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Serine/threonine-protein kinase Chk2 (EC 2.7.11.1) (CHK2 checkpoint homolog) (Cds1 homolog) (Hucds1) (hCds1) (Checkpoint kinase 2)

 CHK2_HUMAN              Reviewed;         543 AA.
O96017; A8K3Y9; B7ZBF3; B7ZBF4; B7ZBF5; Q6QA03; Q6QA04; Q6QA05;
Q6QA06; Q6QA07; Q6QA08; Q6QA10; Q6QA11; Q6QA12; Q6QA13; Q9HBS5;
Q9HCQ8; Q9UGF0; Q9UGF1;
30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
01-MAY-1999, sequence version 1.
22-NOV-2017, entry version 207.
RecName: Full=Serine/threonine-protein kinase Chk2;
EC=2.7.11.1;
AltName: Full=CHK2 checkpoint homolog;
AltName: Full=Cds1 homolog;
Short=Hucds1;
Short=hCds1;
AltName: Full=Checkpoint kinase 2;
Name=CHEK2; Synonyms=CDS1, CHK2, RAD53;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION IN PHOSPHORYLATION OF
CDC25C, AND MUTAGENESIS OF ASP-347.
PubMed=9836640; DOI=10.1126/science.282.5395.1893;
Matsuoka S., Huang M., Elledge S.J.;
"Linkage of ATM to cell cycle regulation by the Chk2 protein kinase.";
Science 282:1893-1897(1998).
[2]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION IN MITOSIS.
PubMed=9889122; DOI=10.1016/S0960-9822(99)80041-4;
Blasina A., van de Weyer I., Laus M.C., Luyten W.H.M.L., Parker A.E.,
McGowan C.H.;
"A human homologue of the checkpoint kinase Cds1 directly inhibits
Cdc25 phosphatase.";
Curr. Biol. 9:1-10(1999).
[3]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND FUNCTION IN
PHOSPHORYLATION OF CDC25C.
PubMed=10097108; DOI=10.1073/pnas.96.7.3745;
Brown A.L., Lee C.-H., Schwarz J.K., Mitiku N., Piwnica-Worms H.,
Chung J.H.;
"A human Cds1-related kinase that functions downstream of ATM protein
in the cellular response to DNA damage.";
Proc. Natl. Acad. Sci. U.S.A. 96:3745-3750(1999).
[4]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2; 3; 4; 5; 6; 7; 8; 9; 10; 11
AND 12), AND SUBCELLULAR LOCATION.
TISSUE=Mammary gland;
PubMed=15361853; DOI=10.1038/sj.onc.1207928;
Staalesen V., Falck J., Geisler S., Bartkova J., Boerresen-Dale A.-L.,
Lukas J., Lillehaug J.R., Bartek J., Lonning P.E.;
"Alternative splicing and mutation status of CHEK2 in stage III breast
cancer.";
Oncogene 23:8535-8544(2004).
[5]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 9).
PubMed=15461802; DOI=10.1186/gb-2004-5-10-r84;
Collins J.E., Wright C.L., Edwards C.A., Davis M.P., Grinham J.A.,
Cole C.G., Goward M.E., Aguado B., Mallya M., Mokrab Y., Huckle E.J.,
Beare D.M., Dunham I.;
"A genome annotation-driven approach to cloning the human ORFeome.";
Genome Biol. 5:R84.1-R84.11(2004).
[6]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
TISSUE=Colon carcinoma;
Shao R.-G., Zhang H., Yu Q., Pommier Y.;
"Chk2/HuCds1 cell cycle checkpoint protein kinase from human colon
carcinoma HT29 cells: regulation by autophosphorylation and DNA-
dependent protein kinase and inhibition by cell cycle regulatory
drugs.";
Submitted (JUL-1999) to the EMBL/GenBank/DDBJ databases.
[7]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 12).
TISSUE=T-cell;
Ogawa A., Okabe-Nakamura A.;
"An alternative spliced Chk2.";
Submitted (MAR-2000) to the EMBL/GenBank/DDBJ databases.
