Q9Z265 (CHK2_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified May 1, 2013. Version 116. History...
Names and origin
|Protein names||Recommended name:|
Serine/threonine-protein kinase Chk2
CHK2 checkpoint homolog
Checkpoint kinase 2
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||546 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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
ATP + a protein = ADP + a phosphoprotein.
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.
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.
Ubiquitously expressed with higher levels in the thymus, spleen and colon (at protein level). Ref.3
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.
No overt morphological phenotype but apoptosis and cell cycle arrest induced by ionizing radiation are abolished. Ref.3
Contains 1 FHA domain.
Contains 1 protein kinase domain.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 546||546||Serine/threonine-protein kinase Chk2||PRO_0000085859|
|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|
|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|
|||"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].
|||"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].
Tissue: Mammary gland.
|||"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.|
|AF086905 mRNA. Translation: AAC83694.1.|
BC056617 mRNA. Translation: AAH56617.1.
|RefSeq||NP_057890.1. NM_016681.3. |
3D structure databases
|SMR||Q9Z265. Positions 94-537. |
Protein-protein interaction databases
|IntAct||Q9Z265. 4 interactions.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSMUST00000066160; ENSMUSP00000066679; ENSMUSG00000029521. |
|MGI||MGI:1355321. Chek2. |
Enzyme and pathway databases
|BRENDA||184.108.40.206. 3474. |
Gene expression databases
|GermOnline||ENSMUSG00000029521. Mus musculus. |
Family and domain databases
|Gene3D||220.127.116.11. 1 hit. |
|InterPro||IPR000253. FHA_dom. |
|Pfam||PF00498. FHA. 1 hit. |
PF00069. Pkinase. 1 hit.
|SMART||SM00240. FHA. 1 hit. |
SM00220. S_TKc. 1 hit.
|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.
|Accession||Primary (citable) accession number: Q9Z265|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|