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Q9Z265

- CHK2_MOUSE

UniProt

Q9Z265 - CHK2_MOUSE

Protein

Serine/threonine-protein kinase Chk2

Gene

Chek2

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 129 (01 Oct 2014)
      Sequence version 1 (01 May 1999)
      Previous versions | rss
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    Functioni

    Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest, activation of DNA repair and apoptosis in response to the presence of DNA double-strand breaks. May also negatively regulate cell cycle progression during unperturbed cell cycles. Following activation, phosphorylates numerous effectors preferentially at the consensus sequence [L-X-R-X-X-S/T]. Regulates cell cycle checkpoint arrest through phosphorylation of CDC25A, CDC25B and CDC25C, inhibiting their activity. Inhibition of CDC25 phosphatase activity leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. May also phosphorylate NEK6 which is involved in G2/M cell cycle arrest. Regulates DNA repair through phosphorylation of BRCA2, enhancing the association of RAD51 with chromatin which promotes DNA repair by homologous recombination. Also stimulates the transcription of genes involved in DNA repair (including BRCA2) through the phosphorylation and activation of the transcription factor FOXM1. Regulates apoptosis through the phosphorylation of p53/TP53, MDM4 and PML. Phosphorylation of p53/TP53 at 'Ser-20' by CHEK2 may alleviate inhibition by MDM2, leading to accumulation of active p53/TP53. Phosphorylation of MDM4 may also reduce degradation of p53/TP53. Also controls the transcription of pro-apoptotic genes through phosphorylation of the transcription factor E2F1. Tumor suppressor, it may also have a DNA damage-independent function in mitotic spindle assembly by phosphorylating BRCA1. Its absence may be a cause of the chromosomal instability observed in some cancer cells.1 Publication

    Catalytic activityi

    ATP + a protein = ADP + a phosphoprotein.

    Cofactori

    Magnesium.

    Enzyme regulationi

    Activated through phosphorylation at Thr-68 by ATM in response to DNA double-strand breaks. Activation is modulated by several mediators including MDC1 and TP53BP1. Induces homodimerization with exchange of the T-loop/activation segment between protomers and transphosphorylation of the protomers. The autophosphorylated kinase dimer is fully active. Negatively regulated by PPM1D through dephosphorylation of Thr-68 By similarity.By similarity

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei253 – 2531ATPPROSITE-ProRule annotation
    Active sitei351 – 3511Proton acceptorPROSITE-ProRule annotation
    Binding sitei372 – 3721ATPPROSITE-ProRule annotation

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi231 – 2388ATPPROSITE-ProRule annotation
    Nucleotide bindingi306 – 3127ATPPROSITE-ProRule annotation
    Nucleotide bindingi355 – 3562ATPPROSITE-ProRule annotation

    GO - Molecular functioni

    1. ATP binding Source: UniProtKB-KW
    2. metal ion binding Source: UniProtKB-KW
    3. protein homodimerization activity Source: UniProtKB
    4. protein serine/threonine kinase activity Source: UniProtKB

    GO - Biological processi

    1. apoptotic process Source: MGI
    2. cellular protein catabolic process Source: Ensembl
    3. cellular response to DNA damage stimulus Source: UniProtKB
    4. DNA damage induced protein phosphorylation Source: UniProtKB
    5. double-strand break repair Source: UniProtKB
    6. G2/M transition of mitotic cell cycle Source: UniProtKB
    7. intrinsic apoptotic signaling pathway in response to DNA damage Source: UniProtKB
    8. positive regulation of transcription, DNA-templated Source: UniProtKB
    9. protein autophosphorylation Source: UniProtKB
    10. protein stabilization Source: Ensembl
    11. regulation of protein catabolic process Source: UniProtKB
    12. regulation of transcription, DNA-templated Source: UniProtKB
    13. response to gamma radiation Source: MGI
    14. signal transduction in response to DNA damage Source: MGI
    15. signal transduction involved in intra-S DNA damage checkpoint Source: UniProtKB
    16. spindle assembly involved in mitosis Source: UniProtKB
    17. transcription, DNA-templated Source: UniProtKB-KW