[8]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
PubMed=14702039; DOI=10.1038/ng1285;
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
"Complete sequencing and characterization of 21,243 full-length human
cDNAs.";
Nat. Genet. 36:40-45(2004).
[9]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 13).
PubMed=15498874; DOI=10.1073/pnas.0404089101;
Wan D., Gong Y., Qin W., Zhang P., Li J., Wei L., Zhou X., Li H.,
Qiu X., Zhong F., He L., Yu J., Yao G., Jiang H., Qian L., Yu Y.,
Shu H., Chen X., Xu H., Guo M., Pan Z., Chen Y., Ge C., Yang S.,
Gu J.;
"Large-scale cDNA transfection screening for genes related to cancer
development and progression.";
Proc. Natl. Acad. Sci. U.S.A. 101:15724-15729(2004).
[10]
NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS LEU-85; THR-157;
MET-436; LYS-446; ILE-447; SER-448; LYS-501 AND VAL-512.
NIEHS SNPs program;
Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
[11]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
PubMed=10591208; DOI=10.1038/990031;
Dunham I., Hunt A.R., Collins J.E., Bruskiewich R., Beare D.M.,
Clamp M., Smink L.J., Ainscough R., Almeida J.P., Babbage A.K.,
Bagguley C., Bailey J., Barlow K.F., Bates K.N., Beasley O.P.,
Bird C.P., Blakey S.E., Bridgeman A.M., Buck D., Burgess J.,
Burrill W.D., Burton J., Carder C., Carter N.P., Chen Y., Clark G.,
Clegg S.M., Cobley V.E., Cole C.G., Collier R.E., Connor R.,
Conroy D., Corby N.R., Coville G.J., Cox A.V., Davis J., Dawson E.,
Dhami P.D., Dockree C., Dodsworth S.J., Durbin R.M., Ellington A.G.,
Evans K.L., Fey J.M., Fleming K., French L., Garner A.A.,
Gilbert J.G.R., Goward M.E., Grafham D.V., Griffiths M.N.D., Hall C.,
Hall R.E., Hall-Tamlyn G., Heathcott R.W., Ho S., Holmes S.,
Hunt S.E., Jones M.C., Kershaw J., Kimberley A.M., King A.,
Laird G.K., Langford C.F., Leversha M.A., Lloyd C., Lloyd D.M.,
Martyn I.D., Mashreghi-Mohammadi M., Matthews L.H., Mccann O.T.,
Mcclay J., Mclaren S., McMurray A.A., Milne S.A., Mortimore B.J.,
Odell C.N., Pavitt R., Pearce A.V., Pearson D., Phillimore B.J.C.T.,
Phillips S.H., Plumb R.W., Ramsay H., Ramsey Y., Rogers L., Ross M.T.,
Scott C.E., Sehra H.K., Skuce C.D., Smalley S., Smith M.L.,
Soderlund C., Spragon L., Steward C.A., Sulston J.E., Swann R.M.,
Vaudin M., Wall M., Wallis J.M., Whiteley M.N., Willey D.L.,
Williams L., Williams S.A., Williamson H., Wilmer T.E., Wilming L.,
Wright C.L., Hubbard T., Bentley D.R., Beck S., Rogers J., Shimizu N.,
Minoshima S., Kawasaki K., Sasaki T., Asakawa S., Kudoh J.,
Shintani A., Shibuya K., Yoshizaki Y., Aoki N., Mitsuyama S.,
Roe B.A., Chen F., Chu L., Crabtree J., Deschamps S., Do A., Do T.,
Dorman A., Fang F., Fu Y., Hu P., Hua A., Kenton S., Lai H., Lao H.I.,
Lewis J., Lewis S., Lin S.-P., Loh P., Malaj E., Nguyen T., Pan H.,
Phan S., Qi S., Qian Y., Ray L., Ren Q., Shaull S., Sloan D., Song L.,
