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P97377

- CDK2_MOUSE

UniProt

P97377 - CDK2_MOUSE

Protein

Cyclin-dependent kinase 2

Gene

Cdk2

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 139 (01 Oct 2014)
      Sequence version 2 (30 May 2000)
      Previous versions | rss
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    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 binding Source: UniProtKB
    8. 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

    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: UniProtKB-SubCell
    2. chromosome, telomeric region Source: MGI
    3. condensed chromosome Source: MGI
    4. cyclin-dependent protein kinase holoenzyme complex Source: MGI
    5. endosome Source: UniProtKB-SubCell
    6. microtubule organizing center Source: UniProtKB-SubCell
    7. nucleoplasm Source: Reactome
    8. nucleus Source: UniProtKB
    9. transcription factor complex Source: MGI
    10. X chromosome Source: MGI
    11. Y chromosome Source: MGI

    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

    ArrayExpressiP97377.
    BgeeiP97377.
    CleanExiMM_CDK2.
    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_dom.
    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

    MENFQKVEKI GEGTYGVVYK AKNKLTGEVV ALKKIRLDTE TEGVPSTAIR    50
    EISLLKELNH PNIVKLLDVI HTENKLYLVF EFLHQDLKKF MDASALTGIP 100
    LPLIKSYLFQ LLQGLAFCHS HRVLHRDLKP QNLLINAEGS IKLADFGLAR 150
    AFGVPVRTYT HEVVTLWYRA PEILLGCKYY STAVDIWSLG CIFAEMHLVC 200
    TQHHAKCCGE HRRNGRHSLC PLCSYLEVAA SQGGGMTAVS APHPVTRRAL 250
    FPGDSEIDQL FRIFRTLGTP DEVVWPGVTS MPDYKPSFPK WARQDFSKVV 300
    PPLDEDGRSL LSQMLHYDPN KRISAKAALA HPFFQDVTKP VPHLRL 346
    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

    ArrayExpressi P97377.
    Bgeei P97377.
    CleanExi MM_CDK2.
    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_dom.
    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

    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 1, 2014
    This is version 139 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