629. Meiotic recombination.
REACT_198649. Factors involved in megakaryocyte development and platelet production.
REACT_199110. G0 and Early G1.
REACT_206033. Senescence-Associated Secretory Phenotype (SASP).
REACT_206803. Cyclin A/B1 associated events during G2/M transition.
REACT_219010. Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexes.
REACT_220647. SCF(Skp2)-mediated degradation of p27/p21.
REACT_223647. Cyclin A:Cdk2-associated events at S phase entry.
REACT_227891. G2 Phase.
REACT_27235. Meiotic Recombination.

Miscellaneous databases

ChiTaRSi CDK2. mouse.
NextBioi 281656.
PROi P97377.
SOURCEi Search...

Gene expression databases

Bgeei P97377.
CleanExi MM_CDK2.
ExpressionAtlasi P97377. baseline and differential.
Genevestigatori P97377.

Family and domain databases

InterProi IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view ]
Pfami PF00069. Pkinase. 2 hits.
[Graphical view ]
SMARTi SM00220. S_TKc. 1 hit.
[Graphical view ]
SUPFAMi SSF56112. SSF56112. 2 hits.
PROSITEi PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  1. "Exon-intron organization of the murine cyclin-dependent kinase-2 genes Cdk2-alpha and Cdk2-beta."
    Jun D., Lee Y.H., Park H.K., Kim Y.H.
    Submitted (JUL-1996) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM CDK2-ALPHA).
    Strain: C57BL/6.
  2. "The 39 kDa form of CDK2 arises through alternative splicing, is expressed in many but not all mammals, and is an active kinase."
    Ellenrieder C., Bartosch B., Lee G.Y., Murphy M., Sweeney C., Hergersberg M., Hunt T., Carrington M., Jaussi R.
    Submitted (JAN-1998) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], ALTERNATIVE SPLICING.
  3. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM CDK2-BETA).
    Strain: FVB/N.
    Tissue: Mammary gland.
  4. "Cables enhances cdk2 tyrosine 15 phosphorylation by Wee1, inhibits cell growth, and is lost in many human colon and squamous cancers."
    Wu C.-L., Kirley S.D., Xiao H., Chuang Y., Chung D.C., Zukerberg L.R.
    Cancer Res. 61:7325-7332(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION AT TYR-15, MUTAGENESIS OF TYR-15, IDENTIFICATION IN A COMPLEX WITH CABLES1; CCNA1 AND CCNE1, INTERACTION WITH CABLES1.
  5. Cited for: FUNCTION AS CABLES1 KINASE.
  6. Cited for: FUNCTION, DISRUPTION PHENOTYPE.
  7. "Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice."
    Ortega S., Prieto I., Odajima J., Martin A., Dubus P., Sotillo R., Barbero J.L., Malumbres M., Barbacid M.
    Nat. Genet. 35:25-31(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, DISRUPTION PHENOTYPE.
  8. "p21 Inhibits Cdk1 in the absence of Cdk2 to maintain the G1/S phase DNA damage checkpoint."
    Satyanarayana A., Hilton M.B., Kaldis P.
    Mol. Biol. Cell 19:65-77(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, DISRUPTION PHENOTYPE.

Entry informationi

Entry nameiCDK2_MOUSE
AccessioniPrimary (citable) accession number: P97377
Secondary accession number(s): O55105
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 15, 1999
Last sequence update: May 30, 2000
Last modified: October 29, 2014
This is version 140 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3