ID   CHK2_MOUSE              Reviewed;         546 AA.
AC   Q9Z265;
DT   30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT   01-MAY-1999, sequence version 1.
DT   27-MAR-2024, entry version 194.
DE   RecName: Full=Serine/threonine-protein kinase Chk2;
DE            EC=2.7.11.1;
DE   AltName: Full=CHK2 checkpoint homolog;
DE   AltName: Full=Checkpoint kinase 2;
GN   Name=Chek2; Synonyms=Chk2, Rad53;
OS   Mus musculus (Mouse).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Mus; Mus.
OX   NCBI_TaxID=10090;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=9836640; DOI=10.1126/science.282.5395.1893;
RA   Matsuoka S., Huang M., Elledge S.J.;
RT   "Linkage of ATM to cell cycle regulation by the Chk2 protein kinase.";
RL   Science 282:1893-1897(1998).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=NMRI; TISSUE=Mammary gland;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [3]
RP   DISRUPTION PHENOTYPE, FUNCTION IN APOPTOSIS, AND TISSUE SPECIFICITY.
RX   PubMed=12192050; DOI=10.1128/mcb.22.18.6521-6532.2002;
RA   Hirao A., Cheung A., Duncan G., Girard P.M., Elia A.J., Wakeham A.,
RA   Okada H., Sarkissian T., Wong J.A., Sakai T., De Stanchina E.,
RA   Bristow R.G., Suda T., Lowe S.W., Jeggo P.A., Elledge S.J., Mak T.W.;
RT   "Chk2 is a tumor suppressor that regulates apoptosis in both an ataxia
RT   telangiectasia mutated (ATM)-dependent and an ATM-independent manner.";
RL   Mol. Cell. Biol. 22:6521-6532(2002).
RN   [4]
RP   FUNCTION, AND MUTAGENESIS OF TYR-394.
RX   PubMed=25619829; DOI=10.1038/onc.2014.443;
RA   Wang N., Ding H., Liu C., Li X., Wei L., Yu J., Liu M., Ying M., Gao W.,
RA   Jiang H., Wang Y.;
RT   "A novel recurrent CHEK2 Y390C mutation identified in high-risk Chinese
RT   breast cancer patients impairs its activity and is associated with
RT   increased breast cancer risk.";
RL   Oncogene 34:5198-5205(2015).
CC   -!- FUNCTION: Serine/threonine-protein kinase which is required for
CC       checkpoint-mediated cell cycle arrest, activation of DNA repair and
CC       apoptosis in response to the presence of DNA double-strand breaks. May
CC       also negatively regulate cell cycle progression during unperturbed cell
CC       cycles. Following activation, phosphorylates numerous effectors
CC       preferentially at the consensus sequence [L-X-R-X-X-S/T]. Regulates
CC       cell cycle checkpoint arrest through phosphorylation of CDC25A, CDC25B
CC       and CDC25C, inhibiting their activity. Inhibition of CDC25 phosphatase
CC       activity leads to increased inhibitory tyrosine phosphorylation of CDK-
CC       cyclin complexes and blocks cell cycle progression. May also
CC       phosphorylate NEK6 which is involved in G2/M cell cycle arrest.
CC       Regulates DNA repair through phosphorylation of BRCA2, enhancing the
CC       association of RAD51 with chromatin which promotes DNA repair by
CC       homologous recombination. Also stimulates the transcription of genes
CC       involved in DNA repair (including BRCA2) through the phosphorylation
CC       and activation of the transcription factor FOXM1. Regulates apoptosis
CC       through the phosphorylation of p53/TP53, MDM4 and PML. Phosphorylation
CC       of p53/TP53 at 'Ser-20' by CHEK2 may alleviate inhibition by MDM2,
CC       leading to accumulation of active p53/TP53. Phosphorylation of MDM4 may
CC       also reduce degradation of p53/TP53. Also controls the transcription of
CC       pro-apoptotic genes through phosphorylation of the transcription factor
CC       E2F1. Tumor suppressor, it may also have a DNA damage-independent
CC       function in mitotic spindle assembly by phosphorylating BRCA1. Its
CC       absence may be a cause of the chromosomal instability observed in some
CC       cancer cells. Promotes the CCAR2-SIRT1 association and is required for
CC       CCAR2-mediated SIRT1 inhibition (By similarity).
