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Protein

Serine/threonine-protein kinase Chk2

Gene

Chek2

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

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.By similarity2 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Cofactori

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. identical protein binding Source: MGI
  3. metal ion binding Source: UniProtKB-KW
  4. protein homodimerization activity Source: UniProtKB
  5. protein kinase binding Source: MGI
  6. protein serine/threonine kinase activity Source: UniProtKB
  7. ubiquitin protein ligase binding Source: MGI

GO - Biological processi

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

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.
ReactomeiREACT_232069. Ubiquitin Mediated Degradation of Phosphorylated Cdc25A.
REACT_251223. G2/M DNA damage checkpoint.

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 Componenti: Chromosome 5

Organism-specific databases

MGIiMGI:1355321. Chek2.

Subcellular locationi

  1. NucleusPML body By similarity
  2. Nucleusnucleoplasm

  3. Note: Recruited into PML bodies together with TP53.By similarity

GO - Cellular componenti

  1. chromosome, telomeric region Source: Ensembl
  2. Golgi apparatus Source: MGI
  3. nucleoplasm Source: MGI
  4. PML body Source: UniProtKB
Complete GO annotation...

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

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi394 – 3941Y → C: Does not inhibit cell survival upon DNA damage. Not phosphorylates p53/TP53. 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

BgeeiQ9Z265.
CleanExiMM_CHEK2.
ExpressionAtlasiQ9Z265. baseline and differential.
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). Interacts with CDKN2AIP.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.
GeneTreeiENSGT00780000121901.
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.
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

« Hide

        10         20         30         40         50
MKSHHQSHSS TSSKAHDSAS CSQSQGGFSQ PQGTPSQLHE LSQYQGSSSS
60 70 80 90 100
STGTVPSSSQ SSHSSSGTLS SLETVSTQEL CSIPEDQEPE EPGPAPWARL
110 120 130 140 150
WALQDGFSNL DCVNDNYWFG RDKSCEYCFD GPLLRRTDKY RTYSKKHFRI
160 170 180 190 200
FREMGPKNCY IVYIEDHSGN GTFVNTELIG KGKRCPLSNN SEIALSLCRN
210 220 230 240 250
KVFVFFDLTV DDQSVYPKEL RDEYIMSKTL GSGACGEVKM AFERKTCQKV
260 270 280 290 300
AIKIISKRRF ALGSSREADT APSVETEIEI LKKLNHPCII KIKDVFDAED
310 320 330 340 350
YYIVLELMEG GELFDRVVGN KRLKEATCKL YFYQMLVAVQ YLHENGIIHR
360 370 380 390 400
DLKPENVLLS SQEEDCLIKI TDFGQSKILG ETSLMRTLCG TPTYLAPEVL
410 420 430 440 450
VSNGTAGYSR AVDCWSLGVI LFICLSGYPP FSEHKTQVSL KDQITSGKYN
460 470 480 490 500
FIPEVWTDVS EEALDLVKKL LVVDPKARLT TEEALNHPWL QDEYMKKKFQ
510 520 530 540
DLLVQEKNSV TLPVAPAQTS SQKRPLELEV EGMPSTKRLS VCGAVL
Length:546
Mass (Da):61,088
Last modified:May 1, 1999 - v1
Checksum:iA7949EFB5572CDAA
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF086905 mRNA. Translation: AAC83694.1.
BC056617 mRNA. Translation: AAH56617.1.
CCDSiCCDS19533.1.
RefSeqiNP_057890.1. NM_016681.3.
XP_006535132.1. XM_006535069.2.
XP_006535133.1. XM_006535070.2.
UniGeneiMm.279308.

Genome annotation databases

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

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF086905 mRNA. Translation: AAC83694.1.
BC056617 mRNA. Translation: AAH56617.1.
CCDSiCCDS19533.1.
RefSeqiNP_057890.1. NM_016681.3.
XP_006535132.1. XM_006535069.2.
XP_006535133.1. XM_006535070.2.
UniGeneiMm.279308.

3D structure databases

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

Protein-protein interaction databases

BioGridi206143. 6 interactions.
IntActiQ9Z265. 4 interactions.

PTM databases

PhosphoSiteiQ9Z265.

Proteomic databases

MaxQBiQ9Z265.
PaxDbiQ9Z265.
PRIDEiQ9Z265.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

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

Organism-specific databases

CTDi11200.
MGIiMGI:1355321. Chek2.

Phylogenomic databases

eggNOGiCOG0515.
GeneTreeiENSGT00780000121901.
HOGENOMiHOG000233016.
HOVERGENiHBG108055.
InParanoidiQ9Z265.
KOiK06641.
OMAiKFAIGSE.
OrthoDBiEOG7C5M7Z.
PhylomeDBiQ9Z265.
TreeFamiTF101082.

Enzyme and pathway databases

BRENDAi2.7.11.1. 3474.
ReactomeiREACT_232069. Ubiquitin Mediated Degradation of Phosphorylated Cdc25A.
REACT_251223. G2/M DNA damage checkpoint.

Miscellaneous databases

NextBioi307865.
PROiQ9Z265.
SOURCEiSearch...

Gene expression databases

BgeeiQ9Z265.
CleanExiMM_CHEK2.
ExpressionAtlasiQ9Z265. baseline and differential.
GenevestigatoriQ9Z265.

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.
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]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  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.
  4. "A novel recurrent CHEK2 Y390C mutation identified in high-risk Chinese breast cancer patients impairs its activity and is associated with increased breast cancer risk."
    Wang N., Ding H., Liu C., Li X., Wei L., Yu J., Liu M., Ying M., Gao W., Jiang H., Wang Y.
    Oncogene 0:0-0(2015) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, MUTAGENESIS OF TYR-394.

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: April 29, 2015
This is version 136 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

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.