Homo sapiens L. (human) [HSA]

FULL NAME: Serine/threonine-protein kinase Chk2


DESCRIPTION:
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.
Regulates cell cycle checkpoints and apoptosis in response to DNA damage, particularly to DNA double-strand breaks. Inhibits CDC25C phosphatase by phosphorylation on 'Ser-216', preventing the entry into mitosis. May also play a role in meiosis. Regulates the TP53 tumor suppressor through phosphorylation at 'Thr-18' and 'Ser-20'. Phosphorylates NEK6.

MISCELLANEOUS:
High expression is found in testis, spleen, colon and peripheral blood leukocytes. Low expression is found in other tissues.


STRUCTURE SIMILARITY:
Contains 1 FHA domain.
Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. CHK2 subfamily.
Contains 1 protein kinase domain.


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.


CATALYTIC ACTIVITY:
ATP + a protein = ADP + a phosphoprotein.


ENZYME REGULATION:
Rapidly phosphorylated on Thr-68 by MLTK in response to DNA damage and to replication block. Kinase activity is also up-regulated by autophosphorylation.


POST-TRANSLATIONAL MODIFICATION:
Phosphorylated. Phosphorylation at Thr-68 induces homodimerization. Autophosphorylates at Thr-383 and Thr-387 in the T-loop/activation segment upon dimerization to become fully active and phosphorylate its substrates like for instance CDC25C. DNA damage-induced autophosphorylation at Ser-379 induces CUL1-mediated ubiquitination and regulates the pro-apoptotic function. Phosphorylation at Ser-456 also regulates ubiquitination. Phosphorylated by PLK4. Ubiquitinated. CUL1-mediated ubiquitination regulates the pro-apoptotic function. Ubiquitination may also regulate protein stability.


PROTEIN TYPE(S):
kinase


RELATED PATHWAY(S):
DNA damage response (DDR)


RELATED DISEASE(S):
osteogenic sarcoma
prostate cancer
breast cancer (BC)
Li-Fraumeni syndrome-2


Amino acids sequence

        10         20         30         40         50         60
MSRESDVEAQ QSHGSSACSQ PHGSVTQSQG SSSQSQGISS SSTSTMPNSS QSSHSSSGTL
        70         80         90        100        110        120
SSLETVSTQE LYSIPEDQEP EDQEPEEPTP APWARLWALQ DGFANLETES GHVTQSDLEL
       130        140        150        160        170        180
LLSSDPPASA SQSAGIRGVR HHPRPVCSLK CVNDNYWFGR DKSCEYCFDE PLLKRTDKYR
       190        200        210        220        230        240
TYSKKHFRIF REVGPKNSYI AYIEDHSGNG TFVNTELVGK GKRRPLNNNS EIALSLSRNK
       250        260        270        280        290        300
VFVFFDLTVD DQSVYPKALR DEYIMSKTLG SGACGEVKLA FERKTCKKVA IKIISKRKFA
       310        320        330        340        350        360
IGSAREADPA LNVETEIEIL KKLNHPCIIK IKNFFDAEDY YIVLELMEGG ELFDKVVGNK
       370        380        390        400        410        420
RLKEATCKLY FYQMLLAVQY LHENGIIHRD LKPENVLLSS QEEDCLIKIT DFGHSKILGE
       430        440        450        460        470        480
TSLMRTLCGT PTYLAPEVLV SVGTAGYNRA VDCWSLGVIL FICLSGYPPF SEHRTQVSLK
       490        500        510        520        530        540
DQITSGKYNF IPEVWAEVSE KALDLVKKLL VVDPKARFTT EEALRHPWLQ DEDMKRKFQD
       550        560        570        580
LLSEENESTA LPQVLAQPST SRKRPREGEA EGAETTKRPA VCAAVL 

Encoded by CHEK2 gene

FULL NAME: CHK2 checkpoint homolog (S. pombe)


OTHER NAME(S):
CDS1
CHK2
HuCds1
LFS2
PP1425
RAD53


DESCRIPTION:
In response to DNA damage and replication blocks, cell cycle progression is halted through the control of critical cell cycle regulators. The protein encoded by this gene is a cell cycle checkpoint regulator and putative tumor suppressor. It contains a forkhead-associated protein interaction domain essential for activation in response to DNA damage and is rapidly phosphorylated in response to replication blocks and DNA damage. When activated, the encoded protein is known to inhibit CDC25C phosphatase, preventing entry into mitosis, and has been shown to stabilize the tumor suppressor protein p53, leading to cell cycle arrest in G1. In addition, this protein interacts with and phosphorylates BRCA1, allowing BRCA1 to restore survival after DNA damage. Mutations in this gene have been linked with Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in TP53. Also, mutations in this gene are thought to confer a predisposition to sarcomas, breast cancer, and brain tumors. This nuclear protein is a member of the CDS1 subfamily of serine/threonine protein kinases. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]