CC       {ECO:0000250|UniProtKB:O96017, ECO:0000269|PubMed:12192050,
CC       ECO:0000269|PubMed:25619829}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC         [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC         COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC         threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC         Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC         ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC         EC=2.7.11.1;
CC   -!- COFACTOR:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC   -!- ACTIVITY REGULATION: Activated through phosphorylation at Thr-68 by ATM
CC       in response to DNA double-strand breaks. Activation is modulated by
CC       several mediators including MDC1 and TP53BP1. Induces homodimerization
CC       with exchange of the T-loop/activation segment between protomers and
CC       transphosphorylation of the protomers. The autophosphorylated kinase
CC       dimer is fully active. Negatively regulated by PPM1D through
CC       dephosphorylation of Thr-68 (By similarity). {ECO:0000250}.
CC   -!- SUBUNIT: Homodimer. Homodimerization is part of the activation process
CC       but the dimer may dissociate following activation. Interacts with PML.
CC       Interacts with TP53. Interacts with RB1; phosphorylates RB1. Interacts
CC       with BRCA1. Interacts (phosphorylated at Thr-68) with MDC1; requires
CC       ATM-mediated phosphorylation of CHEK2. Interacts with TP53BP1;
CC       modulates CHEK2 phosphorylation at Thr-68 in response to ionizing
CC       radiation. Interacts with CDC25A; phosphorylates CDC25A and mediates
CC       its degradation in response to ionizing radiation. Interacts with CUL1;
CC       mediates CHEK2 ubiquitination and regulation. Interacts with CDKN2AIP.
CC       Interacts (via protein kinase domain) with CCAR2 (via N-terminus).
CC       Interacts with SIRT1 (By similarity). {ECO:0000250|UniProtKB:O96017}.
CC   -!- SUBCELLULAR LOCATION: Nucleus, PML body {ECO:0000250}. Nucleus,
CC       nucleoplasm. Note=Recruited into PML bodies together with TP53.
CC       {ECO:0000250}.
CC   -!- TISSUE SPECIFICITY: Ubiquitously expressed with higher levels in the
CC       thymus, spleen and colon (at protein level).
CC       {ECO:0000269|PubMed:12192050}.
CC   -!- PTM: Phosphorylated. Phosphorylated at Ser-82 by PLK3 in response to
CC       DNA damage, promoting phosphorylation at Thr-77 by ATM and the G2/M
CC       transition checkpoint. Phosphorylation at Thr-77 induces
CC       homodimerization. Autophosphorylates at Thr-387 and Thr-391 in the T-
CC       loop/activation segment upon dimerization to become fully active. DNA
CC       damage-induced autophosphorylation at Ser-383 induces CUL1-mediated
CC       ubiquitination and regulates the pro-apoptotic function.
CC       Phosphorylation at Ser-460 also regulates ubiquitination.
CC       Phosphorylated by PLK4 (By similarity). {ECO:0000250}.
CC   -!- PTM: Ubiquitinated. CUL1-mediated ubiquitination regulates the pro-
CC       apoptotic function. Ubiquitination may also regulate protein stability.
CC       Ubiquitinated by RNF8 via 'Lys-48'-linked ubiquitination (By
CC       similarity). {ECO:0000250}.
CC   -!- DISRUPTION PHENOTYPE: No overt morphological phenotype but apoptosis
CC       and cell cycle arrest induced by ionizing radiation are abolished.
CC       {ECO:0000269|PubMed:12192050}.