    Keywords - Molecular functioni

    Kinase, Serine/threonine-protein kinase, Transferase

    Keywords - Biological processi

    Apoptosis, Cell cycle, Cell division, DNA damage, DNA repair, Mitosis, Transcription, Transcription regulation

    Keywords - Ligandi

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

    Enzyme and pathway databases

    BRENDAi2.7.11.1. 3474.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Serine/threonine-protein kinase Chk2 (EC:2.7.11.1)
    Alternative name(s):
    CHK2 checkpoint homolog
    Checkpoint kinase 2
    Gene namesi
    Name:Chek2
    Synonyms:Chk2, Rad53
    OrganismiMus musculus (Mouse)
    Taxonomic identifieri10090 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
    ProteomesiUP000000589: Chromosome 5

    Organism-specific databases

    MGIiMGI:1355321. Chek2.

    Subcellular locationi

    NucleusPML body By similarity. Nucleusnucleoplasm
    Note: Recruited into PML bodies together with TP53.By similarity

    GO - Cellular componenti

    1. chromosome, telomeric region Source: Ensembl
    2. PML body Source: UniProtKB

    Keywords - Cellular componenti

    Nucleus

    Pathology & Biotechi

    Disruption phenotypei

    No overt morphological phenotype but apoptosis and cell cycle arrest induced by ionizing radiation are abolished.1 Publication

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 546546Serine/threonine-protein kinase Chk2PRO_0000085859Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei68 – 681Phosphothreonine; by MLTKBy similarity
    Modified residuei71 – 711Phosphoserine; by PLK3By similarity
    Modified residuei77 – 771Phosphothreonine; by ATM and MLTKBy similarity
    Modified residuei82 – 821Phosphoserine; by PLK3By similarity
    Modified residuei383 – 3831Phosphoserine; by autocatalysisBy similarity
    Modified residuei387 – 3871Phosphothreonine; by autocatalysisBy similarity
    Modified residuei391 – 3911Phosphothreonine; by autocatalysisBy similarity
    Modified residuei460 – 4601PhosphoserineBy similarity

    Post-translational modificationi

    Phosphorylated. Phosphorylated at Ser-82 by PLK3 in response to DNA damage, promoting phosphorylation at Thr-77 by ATM and the G2/M transition checkpoint. Phosphorylation at Thr-77 induces homodimerization. Autophosphorylates at Thr-387 and Thr-391 in the T-loop/activation segment upon dimerization to become fully active. DNA damage-induced autophosphorylation at Ser-383 induces CUL1-mediated ubiquitination and regulates the pro-apoptotic function. Phosphorylation at Ser-460 also regulates ubiquitination. Phosphorylated by PLK4 By similarity.By similarity
    Ubiquitinated. CUL1-mediated ubiquitination regulates the pro-apoptotic function. Ubiquitination may also regulate protein stability. Ubiquitinated by RNF8 via 'Lys-48'-linked ubiquitination By similarity.By similarity

    Keywords - PTMi

    Phosphoprotein, Ubl conjugation

    Proteomic databases

    MaxQBiQ9Z265.
    PaxDbiQ9Z265.
    PRIDEiQ9Z265.

    PTM databases

    PhosphoSiteiQ9Z265.

    Expressioni

    Tissue specificityi

    Ubiquitously expressed with higher levels in the thymus, spleen and colon (at protein level).1 Publication

    Gene expression databases

    ArrayExpressiQ9Z265.
    BgeeiQ9Z265.
    CleanExiMM_CHEK2.
    GenevestigatoriQ9Z265.

    Interactioni

    Subunit structurei

    Homodimer. Homodimerization is part of the activation process but the dimer may dissociate following activation. Interacts with PML. Interacts with TP53. Interacts with RB1; phosphorylates RB1. Interacts with BRCA1. Interacts (phosphorylated at Thr-68) with MDC1; requires ATM-mediated phosphorylation of CHEK2. Interacts with TP53BP1; modulates CHEK2 phosphorylation at Thr-68 in response to ionizing radiation. Interacts with CDC25A; phosphorylates CDC25A and mediates its degradation in response to ionizing radiation. Interacts with CUL1; mediates CHEK2 ubiquitination and regulation By similarity.By similarity

    Protein-protein interaction databases

    BioGridi206143. 6 interactions.
    IntActiQ9Z265. 4 interactions.

