CHK2_MOUSE
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 03-AUG-2022, entry version 185.
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; Q9Z265; -.
DR PRIDE; Q9Z265; -.
DR ProteomicsDB; 281211; -.
DR Antibodypedia; 278; 2059 antibodies from 49 providers.
DR DNASU; 50883; -.
DR Ensembl; ENSMUST00000066160; ENSMUSP00000066679; ENSMUSG00000029521.
DR GeneID; 50883; -.
DR KEGG; mmu:50883; -.
DR UCSC; uc008yrw.1; mouse.
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; 1510589at2759; -.
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; 0 hits in 110 CRISPR screens.
DR PRO; PR:Q9Z265; -.
DR Proteomes; UP000000589; Chromosome 5.
DR RNAct; Q9Z265; protein.
DR Bgee; ENSMUSG00000029521; Expressed in morula and 214 other tissues.
DR ExpressionAtlas; Q9Z265; baseline and differential.
DR Genevisible; Q9Z265; MM.
DR GO; GO:0000781; C:chromosome, telomeric region; ISO:MGI.
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; ISO:MGI.
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:1903926; P:cellular response to bisphenol A; IEA:Ensembl.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; ISS:UniProtKB.
DR GO; GO:0071480; P:cellular response to gamma radiation; IMP:MGI.
DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; IEA:Ensembl.
DR GO; GO:0000077; P:DNA damage checkpoint signaling; ISO:MGI.
DR GO; GO:0006975; P:DNA damage induced protein phosphorylation; 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:0018105; P:peptidyl-serine phosphorylation; IDA:MGI.
DR GO; GO:2000210; P:positive regulation of anoikis; ISO:MGI.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; ISO:MGI.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0046777; P:protein autophosphorylation; ISS:UniProtKB.
DR GO; GO:0030163; P:protein catabolic process; ISO:MGI.
DR GO; GO:0006468; P:protein phosphorylation; ISO:MGI.
DR GO; GO:0050821; P:protein stabilization; ISS:UniProtKB.
DR GO; GO:0051726; P:regulation of cell cycle; ISO:MGI.
DR GO; GO:0042176; P:regulation of protein catabolic process; ISS:UniProtKB.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0010332; P:response to gamma radiation; IDA:MGI.
DR GO; GO:1903416; P:response to glycoside; IEA:Ensembl.
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; cd00060; FHA; 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 Pfam; PF00498; FHA; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00240; FHA; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF49879; SSF49879; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50006; FHA_DOMAIN; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
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
