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Description:
Serine/threonine-protein kinase Chk1 (EC 2.7.1.37).
Molecular weight: 54381
View which proteins in this organism that is involved with DNA Repair;
classified after biological processes (using data from the GOA project):
DNA repair( GO:0006281 )
Important dates:
30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
27-SEP-2005, sequence version 2.
07-MAR-2006, entry version 49.
Phylogenetic order:
Eukaryota Metazoa Chordata Craniata Vertebrata Euteleostomi Mammalia Eutheria Euarchontoglires Glires Rodentia Sciurognathi Muroidea Muridae Murinae Mus.
To calculate the pI (Isoelectric point - the pH where a protein has a neutral charge),
go to this page and enter the protein ID (e.g 3MG_ECOLI): http://us.expasy.org/tools/pi_tool.html
Links to references in other databases for protein CHK1_MOUSE:
| Database | Pointer | Add. info#1 | Add. info#2 |
| EMBL | AF016583 | AAC53334.1 | - |
| EMBL | AK011258 | BAB27500.1 | - |
| EMBL | AK033179 | BAC28185.1 | - |
| EMBL | AK045336 | BAC32315.1 | - |
| EMBL | BC037613 | AAH37613.1 | ALT_INIT |
| EMBL | AF032875 | AAB88853.1 | - |
| HSSP | O14757 | 1IA8 | |
| SMR | O35280 | 2-276.1 | |
| Ensembl | ENSMUSG00000032113 | Mus musculus.1 | |
| MGI | MGI:1202065 | Chek1.1 | |
| Reactome | O35280 | -.1 | |
| GO | GO:0005634 | C:nucleus | IDA. |
| GO | GO:0005657 | C:replication fork | IDA. |
| GO | GO:0005515 | F:protein binding | IPI. |
| GO | GO:0004672 | F:protein kinase activity | IMP. |
| GO | GO:0000077 | P:DNA damage checkpoint | IDA. |
| GO | GO:0006281 | P:DNA repair | IDA. |
| GO | GO:0000086 | P:G2/M transition of mitotic cell cycle | IMP. |
| GO | GO:0006468 | P:protein amino acid phosphorylation | IDA. |
| InterPro | IPR000719 | Prot_kinase. | |
| InterPro | IPR008271 | Ser_thr_pkin_AS. | |
| InterPro | IPR002290 | Ser_thr_pkinase. | |
| InterPro | IPR001245 | Tyr_pkinase. | |
| Pfam | PF00069 | Pkinase | 1. |
| ProDom | PD000001 | Prot_kinase | 1. |
| SMART | SM00220 | S_TKc | 1. |
| PROSITE | PS00107 | PROTEIN_KINASE_ATP | 1. |
| PROSITE | PS50011 | PROTEIN_KINASE_DOM | 1. |
| PROSITE | PS00108 | PROTEIN_KINASE_ST | 1. |
Keywords:
Alternative splicing; ATP-binding; Cell cycle; DNA damage; DNA repair; Kinase; Nuclear protein; Nucleotide-binding; Phosphorylation; Serine/threonine-protein kinase; Transferase; Ubl conjugation.
References:
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY.
RX MEDLINE=97426625; PubMed=9278511; DOI=10.1126/science.277.5331.1497;
RA Sanchez Y., Wong C., Thoma R.S., Richman R., Wu Z., Piwnica-Worms H.,
RA Elledge S.J.;
RT "Conservation of the Chk1 checkpoint pathway in mammals: linkage of
RT DNA damage to Cdk regulation through Cdc25.";
RL Science 277:1497-1501(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC STRAIN=C57BL/6J; TISSUE=Embryo, and Testis;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M.,
RA Davis M.J., Wilming L.G., Aidinis V., Allen J.E.,
RA Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L.,
RA Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M.,
RA Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R.,
RA Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G.,
RA di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G.,
RA Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M.,
RA Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N.,
RA Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T.,
RA Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H.,
RA Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K.,
RA Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J.,
RA Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L.,
RA Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K.,
RA Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P.,
RA Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O.,
RA Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G.,
RA Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M.,
RA Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schonbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B.,