Wang Q., Wang Y., Wang Z., White J., Willingham D., Wu H., Yao Z.,
Zhan M., Zhang G., Chissoe S., Murray J., Miller N., Minx P.,
Fulton R., Johnson D., Bemis G., Bentley D., Bradshaw H., Bourne S.,
Cordes M., Du Z., Fulton L., Goela D., Graves T., Hawkins J.,
Hinds K., Kemp K., Latreille P., Layman D., Ozersky P., Rohlfing T.,
Scheet P., Walker C., Wamsley A., Wohldmann P., Pepin K., Nelson J.,
Korf I., Bedell J.A., Hillier L.W., Mardis E., Waterston R.,
Wilson R., Emanuel B.S., Shaikh T., Kurahashi H., Saitta S.,
Budarf M.L., McDermid H.E., Johnson A., Wong A.C.C., Morrow B.E.,
Edelmann L., Kim U.J., Shizuya H., Simon M.I., Dumanski J.P.,
Peyrard M., Kedra D., Seroussi E., Fransson I., Tapia I., Bruder C.E.,
O'Brien K.P., Wilkinson P., Bodenteich A., Hartman K., Hu X.,
Khan A.S., Lane L., Tilahun Y., Wright H.;
"The DNA sequence of human chromosome 22.";
Nature 402:489-495(1999).
[12]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
Venter J.C.;
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
[13]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
TISSUE=Muscle;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[14]
FUNCTION IN PHOSPHORYLATION OF BRCA1, AND INTERACTION WITH BRCA1.
PubMed=10724175; DOI=10.1038/35004614;
Lee J.S., Collins K.M., Brown A.L., Lee C.H., Chung J.H.;
"hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage
response.";
Nature 404:201-204(2000).
[15]
PHOSPHORYLATION AT THR-68 BY ATM.
PubMed=10973490; DOI=10.1073/pnas.190030497;
Matsuoka S., Rotman G., Ogawa A., Shiloh Y., Tamai K., Elledge S.J.;
"Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in
vitro.";
Proc. Natl. Acad. Sci. U.S.A. 97:10389-10394(2000).
[16]
PHOSPHORYLATION AT THR-383 AND THR-387, AND MUTAGENESIS OF THR-383 AND
THR-387.
PubMed=11390408; DOI=10.1074/jbc.M104414200;
Lee C.H., Chung J.H.;
"The hCds1 (Chk2)-FHA domain is essential for a chain of
phosphorylation events on hCds1 that is induced by ionizing
radiation.";
J. Biol. Chem. 276:30537-30541(2001).
[17]
FUNCTION IN INTRA S-PHASE CHECKPOINT, FUNCTION IN PHOSPHORYLATION OF
CDC25A, INTERACTION WITH CDC25A, MUTAGENESIS OF ASP-347,
CHARACTERIZATION OF VARIANT COLON CANCER TRP-145, AND CHARACTERIZATION
OF VARIANT THR-157.
PubMed=11298456; DOI=10.1038/35071124;
Falck J., Mailand N., Syljuaasen R.G., Bartek J., Lukas J.;
"The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant
DNA synthesis.";
Nature 410:842-847(2001).
[18]
INVOLVEMENT IN SUSCEPTIBILITY TO BC.
PubMed=12094328; DOI=10.1086/341943;
Vahteristo P., Bartkova J., Eerola H., Syrjakoski K., Ojala S.,
Kilpivaara O., Tamminen A., Kononen J., Aittomaki K., Heikkila P.,
Holli K., Blomqvist C., Bartek J., Kallioniemi O.P., Nevanlinna H.;
"A CHEK2 genetic variant contributing to a substantial fraction of
familial breast cancer.";
Am. J. Hum. Genet. 71:432-438(2002).
[19]
HOMODIMERIZATION, AUTOPHOSPHORYLATION, AND MUTAGENESIS OF THR-68.