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. CAMK Ser/Thr
CC       protein kinase family. CHK2 subfamily. {ECO:0000305}.
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DR   EMBL; AF086905; AAC83694.1; -; mRNA.
DR   EMBL; BC056617; AAH56617.1; -; mRNA.
DR   CCDS; CCDS19533.1; -.
DR   RefSeq; NP_057890.1; NM_016681.3.
DR   RefSeq; XP_006535132.1; XM_006535069.2.
DR   RefSeq; XP_006535133.1; XM_006535070.2.
DR   AlphaFoldDB; Q9Z265; -.
DR   SMR; Q9Z265; -.
DR   BioGRID; 206143; 5.
DR   IntAct; Q9Z265; 4.
DR   STRING; 10090.ENSMUSP00000066679; -.
DR   iPTMnet; Q9Z265; -.
DR   PhosphoSitePlus; Q9Z265; -.
DR   EPD; Q9Z265; -.
DR   MaxQB; Q9Z265; -.
DR   PaxDb; 10090-ENSMUSP00000066679; -.
DR   ProteomicsDB; 281211; -.
DR   Pumba; Q9Z265; -.
DR   Antibodypedia; 278; 2290 antibodies from 49 providers.
DR   DNASU; 50883; -.
DR   Ensembl; ENSMUST00000066160.3; ENSMUSP00000066679.2; ENSMUSG00000029521.8.
DR   GeneID; 50883; -.
DR   KEGG; mmu:50883; -.
DR   UCSC; uc008yrw.1; mouse.
DR   AGR; MGI:1355321; -.
DR   CTD; 11200; -.
DR   MGI; MGI:1355321; Chek2.
DR   VEuPathDB; HostDB:ENSMUSG00000029521; -.
DR   eggNOG; KOG0615; Eukaryota.
DR   GeneTree; ENSGT00800000124190; -.
DR   HOGENOM; CLU_000288_63_47_1; -.
DR   InParanoid; Q9Z265; -.
DR   OMA; MLCAVQY; -.
DR   OrthoDB; 20430at2759; -.
DR   PhylomeDB; Q9Z265; -.
DR   TreeFam; TF101082; -.
DR   BRENDA; 2.7.11.1; 3474.
DR   Reactome; R-MMU-5693565; Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks.
DR   Reactome; R-MMU-6804756; Regulation of TP53 Activity through Phosphorylation.
DR   Reactome; R-MMU-6804757; Regulation of TP53 Degradation.
DR   Reactome; R-MMU-6804760; Regulation of TP53 Activity through Methylation.
DR   Reactome; R-MMU-69473; G2/M DNA damage checkpoint.
DR   Reactome; R-MMU-69541; Stabilization of p53.
DR   Reactome; R-MMU-69601; Ubiquitin Mediated Degradation of Phosphorylated Cdc25A.
DR   Reactome; R-MMU-75035; Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex.
DR   BioGRID-ORCS; 50883; 1 hit in 115 CRISPR screens.
DR   PRO; PR:Q9Z265; -.
DR   Proteomes; UP000000589; Chromosome 5.
DR   RNAct; Q9Z265; Protein.
DR   Bgee; ENSMUSG00000029521; Expressed in morula and 217 other cell types or tissues.
DR   ExpressionAtlas; Q9Z265; baseline and differential.
DR   GO; GO:0000781; C:chromosome, telomeric region; IEA:Ensembl.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0005794; C:Golgi apparatus; ISO:MGI.
DR   GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR   GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR   GO; GO:0016605; C:PML body; ISS:UniProtKB.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR   GO; GO:0016301; F:kinase activity; ISO:MGI.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0042803; F:protein homodimerization activity; ISS:UniProtKB.
DR   GO; GO:0004672; F:protein kinase activity; IDA:MGI.
DR   GO; GO:0019901; F:protein kinase binding; ISO:MGI.
