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P97377 (CDK2_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 134. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Cyclin-dependent kinase 2

EC=2.7.11.22
Alternative name(s):
Cell division protein kinase 2
Gene names
Name:Cdk2
Synonyms:Cdkn2
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length346 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.5 Ref.6 Ref.7 Ref.8

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulation

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.

Subunit structure

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. Ref.4

Subcellular location

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.

Post-translational modification

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. Ref.4

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

Disruption phenotype

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. Ref.6 Ref.7 Ref.8

Sequence similarities

Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily.

Contains 1 protein kinase domain.

Ontologies

Keywords
   Biological processCell cycle
Cell division
DNA damage
DNA repair
Meiosis
Mitosis
   Cellular componentCytoplasm
Cytoskeleton
Endosome
Nucleus
   Coding sequence diversityAlternative splicing
   LigandATP-binding
Magnesium
Metal-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMAcetylation
Phosphoprotein
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processDNA repair

Inferred from electronic annotation. Source: UniProtKB-KW

G1/S transition of mitotic cell cycle

Inferred from direct assay PubMed 12970171. Source: MGI

Ras protein signal transduction

Inferred from electronic annotation. Source: Ensembl

meiotic nuclear division

Inferred from electronic annotation. Source: UniProtKB-KW

mitosis

Inferred from electronic annotation. Source: UniProtKB-KW

positive regulation of DNA-dependent DNA replication initiation

Inferred from genetic interaction PubMed 20215406. Source: MGI

positive regulation of cell proliferation

Inferred from electronic annotation. Source: Ensembl

positive regulation of transcription, DNA-templated

Inferred from genetic interaction PubMed 16137671. Source: MGI

potassium ion transport

Inferred from genetic interaction PubMed 16393152. Source: MGI

protein phosphorylation

Inferred from direct assay PubMed 12124778. Source: MGI

regulation of gene silencing

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentCajal body

Inferred from electronic annotation. Source: UniProtKB-SubCell

X chromosome

Inferred from direct assay PubMed 17784788. Source: MGI

Y chromosome

Inferred from direct assay PubMed 17784788. Source: MGI

chromosome, telomeric region

Inferred from direct assay PubMed 17784788. Source: MGI

condensed chromosome

Inferred from direct assay PubMed 17784788. Source: MGI

cyclin-dependent protein kinase holoenzyme complex

Inferred from physical interaction PubMed 12970760. Source: MGI

endosome

Inferred from electronic annotation. Source: UniProtKB-SubCell

microtubule organizing center

Inferred from electronic annotation. Source: UniProtKB-SubCell

nucleoplasm

Traceable author statement. Source: Reactome

nucleus

Inferred from direct assay PubMed 19773423. Source: UniProtKB

transcription factor complex

Inferred from direct assay PubMed 10082561. Source: MGI

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

cyclin binding

Inferred from physical interaction PubMed 11981756. Source: MGI

cyclin-dependent protein serine/threonine kinase activity

Inferred from direct assay PubMed 12970171PubMed 12970760. Source: MGI

histone kinase activity

Inferred from electronic annotation. Source: Ensembl

kinase activity

Inferred from direct assay PubMed 12124778. Source: MGI

metal ion binding

Inferred from electronic annotation. Source: UniProtKB-KW

protein kinase activity

Inferred from direct assay PubMed 21508411. Source: MGI

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Ccna2P519433EBI-847048,EBI-846980
Ccne1Q614573EBI-847048,EBI-643090

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform CDK2-beta (identifier: P97377-1)

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.
Isoform CDK2-alpha (identifier: P97377-2)

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

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 346346Cyclin-dependent kinase 2
PRO_0000085771

Regions

Domain4 – 334331Protein kinase
Nucleotide binding10 – 189ATP By similarity
Nucleotide binding81 – 833ATP By similarity
Nucleotide binding129 – 1324ATP By similarity

Sites

Active site1271Proton acceptor By similarity
Metal binding1321Magnesium; catalytic By similarity
Metal binding1451Magnesium; catalytic By similarity
Binding site331ATP By similarity
Binding site861ATP By similarity
Binding site1451ATP By similarity
Site91CDK7 binding By similarity
Site88 – 892CDK7 binding By similarity
Site1661CDK7 binding By similarity

Amino acid modifications

Modified residue11N-acetylmethionine By similarity
Modified residue61N6-acetyllysine By similarity
Modified residue141Phosphothreonine By similarity
Modified residue151Phosphotyrosine; by WEE1 Ref.4
Modified residue191Phosphotyrosine By similarity
Modified residue1601Phosphothreonine; by CAK and CCRK By similarity

Natural variations

Alternative sequence197 – 24448Missing in isoform CDK2-alpha.
VSP_004800

Experimental info

Mutagenesis151Y → F: Loss of thyrosine phosphorylation by WEE1 and CABLES1. Ref.4

Sequences

Sequence LengthMass (Da)Tools
Isoform CDK2-beta [UniParc].