PubMed=11901158; DOI=10.1074/jbc.M200822200;
Ahn J.Y., Li X., Davis H.L., Canman C.E.;
"Phosphorylation of threonine 68 promotes oligomerization and
autophosphorylation of the Chk2 protein kinase via the forkhead-
associated domain.";
J. Biol. Chem. 277:19389-19395(2002).
[20]
FUNCTION IN APOPTOSIS, FUNCTION IN PHOSPHORYLATION OF PML, AND
SUBCELLULAR LOCATION.
PubMed=12402044; DOI=10.1038/ncb869;
Yang S., Kuo C., Bisi J.E., Kim M.K.;
"PML-dependent apoptosis after DNA damage is regulated by the
checkpoint kinase hCds1/Chk2.";
Nat. Cell Biol. 4:865-870(2002).
[21]
INTERACTION WITH TP53BP1.
PubMed=12364621; DOI=10.1126/science.1076182;
Wang B., Matsuoka S., Carpenter P.B., Elledge S.J.;
"53BP1, a mediator of the DNA damage checkpoint.";
Science 298:1435-1438(2002).
[22]
FUNCTION, INTERACTION WITH PML AND TP53, AND SUBCELLULAR LOCATION.
PubMed=12810724; DOI=10.1074/jbc.M301264200;
Louria-Hayon I., Grossman T., Sionov R.V., Alsheich O., Pandolfi P.P.,
Haupt Y.;
"The promyelocytic leukemia protein protects p53 from Mdm2-mediated
inhibition and degradation.";
J. Biol. Chem. 278:33134-33141(2003).
[23]
FUNCTION IN TRANSCRIPTION REGULATION, FUNCTION IN APOPTOSIS, AND
FUNCTION IN PHOSPHORYLATION OF E2F1.
PubMed=12717439; DOI=10.1038/ncb974;
Stevens C., Smith L., La Thangue N.B.;
"Chk2 activates E2F-1 in response to DNA damage.";
Nat. Cell Biol. 5:401-409(2003).
[24]
FUNCTION IN DNA DAMAGE RESPONSE, AND INTERACTION WITH MDC1.
PubMed=12607004; DOI=10.1038/nature01447;
Lou Z., Minter-Dykhouse K., Wu X., Chen J.;
"MDC1 is coupled to activated CHK2 in mammalian DNA damage response
pathways.";
Nature 421:957-961(2003).
[25]
REVIEW ON PHOSPHORYLATION OF TP53 AND OTHER SUBSTRATES.
PubMed=15279791; DOI=10.1016/j.dnarep.2004.03.033;
Ahn J., Urist M., Prives C.;
"The Chk2 protein kinase.";
DNA Repair 3:1039-1047(2004).
[26]
ENZYME REGULATION, PHOSPHORYLATION AT THR-68 BY MAP3K20, AND
MUTAGENESIS OF THR-68 AND ASP-368.
PubMed=15342622; DOI=10.1074/jbc.M409961200;
Tosti E., Waldbaum L., Warshaw G., Gross E.A., Ruggieri R.;
"The stress kinase MRK contributes to regulation of DNA damage
checkpoints through a p38gamma-independent pathway.";
J. Biol. Chem. 279:47652-47660(2004).
[27]
FUNCTION IN TP53 ACTIVATION, AND FUNCTION IN PHOSPHORYLATION OF MDM4.
PubMed=16163388; DOI=10.1038/sj.emboj.7600812;
Chen L., Gilkes D.M., Pan Y., Lane W.S., Chen J.;
"ATM and Chk2-dependent phosphorylation of MDMX contribute to p53
activation after DNA damage.";
EMBO J. 24:3411-3422(2005).
[28]
PHOSPHORYLATION AT THR-68, AND DEPHOSPHORYLATION AT THR-68 BY PPM1D.
PubMed=16311512; DOI=10.1038/sj.cdd.4401801;
Fujimoto H., Onishi N., Kato N., Takekawa M., Xu X.Z., Kosugi A.,
Kondo T., Imamura M., Oishi I., Yoda A., Minami Y.;
"Regulation of the antioncogenic Chk2 kinase by the oncogenic Wip1
phosphatase.";
Cell Death Differ. 13:1170-1180(2006).