DR   GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR   GO; GO:0004674; F:protein serine/threonine kinase activity; ISS:UniProtKB.
DR   GO; GO:0031625; F:ubiquitin protein ligase binding; ISO:MGI.
DR   GO; GO:0051301; P:cell division; IEA:UniProtKB-KW.
DR   GO; GO:0071480; P:cellular response to gamma radiation; IMP:MGI.
DR   GO; GO:0000077; P:DNA damage checkpoint signaling; ISO:MGI.
DR   GO; GO:0006974; P:DNA damage response; ISS:UniProtKB.
DR   GO; GO:0006978; P:DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator; IMP:MGI.
DR   GO; GO:0006302; P:double-strand break repair; ISS:UniProtKB.
DR   GO; GO:0000086; P:G2/M transition of mitotic cell cycle; ISS:UniProtKB.
DR   GO; GO:0008630; P:intrinsic apoptotic signaling pathway in response to DNA damage; ISS:UniProtKB.
DR   GO; GO:0042771; P:intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator; IMP:MGI.
DR   GO; GO:0044773; P:mitotic DNA damage checkpoint signaling; IBA:GO_Central.
DR   GO; GO:0031573; P:mitotic intra-S DNA damage checkpoint signaling; ISS:UniProtKB.
DR   GO; GO:0090307; P:mitotic spindle assembly; ISS:UniProtKB.
DR   GO; GO:2000002; P:negative regulation of DNA damage checkpoint; ISO:MGI.
DR   GO; GO:2000210; P:positive regulation of anoikis; ISO:MGI.
DR   GO; GO:0045893; P:positive regulation of DNA-templated transcription; ISS:UniProtKB.
DR   GO; GO:0001934; P:positive regulation of protein phosphorylation; ISO:MGI.
DR   GO; GO:0046777; P:protein autophosphorylation; ISS:UniProtKB.
DR   GO; GO:0030163; P:protein catabolic process; ISO:MGI.
DR   GO; GO:0050821; P:protein stabilization; ISS:UniProtKB.
DR   GO; GO:0006355; P:regulation of DNA-templated transcription; ISS:UniProtKB.
DR   GO; GO:0042176; P:regulation of protein catabolic process; ISS:UniProtKB.
DR   GO; GO:0010332; P:response to gamma radiation; IDA:MGI.
DR   GO; GO:0042770; P:signal transduction in response to DNA damage; IDA:MGI.
DR   GO; GO:0070242; P:thymocyte apoptotic process; IMP:MGI.
DR   CDD; cd22666; FHA_CHK2; 1.
DR   CDD; cd14084; STKc_Chk2; 1.
DR   Gene3D; 2.60.200.20; -; 1.
DR   Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1.
DR   InterPro; IPR000253; FHA_dom.
DR   InterPro; IPR011009; Kinase-like_dom_sf.
DR   InterPro; IPR000719; Prot_kinase_dom.
DR   InterPro; IPR008271; Ser/Thr_kinase_AS.
DR   InterPro; IPR008984; SMAD_FHA_dom_sf.
DR   PANTHER; PTHR44167; OVARIAN-SPECIFIC SERINE/THREONINE-PROTEIN KINASE LOK-RELATED; 1.
DR   PANTHER; PTHR44167:SF9; SERINE_THREONINE-PROTEIN KINASE CHK2; 1.
DR   Pfam; PF00498; FHA; 1.
DR   Pfam; PF00069; Pkinase; 1.
DR   SMART; SM00240; FHA; 1.
DR   SMART; SM00220; S_TKc; 1.
DR   SUPFAM; SSF56112; Protein kinase-like (PK-like); 1.
DR   SUPFAM; SSF49879; SMAD/FHA domain; 1.
DR   PROSITE; PS50006; FHA_DOMAIN; 1.
DR   PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR   PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
DR   Genevisible; Q9Z265; MM.
PE   1: Evidence at protein level;
KW   Apoptosis; ATP-binding; Cell cycle; Cell division; DNA damage; DNA repair;
KW   Kinase; Magnesium; Metal-binding; Mitosis; Nucleotide-binding; Nucleus;
KW   Phosphoprotein; Reference proteome; Serine/threonine-protein kinase;
KW   Transcription; Transcription regulation; Transferase; Ubl conjugation.
FT   CHAIN           1..546
FT                   /note="Serine/threonine-protein kinase Chk2"
FT                   /id="PRO_0000085859"
FT   DOMAIN          117..179
FT                   /note="FHA"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00086"
FT   DOMAIN          224..490
FT                   /note="Protein kinase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   REGION          1..70
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          372..398
FT                   /note="T-loop/activation segment"
FT                   /evidence="ECO:0000250"
FT   COMPBIAS        10..70
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        351
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT                   ECO:0000255|PROSITE-ProRule:PRU10027"
FT   BINDING         231..238
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         253
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         306..312
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         355..356
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         372
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   MOD_RES         68
FT                   /note="Phosphothreonine; by MAP3K20"
FT                   /evidence="ECO:0000250"
FT   MOD_RES         71
FT                   /note="Phosphoserine; by PLK3"
FT                   /evidence="ECO:0000250|UniProtKB:O96017"
FT   MOD_RES         77
FT                   /note="Phosphothreonine; by ATM and MAP3K20"
FT                   /evidence="ECO:0000250|UniProtKB:O96017"
FT   MOD_RES         82
FT                   /note="Phosphoserine; by PLK3"
FT                   /evidence="ECO:0000250|UniProtKB:O96017"
FT   MOD_RES         383
FT                   /note="Phosphoserine; by autocatalysis"
FT                   /evidence="ECO:0000250|UniProtKB:O96017"
FT   MOD_RES         387
FT                   /note="Phosphothreonine; by autocatalysis"
FT                   /evidence="ECO:0000250|UniProtKB:O96017"
FT   MOD_RES         391
FT                   /note="Phosphothreonine; by autocatalysis"
FT                   /evidence="ECO:0000250|UniProtKB:O96017"
FT   MOD_RES         460
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:O96017"
FT   MUTAGEN         394
FT                   /note="Y->C: Does not inhibit cell survival upon DNA
FT                   damage. Not phosphorylates p53/TP53."
FT                   /evidence="ECO:0000269|PubMed:25619829"
SQ   SEQUENCE   546 AA;  61088 MW;  A7949EFB5572CDAA CRC64;
     MKSHHQSHSS TSSKAHDSAS CSQSQGGFSQ PQGTPSQLHE LSQYQGSSSS STGTVPSSSQ
     SSHSSSGTLS SLETVSTQEL CSIPEDQEPE EPGPAPWARL WALQDGFSNL DCVNDNYWFG
     RDKSCEYCFD GPLLRRTDKY RTYSKKHFRI FREMGPKNCY IVYIEDHSGN GTFVNTELIG
     KGKRCPLSNN SEIALSLCRN KVFVFFDLTV DDQSVYPKEL RDEYIMSKTL GSGACGEVKM
     AFERKTCQKV AIKIISKRRF ALGSSREADT APSVETEIEI LKKLNHPCII KIKDVFDAED
     YYIVLELMEG GELFDRVVGN KRLKEATCKL YFYQMLVAVQ YLHENGIIHR DLKPENVLLS
     SQEEDCLIKI TDFGQSKILG ETSLMRTLCG TPTYLAPEVL VSNGTAGYSR AVDCWSLGVI
     LFICLSGYPP FSEHKTQVSL KDQITSGKYN FIPEVWTDVS EEALDLVKKL LVVDPKARLT
     TEEALNHPWL QDEYMKKKFQ DLLVQEKNSV TLPVAPAQTS SQKRPLELEV EGMPSTKRLS
     VCGAVL
//