RA Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K.,
RA Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A.,
RA Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K.,
RA Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C.,
RA Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J.,
RA Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y.,
RA Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T.,
RA Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N.,
RA Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N.,
RA Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S.,
RA Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J.,
RA Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Mammary gland;
RX MEDLINE=22388257; PubMed=12477932; DOI=10.1073/pnas.242603899;
RA Strausberg R.L., Feingold E.A., Grouse L.H., Derge J.G.,
RA Klausner R.D., Collins F.S., Wagner L., Shenmen C.M., Schuler G.D.,
RA Altschul S.F., Zeeberg B., Buetow K.H., Schaefer C.F., Bhat N.K.,
RA Hopkins R.F., Jordan H., Moore T., Max S.I., Wang J., Hsieh F.,
RA Diatchenko L., Marusina K., Farmer A.A., Rubin G.M., Hong L.,
RA Stapleton M., Soares M.B., Bonaldo M.F., Casavant T.L., Scheetz T.E.,
RA Brownstein M.J., Usdin T.B., Toshiyuki S., Carninci P., Prange C.,
RA Raha S.S., Loquellano N.A., Peters G.J., Abramson R.D., Mullahy S.J.,
RA Bosak S.A., McEwan P.J., McKernan K.J., Malek J.A., Gunaratne P.H.,
RA Richards S., Worley K.C., Hale S., Garcia A.M., Gay L.J., Hulyk S.W.,
RA Villalon D.K., Muzny D.M., Sodergren E.J., Lu X., Gibbs R.A.,
RA Fahey J., Helton E., Ketteman M., Madan A., Rodrigues S., Sanchez A.,
RA Whiting M., Madan A., Young A.C., Shevchenko Y., Bouffard G.G.,
RA Blakesley R.W., Touchman J.W., Green E.D., Dickson M.C.,
RA Rodriguez A.C., Grimwood J., Schmutz J., Myers R.M.,
RA Butterfield Y.S.N., Krzywinski M.I., Skalska U., Smailus D.E.,
RA Schnerch A., Schein J.E., Jones S.J.M., Marra M.A.;
RT "Generation and initial analysis of more than 15,000 full-length human
RT and mouse cDNA sequences.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:16899-16903(2002).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 204-450 (ISOFORMS 1/2), SUBCELLULAR
RP LOCATION, AND DEVELOPMENTAL STAGE.
RX MEDLINE=98044285; PubMed=9382850; DOI=10.1016/S0960-9822(06)00417-9;
RA Flaggs G., Plug A.W., Dunks K.M., Mundt K.E., Ford J.C.,
RA Quiggle M.R.E., Taylor E.M., Westphal C.H., Ashley T., Hoekstra M.F.,
RA Carr A.M.;
RT "Atm-dependent interactions of a mammalian chk1 homolog with meiotic
RT chromosomes.";
RL Curr. Biol. 7:977-986(1997).
RN [5]
RP FUNCTION.
RA Takai H., Tominaga K., Motoyama N., Minamishima Y.A., Nagahama H.,
RA Tsukiyama T., Ikeda K., Nakayama K., Nakanishi M., Nakayama K.;
RT "Aberrant cell cycle checkpoint function and early embryonic death in
RT Chk1(-/-) mice.";
RL Genes Dev. 14:1439-1447(2000).
RN [6]
RP FUNCTION.
RX MEDLINE=20317029; PubMed=10859164;
RA Liu Q., Guntuku S., Cui X.-S., Matsuoka S., Cortez D., Tamai K.,
RA Luo G., Carattini-Rivera S., DeMayo F., Bradley A., Donehower L.A.,
RA Elledge S.J.;
RT "Chk1 is an essential kinase that is regulated by Atr and required for
RT the G(2)/M DNA damage checkpoint.";
RL Genes Dev. 14:1448-1459(2000).
RN [7]
RP FUNCTION.
RX PubMed=15261141; DOI=10.1016/j.ccr.2004.06.015;
RA Lam M.H., Liu Q., Elledge S.J., Rosen J.M.;
RT "Chk1 is haploinsufficient for multiple functions critical to tumor
RT suppression.";
RL Cancer Cell 6:45-59(2004).
RN [8]
RP SUBCELLULAR LOCATION, UBIQUITINATION, PHOSPHORYLATION SITES SER-280
RP AND SER-345, AND MUTAGENESIS OF SER-280.
RX PubMed=15710331; DOI=10.1016/j.ccr.2005.01.009;
RA Puc J., Keniry M., Li H.S., Pandita T.K., Choudhury A.D., Memeo L.,
RA Mansukhani M., Murty V.V.V.S., Gaciong Z., Meek S.E.M.,
RA Piwnica-Worms H., Hibshoosh H., Parsons R.;
RT "Lack of PTEN sequesters CHK1 and initiates genetic instability.";
RL Cancer Cell 7:193-204(2005).
Feature:
CHAIN 1 476 Serine/threonine-protein kinase Chk1.
/FTId=PRO_0000085849.
