Mus musculus L. (mouse) [MMU]

FULL NAME: Serine/threonine-protein kinase Chk1


DESCRIPTION:
Required for checkpoint mediated cell cycle arrest in response to DNA damage or the presence of unreplicated DNA. May also negatively regulate cell cycle progression during unperturbed cell cycles. Recognizes the substrate consensus sequence [R-X-X-S/T]. Binds to and phosphorylates CDC25A, CDC25B and CDC25C. Phosphorylation of CDC25A at 'Ser-171' and 'Thr-497' and phosphorylation of CDC25C creates binding sites for 14-3-3 proteins which inhibit CDC25A and CDC25C. Phosphorylation of CDC25A at 'Ser-74', 'Ser-122', 'Ser-171', 'Ser-271' and 'Ser-284' promotes proteolysis of CDC25A. Inhibition of CDC25 activity leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. Binds to and phosphorylates RAD51 at 'Thr-309', which may enhance the association of RAD51 with chromatin and promote DNA repair by homologous recombination. Binds to and phosphorylates TLK1 at 'Ser-743', which prevents the TLK1-dependent phosphorylation of the chromatin assembly factor ASF1A. This may affect chromatin assembly during S phase or DNA repair. May also phosphorylate multiple sites within the C-terminus of TP53, which promotes activation of TP53 by acetylation and enhances suppression of cellular proliferation. Phosphorylates NEK6 and NEK11. Phosphorylation of CDC25A at Ser-74 primes it for subsequent phosphorylation at Ser-77, Ser-80 and Ser-86 by NEK11 (By similarity). Essential for early embryogenesis.

MISCELLANEOUS:
Haploinsufficient for the suppression of genomic instability and tumor progression.


STRUCTURE SIMILARITY:
Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. NIM1 subfamily.
Contains 1 protein kinase domain.


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


POST-TRANSLATIONAL MODIFICATION:
Phosphorylated by ATR in response to ultraviolet irradiation and inhibition of DNA replication. May also be phosphorylated by ATM in response to ionizing irradiation. ATM and ATR may phosphorylate both Ser-317 and Ser-345 and this results in enhanced kinase activity. Phosphorylation at Ser-345 induces a change in the conformation of the protein, activates the kinase activity and is a prerequisite for interaction with FBXO6 and subsequent ubiquitination at Lys-436. Phosphorylation at Ser-345 also increases binding to 14-3-3 proteins and promotes nuclear retention. Conversely, dephosphorylation at Ser-345 by PPM1D may contribute to exit from checkpoint mediated cell cycle arrest. Phosphorylated at Ser-280 by AKT1/PKB, which may promote mono and/or diubiquitination. May also be phosphorylated at undefined residues during mitotic arrest, which results in decreased activity.
The activated form (phosphorylated on Ser-345) is polyubiquitinated at Lys-436 by some SCF-type E3 ubiquitin ligase complex containing FBXO6 promoting its degradation. Ubiquitination of activated form is required to insure that activated CHK1 does not accumulate as cells progress through S phase, or when replication forks encounter transient impediments during normal DNA replication (By similarity). Ubiquitinated. Mono or diubiquitination promotes nuclear exclusion.


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


Amino acids sequence

        10         20         30         40         50         60
MAVPFVEDWD LVQTLGEGAY GEVQLAVNRI TEEAVAVKIV DMKRAIDCPE NIKKEICINK
        70         80         90        100        110        120
MLSHENVVKF YGHRREGHIQ YLFLEYCSGG ELFDRIEPDI GMPEQDAQRF FHQLMAGVVY
       130        140        150        160        170        180
LHGIGITHRD IKPENLLLDE RDNLKISDFG LATVFRHNNR ERLLNKMCGT LPYVAPELLK
       190        200        210        220        230        240
RKEFHAEPVD VWSCGIVLTA MLAGELPWDQ PSDSCQEYSD WKEKKTYLNP WKKIDSAPLA
       250        260        270        280        290        300
LLHKILVETP SARITIPDIK KDRWYNKPLN RGAKRPRATS GGMSESSSGF SKHIHSNLDF
       310        320        330        340        350        360
SPVNNGSSEE TVKFSSSQPE PRTGLSLWDT GPSNVDKLVQ GISFSQPTCP EHMLVNSQLL
       370        380        390        400        410        420
GTPGSSQNPW QRLVKRMTRF FTKLDADKSY QCLKETFEKL GYQWKKSCMN QVTVSTTDRR
       430        440        450        460        470
NNKLIFKINL VEMDEKILVD FRLSKGDGLE FKRHFLKIKG KLSDVVSSQK VWFPVT