    Structurei

    3D structure databases

    ProteinModelPortaliQ9Z265.
    SMRiQ9Z265. Positions 94-506.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini117 – 17963FHAPROSITE-ProRule annotationAdd
    BLAST
    Domaini224 – 490267Protein kinasePROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni372 – 39827T-loop/activation segmentBy similarityAdd
    BLAST

    Sequence similaritiesi

    Contains 1 FHA domain.PROSITE-ProRule annotation
    Contains 1 protein kinase domain.PROSITE-ProRule annotation

    Phylogenomic databases

    eggNOGiCOG0515.
    GeneTreeiENSGT00710000106821.
    HOGENOMiHOG000233016.
    HOVERGENiHBG108055.
    InParanoidiQ9Z265.
    KOiK06641.
    OMAiKFAIGSE.
    OrthoDBiEOG7C5M7Z.
    PhylomeDBiQ9Z265.
    TreeFamiTF101082.

    Family and domain databases

    Gene3Di2.60.200.20. 1 hit.
    InterProiIPR000253. FHA_dom.
    IPR011009. Kinase-like_dom.
    IPR000719. Prot_kinase_dom.
    IPR002290. Ser/Thr_dual-sp_kinase_dom.
    IPR008271. Ser/Thr_kinase_AS.
    IPR008984. SMAD_FHA_domain.
    [Graphical view]
    PfamiPF00498. FHA. 1 hit.
    PF00069. Pkinase. 1 hit.
    [Graphical view]
    SMARTiSM00240. FHA. 1 hit.
    SM00220. S_TKc. 1 hit.
    [Graphical view]
    SUPFAMiSSF49879. SSF49879. 1 hit.
    SSF56112. SSF56112. 1 hit.
    PROSITEiPS50006. FHA_DOMAIN. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS00108. PROTEIN_KINASE_ST. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    Q9Z265-1 [UniParc]FASTAAdd to Basket

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    MKSHHQSHSS TSSKAHDSAS CSQSQGGFSQ PQGTPSQLHE LSQYQGSSSS    50
    STGTVPSSSQ SSHSSSGTLS SLETVSTQEL CSIPEDQEPE EPGPAPWARL 100
    WALQDGFSNL DCVNDNYWFG RDKSCEYCFD GPLLRRTDKY RTYSKKHFRI 150
    FREMGPKNCY IVYIEDHSGN GTFVNTELIG KGKRCPLSNN SEIALSLCRN 200
    KVFVFFDLTV DDQSVYPKEL RDEYIMSKTL GSGACGEVKM AFERKTCQKV 250
    AIKIISKRRF ALGSSREADT APSVETEIEI LKKLNHPCII KIKDVFDAED 300
    YYIVLELMEG GELFDRVVGN KRLKEATCKL YFYQMLVAVQ YLHENGIIHR 350
    DLKPENVLLS SQEEDCLIKI TDFGQSKILG ETSLMRTLCG TPTYLAPEVL 400
    VSNGTAGYSR AVDCWSLGVI LFICLSGYPP FSEHKTQVSL KDQITSGKYN 450
    FIPEVWTDVS EEALDLVKKL LVVDPKARLT TEEALNHPWL QDEYMKKKFQ 500
    DLLVQEKNSV TLPVAPAQTS SQKRPLELEV EGMPSTKRLS VCGAVL 546
    Length:546
    Mass (Da):61,088
    Last modified:May 1, 1999 - v1
    Checksum:iA7949EFB5572CDAA
    GO

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AF086905 mRNA. Translation: AAC83694.1.
    BC056617 mRNA. Translation: AAH56617.1.
    CCDSiCCDS19533.1.
    RefSeqiNP_057890.1. NM_016681.3.
    XP_006535132.1. XM_006535069.1.
    XP_006535133.1. XM_006535070.1.
    UniGeneiMm.279308.