DOMAIN 9 265 Protein kinase.
NP_BIND 15 23 ATP (By similarity).
REGION 391 476 Autoinhibitory region (By similarity).
ACT_SITE 130 130 Proton acceptor (By similarity).
BINDING 38 38 ATP (By similarity).
MOD_RES 280 280 Phosphoserine (by PKB/AKT1).
MOD_RES 296 296 Phosphoserine (By similarity).
MOD_RES 317 317 Phosphoserine (by ATM and ATR) (By
similarity).
MOD_RES 345 345 Phosphoserine (by ATR).
VARSPLIC 1 94 Missing (in isoform 2).
/FTId=VSP_015791.
VARSPLIC 95 97 RIE -> MEK (in isoform 2).
/FTId=VSP_015792.
MUTAGEN 280 280 S->A: Enhances cell cycle arrest.
MUTAGEN 280 280 S->E: Promotes mono and/or
diubiquitination and nuclear exclusion.
Reduces phosphorylation at S-345.
CONFLICT 33 33 E -> Q (in Ref. 1).
CONFLICT 50 50 E -> Q (in Ref. 1).
CONFLICT 219 223 SDWKE -> LIVKK (in Ref. 4).
CONFLICT 252 252 A -> S (in Ref. 4).
CONFLICT 365 365 S -> F (in Ref. 1).
CONFLICT 449 450 LE -> YN (in Ref. 4).
Comments:
-!- FUNCTION: 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 (By
similarity). Essential for early embryogenesis.
-!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
-!- SUBUNIT: Interacts with BRCA1, CLSPN, PPM1D, RAD51, XPO1/CRM1 and
YWHAZ/14-3-3 zeta (By similarity).
-!- SUBCELLULAR LOCATION: Nuclear and cytoplasmic. Nuclear export is
mediated at least in part by XPO1/CRM1. Also localizes to the
centrosome specifically during interphase, where it may protect
centrosomal CDC2 kinase from inappropriate activation by
cytoplasmic CDC25B (By similarity).
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=2;
Name=1;
IsoId=O35280-1; Sequence=Displayed;
Name=2;
IsoId=O35280-2; Sequence=VSP_015791, VSP_015792;
Note=No experimental confirmation available;
-!- TISSUE SPECIFICITY: Found in all adult tissues tested. Elevated
expression in testis, lung and spleen. 15.5 day old embryos show
ubiquitous expression with strong expression in brain, liver,
kidney, pancreas, intestine, thymus and lung.
-!- DEVELOPMENTAL STAGE: In the testis, present in cells undergoing
meiosis I. Not detected in peripheral cells in seminiferous
tubules that are undergoing pre-meiotic DNA synthesis or in late
condensing or mature sperm.
-!- DOMAIN: The autoinhibitory region (AIR) inhibits the activity of
the kinase domain (By similarity).
-!- PTM: 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 may also
increase binding to 14-3-3 proteins and promote 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.
-!- PTM: Ubiquitinated. Mono or diubiquitination promotes nuclear
exclusion.
-!- MISCELLANEOUS: Mice lacking Chk1 die of apoptosis at the
blastocyst stage.
-!- MISCELLANEOUS: Haploinsufficient for the suppression of genomic
instability and tumor progression.
-!- SIMILARITY: Belongs to the Ser/Thr protein kinase family. NIM1
subfamily.
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Sequence length: 476
MAVPFVEDWD LVQTLGEGAY GEVQLAVNRI TEEAVAVKIV DMKRAIDCPE NIKKEICINK
MLSHENVVKF YGHRREGHIQ YLFLEYCSGG ELFDRIEPDI GMPEQDAQRF FHQLMAGVVY
LHGIGITHRD IKPENLLLDE RDNLKISDFG LATVFRHNNR ERLLNKMCGT LPYVAPELLK
RKEFHAEPVD VWSCGIVLTA MLAGELPWDQ PSDSCQEYSD WKEKKTYLNP WKKIDSAPLA
LLHKILVETP SARITIPDIK KDRWYNKPLN RGAKRPRATS GGMSESSSGF SKHIHSNLDF
SPVNNGSSEE TVKFSSSQPE PRTGLSLWDT GPSNVDKLVQ GISFSQPTCP EHMLVNSQLL
GTPGSSQNPW QRLVKRMTRF FTKLDADKSY QCLKETFEKL GYQWKKSCMN QVTVSTTDRR
NNKLIFKINL VEMDEKILVD FRLSKGDGLE FKRHFLKIKG KLSDVVSSQK VWFPVT