[29]
PHOSPHORYLATION AT SER-62; THR-68 AND SER-73, AND MUTAGENESIS OF
SER-73.
PubMed=16481012; DOI=10.1016/j.mrfmmm.2005.12.002;
Bahassi el M., Myer D.L., McKenney R.J., Hennigan R.F.,
Stambrook P.J.;
"Priming phosphorylation of Chk2 by polo-like kinase 3 (Plk3) mediates
its full activation by ATM and a downstream checkpoint in response to
DNA damage.";
Mutat. Res. 596:166-176(2006).
[30]
FUNCTION IN PHOSPHORYLATION OF RB1.
PubMed=17380128; DOI=10.1038/sj.emboj.7601652;
Inoue Y., Kitagawa M., Taya Y.;
"Phosphorylation of pRB at Ser612 by Chk1/2 leads to a complex between
pRB and E2F-1 after DNA damage.";
EMBO J. 26:2083-2093(2007).
[31]
FUNCTION IN APOPTOSIS, PHOSPHORYLATION AT SER-456, UBIQUITINATION, AND
MUTAGENESIS OF SER-456.
PubMed=17715138; DOI=10.1074/jbc.M704642200;
Kass E.M., Ahn J., Tanaka T., Freed-Pastor W.A., Keezer S., Prives C.;
"Stability of checkpoint kinase 2 is regulated via phosphorylation at
serine 456.";
J. Biol. Chem. 282:30311-30321(2007).
[32]
FUNCTION IN DNA REPAIR, AND FUNCTION IN PHOSPHORYLATION OF FOXM1.
PubMed=17101782; DOI=10.1128/MCB.01068-06;
Tan Y., Raychaudhuri P., Costa R.H.;
"Chk2 mediates stabilization of the FoxM1 transcription factor to
stimulate expression of DNA repair genes.";
Mol. Cell. Biol. 27:1007-1016(2007).
[33]
FUNCTION IN PHOSPHORYLATION OF NEK6.
PubMed=18728393; DOI=10.4161/cc.7.17.6551;
Lee M.Y., Kim H.J., Kim M.A., Jee H.J., Kim A.J., Bae Y.S., Park J.I.,
Chung J.H., Yun J.;
"Nek6 is involved in G2/M phase cell cycle arrest through DNA damage-
induced phosphorylation.";
Cell Cycle 7:2705-2709(2008).
[34]
FUNCTION IN APOPTOSIS, PHOSPHORYLATION AT SER-379, MUTAGENESIS OF
SER-379, UBIQUITINATION, AND INTERACTION WITH CUL1.
PubMed=18644861; DOI=10.1128/MCB.00821-08;
Lovly C.M., Yan L., Ryan C.E., Takada S., Piwnica-Worms H.;
"Regulation of Chk2 ubiquitination and signaling through
autophosphorylation of serine 379.";
Mol. Cell. Biol. 28:5874-5885(2008).
[35]
FUNCTION IN RAD51-MEDIATED DNA REPAIR, AND FUNCTION IN PHOSPHORYLATION
OF BRCA2.
PubMed=18317453; DOI=10.1038/onc.2008.17;
Bahassi E.M., Ovesen J.L., Riesenberg A.L., Bernstein W.Z.,
Hasty P.E., Stambrook P.J.;
"The checkpoint kinases Chk1 and Chk2 regulate the functional
associations between hBRCA2 and Rad51 in response to DNA damage.";
Oncogene 27:3977-3985(2008).
[36]
PHOSPHORYLATION BY PLK4.
PubMed=19164942; DOI=10.4161/cc.8.2.7355;
Petrinac S., Ganuelas M.L., Bonni S., Nantais J., Hudson J.W.;
"Polo-like kinase 4 phosphorylates Chk2.";
Cell Cycle 8:327-329(2009).
[37]
FUNCTION IN PHOSPHORYLATION OF BRCA1, AND FUNCTION IN CHROMOSOMAL
STABILITY.
PubMed=20364141; DOI=10.1038/ncb2051;
Stolz A., Ertych N., Kienitz A., Vogel C., Schneider V., Fritz B.,
Jacob R., Dittmar G., Weichert W., Petersen I., Bastians H.;
"The CHK2-BRCA1 tumour suppressor pathway ensures chromosomal
stability in human somatic cells.";
Nat. Cell Biol. 12:492-499(2010).
[38]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=21269460; DOI=10.1186/1752-0509-5-17;
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
"Initial characterization of the human central proteome.";
BMC Syst. Biol. 5:17-17(2011).
[39]
INVOLVEMENT IN SUSCEPTIBILITY TO BC, VARIANTS CYS-180 AND TYR-371, AND
CHARACTERIZATION OF VARIANT TYR-371.
PubMed=21618645; DOI=10.1002/humu.21538;
Liu Y., Liao J., Xu Y., Chen W., Liu D., Ouyang T., Li J., Wang T.,
Fan Z., Fan T., Lin B., Xu X., Xie Y.;
"A recurrent CHEK2 p.H371Y mutation is associated with breast cancer
risk in Chinese women.";
Hum. Mutat. 32:1000-1003(2011).
[40]
UBIQUITINATION BY RNF8.
PubMed=22266820; DOI=10.1038/nsmb.2211;
Feng L., Chen J.;
"The E3 ligase RNF8 regulates KU80 removal and NHEJ repair.";
Nat. Struct. Mol. Biol. 19:201-206(2012).
[41]
FUNCTION, AND INTERACTION WITH CCAR2 AND SIRT1.
PubMed=25361978; DOI=10.1093/nar/gku1065;
Magni M., Ruscica V., Buscemi G., Kim J.E., Nachimuthu B.T.,
Fontanella E., Delia D., Zannini L.;
"Chk2 and REGgamma-dependent DBC1 regulation in DNA damage induced
apoptosis.";
Nucleic Acids Res. 42:13150-13160(2014).
[42]
X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 64-212.
PubMed=12049740; DOI=10.1016/S1097-2765(02)00527-0;
Li J., Williams B.L., Haire L.F., Goldberg M., Wilker E., Durocher D.,
Yaffe M.B., Jackson S.P., Smerdon S.J.;
"Structural and functional versatility of the FHA domain in DNA-damage
signaling by the tumor suppressor kinase Chk2.";
Mol. Cell 9:1045-1054(2002).
[43]
X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 210-531 IN COMPLEX WITH ADP
AND INHIBITOR, HOMODIMERIZATION, AND AUTOPHOSPHORYLATION.
PubMed=16794575; DOI=10.1038/sj.emboj.7601209;
Oliver A.W., Paul A., Boxall K.J., Barrie S.E., Aherne G.W.,
Garrett M.D., Mittnacht S., Pearl L.H.;
"Trans-activation of the DNA-damage signalling protein kinase Chk2 by
T-loop exchange.";
EMBO J. 25:3179-3190(2006).
[44]
X-RAY CRYSTALLOGRAPHY (3.00 ANGSTROMS) OF 84-502 OF HOMODIMER.
PubMed=19782031; DOI=10.1016/j.molcel.2009.09.007;
Cai Z., Chehab N.H., Pavletich N.P.;
"Structure and activation mechanism of the CHK2 DNA damage checkpoint
kinase.";
Mol. Cell 35:818-829(2009).
[45]
INTERACTION WITH CDKN2AIP.
PubMed=24825908; DOI=10.1074/jbc.M114.547208;
Cheung C.T., Singh R., Kalra R.S., Kaul S.C., Wadhwa R.;
"Collaborator of ARF (CARF) regulates proliferative fate of human
cells by dose-dependent regulation of DNA damage signaling.";
J. Biol. Chem. 289:18258-18269(2014).
[46]
VARIANT THR-157, AND VARIANT COLON CANCER TRP-145.