Last modified May 30, 2000. Version 2.
Checksum: D806BC2F150AEDFC

FASTA34638,978
        10         20         30         40         50         60 
MENFQKVEKI GEGTYGVVYK AKNKLTGEVV ALKKIRLDTE TEGVPSTAIR EISLLKELNH 

        70         80         90        100        110        120 
PNIVKLLDVI HTENKLYLVF EFLHQDLKKF MDASALTGIP LPLIKSYLFQ LLQGLAFCHS 

       130        140        150        160        170        180 
HRVLHRDLKP QNLLINAEGS IKLADFGLAR AFGVPVRTYT HEVVTLWYRA PEILLGCKYY 

       190        200        210        220        230        240 
STAVDIWSLG CIFAEMHLVC TQHHAKCCGE HRRNGRHSLC PLCSYLEVAA SQGGGMTAVS 

       250        260        270        280        290        300 
APHPVTRRAL FPGDSEIDQL FRIFRTLGTP DEVVWPGVTS MPDYKPSFPK WARQDFSKVV 

       310        320        330        340 
PPLDEDGRSL LSQMLHYDPN KRISAKAALA HPFFQDVTKP VPHLRL 

« Hide

Isoform CDK2-alpha [UniParc].

Checksum: FB28DBD8BA587BDA
Show »

FASTA29833,887

References

« Hide 'large scale' references
[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]"ik3-1/Cables is a substrate for cyclin-dependent kinase 3 (cdk 3)."
Yamochi T., Semba K., Tsuji K., Mizumoto K., Sato H., Matsuura Y., Nishimoto I., Matsuoka M.
Eur. J. Biochem. 268:6076-6082(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION AS CABLES1 KINASE.
[6]"Cdk2 knockout mice are viable."
Berthet C., Aleem E., Coppola V., Tessarollo L., Kaldis P.
Curr. Biol. 13:1775-1785(2003) [PubMed] [Europe PMC] [Abstract]
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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
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.
RefSeqNP_058036.1. NM_016756.4.
NP_904326.1. NM_183417.3.
UniGeneMm.111326.

3D structure databases

ProteinModelPortalP97377.
SMRP97377. Positions 1-346.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid198644. 27 interactions.
DIPDIP-24176N.
IntActP97377. 5 interactions.
MINTMINT-4090366.

PTM databases

PhosphoSiteP97377.

Proteomic databases

PaxDbP97377.
PRIDEP97377.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000026415; ENSMUSP00000026415; ENSMUSG00000025358. [P97377-2]
ENSMUST00000026416; ENSMUSP00000026416; ENSMUSG00000025358. [P97377-1]
GeneID12566.
KEGGmmu:12566.
UCSCuc007hny.2. mouse. [P97377-1]

Organism-specific databases

CTD1017.
MGIMGI:104772. Cdk2.

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000233024.
HOVERGENHBG014652.
InParanoidP97377.
KOK02206.
OMAEMMLVYD.
OrthoDBEOG7966H8.
PhylomeDBP97377.
TreeFamTF101021.

Enzyme and pathway databases

ReactomeREACT_198624. Meiosis.
REACT_27235. Meiotic Recombination.

Gene expression databases

ArrayExpressP97377.
BgeeP97377.
CleanExMM_CDK2.
GenevestigatorP97377.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF00069. Pkinase. 2 hits.
[Graphical view]
SMARTSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 2 hits.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSCDK2. mouse.
NextBio281656.
PROP97377.
SOURCESearch...

Entry information

Entry nameCDK2_MOUSE
AccessionPrimary (citable) accession number: P97377
Secondary accession number(s): O55105
Entry history
Integrated into UniProtKB/Swiss-Prot: July 15, 1999
Last sequence update: May 30, 2000
Last modified: April 16, 2014
This is version 134 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot