Q9Z265 (CHK2_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Serine/threonine-protein kinase Chk2
EC=2.7.11.1

Alternative name(s):
CHK2 checkpoint homolog
Checkpoint kinase 2

Gene names

Name:	Chek2
Synonyms:	Chk2, Rad53

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	546 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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. Ref.3
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Cofactor	Magnesium.
Enzyme regulation	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.
Subunit structure	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.
Subcellular location	Nucleus › PML body By similarity. Nucleus › nucleoplasm. Note: Recruited into PML bodies together with TP53 By similarity.
Tissue specificity	Ubiquitously expressed with higher levels in the thymus, spleen and colon (at protein level). Ref.3
Post-translational modification	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. 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.
Disruption phenotype	No overt morphological phenotype but apoptosis and cell cycle arrest induced by ionizing radiation are abolished. Ref.3
Sequence similarities	Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. CHK2 subfamily. Contains 1 FHA domain. Contains 1 protein kinase domain.

Ontologies

Keywords
Biological process	Apoptosis Cell cycle Cell division DNA damage DNA repair Mitosis Transcription Transcription regulation
Cellular component	Nucleus
Ligand	ATP-binding Magnesium Metal-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	DNA damage induced protein phosphorylation Inferred from sequence or structural similarity. Source: UniProtKB G2/M transition of mitotic cell cycle Inferred from sequence or structural similarity. Source: UniProtKB cell division Inferred from electronic annotation. Source: UniProtKB-KW cellular protein catabolic process Inferred from electronic annotation. Source: Compara double-strand break repair Inferred from sequence or structural similarity. Source: UniProtKB intrinsic apoptotic signaling pathway in response to DNA damage Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of transcription, DNA-dependent Inferred from sequence or structural similarity. Source: UniProtKB protein autophosphorylation Inferred from sequence or structural similarity. Source: UniProtKB regulation of protein catabolic process Inferred from sequence or structural similarity. Source: UniProtKB response to gamma radiation Inferred from direct assay PubMed 14744935. Source: MGI signal transduction involved in intra-S DNA damage checkpoint Inferred from sequence or structural similarity. Source: UniProtKB spindle assembly involved in mitosis Inferred from sequence or structural similarity. Source: UniProtKB transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	PML body Inferred from sequence or structural similarity. Source: UniProtKB chromosome, telomeric region Inferred from electronic annotation. Source: Compara
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW protein homodimerization activity Inferred from sequence or structural similarity. Source: UniProtKB protein serine/threonine kinase activity Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 546	546	Serine/threonine-protein kinase Chk2		PRO_0000085859
Regions
	Domain	117 – 179	63	FHA
	Domain	224 – 490	267	Protein kinase
	Nucleotide binding	231 – 238	8	ATP By similarity
	Nucleotide binding	306 – 312	7	ATP By similarity
	Nucleotide binding	355 – 356	2	ATP By similarity
	Region	372 – 398	27	T-loop/activation segment By similarity
Sites
	Active site	351	1	Proton acceptor By similarity
	Binding site	253	1	ATP By similarity
	Binding site	372	1	ATP By similarity
Amino acid modifications
	Modified residue	68	1	Phosphothreonine; by MLTK By similarity
	Modified residue	71	1	Phosphoserine; by PLK3 By similarity
	Modified residue	77	1	Phosphothreonine; by ATM and MLTK By similarity
	Modified residue	82	1	Phosphoserine; by PLK3 By similarity
	Modified residue	383	1	Phosphoserine; by autocatalysis By similarity
	Modified residue	387	1	Phosphothreonine; by autocatalysis By similarity
	Modified residue	391	1	Phosphothreonine; by autocatalysis By similarity
	Modified residue	460	1	Phosphoserine By similarity

Sequences

	Sequence		Length	Mass (Da)
	Q9Z265 [UniParc]. Last modified May 1, 1999. Version 1. Checksum: A7949EFB5572CDAA	FASTA	546	61,088
	10 20 30 40 50 60 MKSHHQSHSS TSSKAHDSAS CSQSQGGFSQ PQGTPSQLHE LSQYQGSSSS STGTVPSSSQ 70 80 90 100 110 120 SSHSSSGTLS SLETVSTQEL CSIPEDQEPE EPGPAPWARL WALQDGFSNL DCVNDNYWFG 130 140 150 160 170 180 RDKSCEYCFD GPLLRRTDKY RTYSKKHFRI FREMGPKNCY IVYIEDHSGN GTFVNTELIG 190 200 210 220 230 240 KGKRCPLSNN SEIALSLCRN KVFVFFDLTV DDQSVYPKEL RDEYIMSKTL GSGACGEVKM 250 260 270 280 290 300 AFERKTCQKV AIKIISKRRF ALGSSREADT APSVETEIEI LKKLNHPCII KIKDVFDAED 310 320 330 340 350 360 YYIVLELMEG GELFDRVVGN KRLKEATCKL YFYQMLVAVQ YLHENGIIHR DLKPENVLLS 370 380 390 400 410 420 SQEEDCLIKI TDFGQSKILG ETSLMRTLCG TPTYLAPEVL VSNGTAGYSR AVDCWSLGVI 430 440 450 460 470 480 LFICLSGYPP FSEHKTQVSL KDQITSGKYN FIPEVWTDVS EEALDLVKKL LVVDPKARLT 490 500 510 520 530 540 TEEALNHPWL QDEYMKKKFQ DLLVQEKNSV TLPVAPAQTS SQKRPLELEV EGMPSTKRLS VCGAVL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[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.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF086905 mRNA. Translation: AAC83694.1. BC056617 mRNA. Translation: AAH56617.1.
IPI	IPI00130553.
RefSeq	NP_057890.1. NM_016681.3.
UniGene	Mm.279308.
3D structure databases
ProteinModelPortal	Q9Z265.
SMR	Q9Z265. Positions 94-537.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q9Z265. 4 interactions.
PTM databases
PhosphoSite	Q9Z265.
Proteomic databases
PaxDb	Q9Z265.
PRIDE	Q9Z265.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000066160; ENSMUSP00000066679; ENSMUSG00000029521.
GeneID	50883.
KEGG	mmu:50883.
Organism-specific databases
CTD	11200.
MGI	MGI:1355321. Chek2.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00680000099894.
HOGENOM	HOG000233016.
HOVERGEN	HBG108055.
InParanoid	Q9Z265.
KO	K06641.
OMA	KFAIGSE.
OrthoDB	EOG4M0F1R.
Enzyme and pathway databases
BRENDA	2.7.11.1. 3474.
Gene expression databases
ArrayExpress	Q9Z265.
Bgee	Q9Z265.
CleanEx	MM_CHEK2.
Genevestigator	Q9Z265.
GermOnline	ENSMUSG00000029521. Mus musculus.
Family and domain databases
Gene3D	2.60.200.20. 1 hit.
InterPro	IPR000253. FHA_dom. IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR002290. Ser/Thr_dual-sp_kinase_dom. IPR008271. Ser/Thr_kinase_AS. IPR008984. SMAD_FHA_domain. [Graphical view]
Pfam	PF00498. FHA. 1 hit. PF00069. Pkinase. 1 hit. [Graphical view]
SMART	SM00240. FHA. 1 hit. SM00220. S_TKc. 1 hit. [Graphical view]
SUPFAM	SSF56112. Kinase_like. 1 hit. SSF49879. SMAD_FHA. 1 hit.
PROSITE	PS50006. FHA_DOMAIN. 1 hit. PS00107. PROTEIN_KINASE_ATP. False negative. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	307865.
SOURCE	Search...

Entry information

Entry name

CHK2_MOUSE

Accession

Primary (citable) accession number: Q9Z265

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 30, 2000
Last sequence update:	May 1, 1999
Last modified:	May 1, 2013
This is version 116 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program