Nucleic acid sequence

        10         20         30         40         50         60
atgtctcggg agtcggatgt tgaggctcag cagtctcatg gcagcagtgc ctgttcacag
        70         80         90        100        110        120
ccccatggca gcgttaccca gtcccaaggc tcctcctcac agtcccaggg catatccagc
       130        140        150        160        170        180
tcctctacca gcacgatgcc aaactccagc cagtcctctc actccagctc tgggacactg
       190        200        210        220        230        240
agctccttag agacagtgtc cactcaggaa ctctattcta ttcctgagga ccaagaacct
       250        260        270        280        290        300
gaggaccaag aacctgagga gcctacccct gccccctggg ctcgattatg ggcccttcag
       310        320        330        340        350        360
gatggatttg ccaatcttga gacagagtct ggccatgtta cccaatctga tcttgaactc
       370        380        390        400        410        420
ctgctgtcat ctgatcctcc tgcctcagcc tcccaaagtg ctgggataag aggtgtgagg
       430        440        450        460        470        480
caccatcccc ggccagtttg cagtctaaaa tgtgtgaatg acaactactg gtttgggagg
       490        500        510        520        530        540
gacaaaagct gtgaatattg ctttgatgaa ccactgctga aaagaacaga taaataccga
       550        560        570        580        590        600
acatacagca agaaacactt tcggattttc agggaagtgg gtcctaaaaa ctcttacatt
       610        620        630        640        650        660
gcatacatag aagatcacag tggcaatgga acctttgtaa atacagagct tgtagggaaa
       670        680        690        700        710        720
ggaaaacgcc gtcctttgaa taacaattct gaaattgcac tgtcactaag cagaaataaa
       730        740        750        760        770        780
gtttttgtct tttttgatct gactgtagat gatcagtcag tttatcctaa ggcattaaga
       790        800        810        820        830        840
gatgaataca tcatgtcaaa aactcttgga agtggtgcct gtggagaggt aaagctggct
       850        860        870        880        890        900
ttcgagagga aaacatgtaa gaaagtagcc ataaagatca tcagcaaaag gaagtttgct
       910        920        930        940        950        960
attggttcag caagagaggc agacccagct ctcaatgttg aaacagaaat agaaattttg
       970        980        990       1000       1010       1020
aaaaagctaa atcatccttg catcatcaag attaaaaact tttttgatgc agaagattat
      1030       1040       1050       1060       1070       1080
tatattgttt tggaattgat ggaaggggga gagctgtttg acaaagtggt ggggaataaa
      1090       1100       1110       1120       1130       1140
cgcctgaaag aagctacctg caagctctat ttttaccaga tgctcttggc tgtgcagtac
      1150       1160       1170       1180       1190       1200
cttcatgaaa acggtattat acaccgtgac ttaaagccag agaatgtttt actgtcatct
      1210       1220       1230       1240       1250       1260
caagaagagg actgtcttat aaagattact gattttgggc actccaagat tttgggagag
      1270       1280       1290       1300       1310       1320
acctctctca tgagaacctt atgtggaacc cccacctact tggcgcctga agttcttgtt
      1330       1340       1350       1360       1370       1380
tctgttggga ctgctgggta taaccgtgct gtggactgct ggagtttagg agttattctt
      1390       1400       1410       1420       1430       1440
tttatctgcc ttagtgggta tccacctttc tctgagcata ggactcaagt gtcactgaag
      1450       1460       1470       1480       1490       1500
gatcagatca ccagtggaaa atacaacttc attcctgaag tctgggcaga agtctcagag
      1510       1520       1530       1540       1550       1560
aaagctctgg accttgtcaa gaagttgttg gtagtggatc caaaggcacg ttttacgaca
      1570       1580       1590       1600       1610       1620
gaagaagcct taagacaccc gtggcttcag gatgaagaca tgaagagaaa gtttcaagat
      1630       1640       1650       1660       1670       1680
cttctgtctg aggaaaatga atccacagct ctaccccagg ttctagccca gccttctact
      1690       1700       1710       1720       1730       1740
agtcgaaagc ggccccgtga aggggaagcc gagggtgccg agaccacaaa gcgcccagct
      1750       1760
gtgtgtgctg ctgtgttgtg a   

Last modification date: Nov. 23, 2011