PubMed=10617473; DOI=10.1126/science.286.5449.2528;
Bell D.W., Varley J.M., Szydlo T.E., Kang D.H., Wahrer D.C.R.,
Shannon K.E., Lubratovich M., Versalis S.J., Isselbacher K.J.,
Fraumeni J.F. Jr., Birch J.M., Li F.P., Garber J.E., Haber D.A.;
"Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome.";
Science 286:2528-2531(1999).
[47]
VARIANT THR-157.
PubMed=11461078; DOI=10.1054/bjoc.2001.1858;
Allinen M., Huusko P., Maentyniemi S., Launonen V., Winqvist R.;
"Mutation analysis of the CHK2 gene in families with hereditary breast
cancer.";
Br. J. Cancer 85:209-212(2001).
[48]
VARIANT LFS2 TRP-145.
PubMed=11719428;
Lee S.B., Kim S.H., Bell D.W., Wahrer D.C.R., Schiripo T.A.,
Jorczak M.M., Sgroi D.C., Garber J.E., Li F.P., Nichols K.E.,
Varley J.M., Godwin A.K., Shannon K.M., Harlow E., Haber D.A.;
"Destabilization of CHK2 by a missense mutation associated with Li-
Fraumeni Syndrome.";
Cancer Res. 61:8062-8067(2001).
[49]
VARIANT MULTIPLE CANCERS LYS-59.
PubMed=12052256; DOI=10.1186/bcr435;
Ingvarsson S., Sigbjornsdottir B.I., Huiping C., Hafsteinsdottir S.H.,
Ragnarsson G., Barkardottir R.B., Arason A., Egilsson V.,
Bergthorsson J.T.;
"Mutation analysis of the CHK2 gene in breast carcinoma and other
cancers.";
Breast Cancer Res. 4:R4-R4(2002).
[50]
VARIANTS GLY-117; GLN-137 AND HIS-180.
PubMed=12454775; DOI=10.1038/sj.bjc.6600637;
Sodha N., Bullock S., Taylor R., Mitchell G., Guertl-Lackner B.,
Williams R.D., Bevan S., Bishop K., McGuire S., Houlston R.S.,
Eeles R.A.;
"CHEK2 variants in susceptibility to breast cancer and evidence of
retention of the wild type allele in tumours.";
Br. J. Cancer 87:1445-1448(2002).
[51]
VARIANTS OSTEOSARCOMA SER-17 AND LEU-85.
PubMed=11746983; DOI=10.1002/gcc.1207;
Miller C.W., Ikezoe T., Krug U., Hofmann W.K., Tavor S., Vegesna V.,
Tsukasaki K., Takeuchi S., Koeffler H.P.;
"Mutations of the CHK2 gene are found in some osteosarcomas, but are
rare in breast, lung, and ovarian tumors.";
Genes Chromosomes Cancer 33:17-21(2002).
[52]
VARIANTS PROSTATE CANCER LYS-64; PRO-145; ARG-167; CYS-180; HIS-180;
CYS-181; HIS-181; LYS-239; PHE-251; HIS-318; PRO-323; CYS-327 AND
LYS-476, AND VARIANT THR-157.
PubMed=12533788; DOI=10.1086/346094;
Dong X., Wang L., Taniguchi K., Wang X., Cunningham J.M.,
McDonnell S.K., Qian C., Marks A.F., Slager S.L., Peterson B.J.,
Smith D.I., Cheville J.C., Blute M.L., Jacobsen S.J., Schaid D.J.,
Tindall D.J., Thibodeau S.N., Liu W.;
"Mutations in CHEK2 associated with prostate cancer risk.";
Am. J. Hum. Genet. 72:270-280(2003).
[53]
VARIANTS GLY-117; TRP-145 AND THR-157.