Encoded by Chek1 gene

FULL NAME: checkpoint kinase 1 homolog (S. pombe)


OTHER NAME(S):
C85740
Chk1
rad27


Nucleic acid sequence

        10         20         30         40         50         60
atggcagtgc cttttgtgga agactgggat ttggtgcaaa ctttgggaga aggtgcctat
        70         80         90        100        110        120
ggagaagttc aacttgctgt gaatagaata actgaagaag ctgttgcagt gaaaattgta
       130        140        150        160        170        180
gacatgaagc gggccataga ctgtccagaa aatattaaga aagagatctg catcaataaa
       190        200        210        220        230        240
atgttaagcc acgagaatgt agtgaaattc tatggccaca ggagggaagg ccatatccag
       250        260        270        280        290        300
tatctgtttc tggagtactg tagtggagga gaactttttg atagaattga gccagacata
       310        320        330        340        350        360
gggatgcctg aacaagatgc tcagaggttc ttccaccaac tcatggcagg ggtggtttat
       370        380        390        400        410        420
cttcatggaa ttggaataac tcacagggat attaaaccag aaaacctcct cttggatgaa
       430        440        450        460        470        480
agggataacc tcaaaatctc tgactttggc ttggcaacgg tatttcggca taataatcgt
       490        500        510        520        530        540
gaacgcttac tgaacaagat gtgtgggact ttaccttatg ttgctccgga gcttctaaag
       550        560        570        580        590        600
agaaaagaat ttcatgcaga accagttgat gtttggtcct gtggaatagt acttactgca
       610        620        630        640        650        660
atgttggctg gagaattgcc gtgggaccag cccagtgata gctgtcagga atattctgat
       670        680        690        700        710        720
tggaaagaaa aaaaaaccta tctcaatcct tggaaaaaaa ttgattctgc tcctctggct
       730        740        750        760        770        780
ttgcttcata aaattctagt tgagactcca tcagcaagga tcaccatccc agacattaag
       790        800        810        820        830        840
aaagatagat ggtacaacaa accacttaac agaggagcaa agaggccacg cgccacatca
       850        860        870        880        890        900
ggtggtatgt cagagtcttc tagtggattc tctaagcaca ttcattccaa tttggacttt
       910        920        930        940        950        960
tctccagtaa ataatggttc cagtgaagaa accgtgaagt tctctagttc ccagccagag
       970        980        990       1000       1010       1020
ccgagaacag ggctttcctt gtgggacact ggtccctcga acgtggacaa actggttcag
      1030       1040       1050       1060       1070       1080
ggcatcagtt tttcccagcc tacgtgtcct gagcatatgc ttgtaaacag tcagttactc
      1090       1100       1110       1120       1130       1140
ggtacccctg gatcttcaca gaacccctgg cagcgcttgg tcaaaaggat gacacgattc
      1150       1160       1170       1180       1190       1200
tttactaaat tggatgcgga caaatcttac caatgcctga aagagacctt cgagaagttg
      1210       1220       1230       1240       1250       1260
ggctatcagt ggaagaagag ttgtatgaat caggttactg tatcaacaac tgatagaaga
      1270       1280       1290       1300       1310       1320
aacaataagt tgattttcaa aataaatttg gtagaaatgg atgagaagat actggttgac
      1330       1340       1350       1360       1370       1380
ttccgacttt ctaagggtga tggattagag ttcaagagac acttcctgaa gattaaaggg
      1390       1400       1410       1420       1430
aagctcagcg atgttgtgag cagccagaag gtttggtttc ctgttacatg a

Last modification date: Oct. 2, 2011