    Genome annotation databases

    EnsembliENSMUST00000066160; ENSMUSP00000066679; ENSMUSG00000029521.
    GeneIDi50883.
    KEGGimmu:50883.
    UCSCiuc008yrw.1. mouse.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AF086905 mRNA. Translation: AAC83694.1 .
    BC056617 mRNA. Translation: AAH56617.1 .
    CCDSi CCDS19533.1.
    RefSeqi NP_057890.1. NM_016681.3.
    XP_006535132.1. XM_006535069.1.
    XP_006535133.1. XM_006535070.1.
    UniGenei Mm.279308.

    3D structure databases

    ProteinModelPortali Q9Z265.
    SMRi Q9Z265. Positions 94-506.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 206143. 6 interactions.
    IntActi Q9Z265. 4 interactions.

    PTM databases

    PhosphoSitei Q9Z265.

    Proteomic databases

    MaxQBi Q9Z265.
    PaxDbi Q9Z265.
    PRIDEi Q9Z265.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSMUST00000066160 ; ENSMUSP00000066679 ; ENSMUSG00000029521 .
    GeneIDi 50883.
    KEGGi mmu:50883.
    UCSCi uc008yrw.1. mouse.

    Organism-specific databases

    CTDi 11200.
    MGIi MGI:1355321. Chek2.

    Phylogenomic databases

    eggNOGi COG0515.
    GeneTreei ENSGT00710000106821.
    HOGENOMi HOG000233016.
    HOVERGENi HBG108055.
    InParanoidi Q9Z265.
    KOi K06641.
    OMAi KFAIGSE.
    OrthoDBi EOG7C5M7Z.
    PhylomeDBi Q9Z265.
    TreeFami TF101082.

    Enzyme and pathway databases

    BRENDAi 2.7.11.1. 3474.

    Miscellaneous databases

    NextBioi 307865.
    PROi Q9Z265.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi Q9Z265.
    Bgeei Q9Z265.
    CleanExi MM_CHEK2.
    Genevestigatori Q9Z265.

    Family and domain databases

    Gene3Di 2.60.200.20. 1 hit.
    InterProi IPR000253. FHA_dom.
    IPR011009. Kinase-like_dom.
    IPR000719. Prot_kinase_dom.
    IPR002290. Ser/Thr_dual-sp_kinase_dom.
    IPR008271. Ser/Thr_kinase_AS.
    IPR008984. SMAD_FHA_domain.
    [Graphical view ]
    Pfami PF00498. FHA. 1 hit.
    PF00069. Pkinase. 1 hit.
    [Graphical view ]
    SMARTi SM00240. FHA. 1 hit.
    SM00220. S_TKc. 1 hit.
    [Graphical view ]
    SUPFAMi SSF49879. SSF49879. 1 hit.
    SSF56112. SSF56112. 1 hit.
    PROSITEi PS50006. FHA_DOMAIN. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS00108. PROTEIN_KINASE_ST. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Linkage of ATM to cell cycle regulation by the Chk2 protein kinase."
      Matsuoka S., Huang M., Elledge S.J.
      Science 282:1893-1897(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    2. "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].
      Strain: NMRI.
      Tissue: Mammary gland.
    3. "Chk2 is a tumor suppressor that regulates apoptosis in both an ataxia telangiectasia mutated (ATM)-dependent and an ATM-independent manner."
      Hirao A., Cheung A., Duncan G., Girard P.M., Elia A.J., Wakeham A., Okada H., Sarkissian T., Wong J.A., Sakai T., De Stanchina E., Bristow R.G., Suda T., Lowe S.W., Jeggo P.A., Elledge S.J., Mak T.W.
      Mol. Cell. Biol. 22:6521-6532(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: DISRUPTION PHENOTYPE, FUNCTION IN APOPTOSIS, TISSUE SPECIFICITY.

    Entry informationi

    Entry nameiCHK2_MOUSE
    AccessioniPrimary (citable) accession number: Q9Z265
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: May 30, 2000
    Last sequence update: May 1, 1999
    Last modified: October 1, 2014
    This is version 129 of the entry and version 1 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