PubMed=12610780; DOI=10.1086/373965;
Schutte M., Seal S., Barfoot R., Meijers-Heijboer H., Wasielewski M.,
Evans D.G., Eccles D., Meijers C., Lohman F., Klijn J.,
van den Ouweland A., Brady A., Cole T., Collins A., Cox H.,
Donaldson A., Eeles R., Evans G., Gregory H., Gray J., Houlston R.,
Lalloo F., Lucassen A., Mackay J., Mitchell G., Morrison P.,
Murday V., Narod S., Patterson J., Peretz T., Phelan C.M., Rogers M.,
Schofield A., Tonin P., Weber B., Weber W., Futreal P.A.,
Nathanson K.L., Weber B.L., Easton D.F., Stratton M.R., Rahman N.;
"Variants in CHEK2 other than 1100delC do not make a major
contribution to breast cancer susceptibility.";
Am. J. Hum. Genet. 72:1023-1028(2003).
[54]
VARIANT THR-157.
PubMed=14612911; DOI=10.1038/sj.bjc.6601425;
Seppaelae E.H., Ikonen T., Mononen N., Autio V., Roekman A.,
Matikainen M.P., Tammela T.L.J., Schleutker J.;
"CHEK2 variants associate with hereditary prostate cancer.";
Br. J. Cancer 89:1966-1970(2003).
[55]
VARIANT THR-157.
PubMed=15492928; DOI=10.1086/426403;
Cybulski C., Gorski B., Huzarski T., Masojc B., Mierzejewski M.,
Debniak T., Teodorczyk U., Byrski T., Gronwald J., Matyjasik J.,
Zlowocka E., Lenner M., Grabowska E., Nej K., Castaneda J., Medrek K.,
Szymanska A., Szymanska J., Kurzawski G., Suchy J., Oszurek O.,
Witek A., Narod S.A., Lubinski J.;
"CHEK2 is a multiorgan cancer susceptibility gene.";
Am. J. Hum. Genet. 75:1131-1135(2004).
[56]
VARIANTS TRP-145 AND THR-157.
PubMed=15535844; DOI=10.1186/bcr933;
Friedrichsen D.M., Malone K.E., Doody D.R., Daling J.R.,
Ostrander E.A.;
"Frequency of CHEK2 mutations in a population based, case-control
study of breast cancer in young women.";
Breast Cancer Res. 6:R629-R635(2004).
[57]
VARIANT THR-157.
PubMed=15087378; DOI=10.1158/0008-5472.CAN-04-0341;
Cybulski C., Huzarski T., Gorski B., Masojc B., Mierzejewski M.,
Debniak T., Gliniewicz B., Matyjasik J., Zlowocka E., Kurzawski G.,
Sikorski A., Posmyk M., Szwiec M., Czajka R., Narod S.A., Lubinski J.;
"A novel founder CHEK2 mutation is associated with increased prostate
cancer risk.";
Cancer Res. 64:2677-2679(2004).
[58]
VARIANT THR-157.
PubMed=15095295; DOI=10.1002/ijc.20073;
Dufault M.R., Betz B., Wappenschmidt B., Hofmann W., Bandick K.,
Golla A., Pietschmann A., Nestle-Kraemling C., Rhiem K., Huettner C.,
von Lindern C., Dall P., Kiechle M., Untch M., Jonat W., Meindl A.,
Scherneck S., Niederacher D., Schmutzler R.K., Arnold N.;
"Limited relevance of the CHEK2 gene in hereditary breast cancer.";
Int. J. Cancer 110:320-325(2004).
[59]
VARIANT THR-157.
PubMed=15239132; DOI=10.1002/ijc.20299;
Kilpivaara O., Vahteristo P., Falck J., Syrjaekoski K., Eerola H.,
Easton D., Bartkova J., Lukas J., Heikkilae P., Aittomaeki K.,
Holli K., Blomqvist C., Kallioniemi O.-P., Bartek J., Nevanlinna H.;
"CHEK2 variant I157T may be associated with increased breast cancer
risk.";
Int. J. Cancer 111:543-547(2004).
[60]
VARIANTS LEU-85 AND PHE-428.
PubMed=15649950; DOI=10.1093/hmg/ddi052;
Shaag A., Walsh T., Renbaum P., Kirchhoff T., Nafa K., Shiovitz S.,
Mandell J.B., Welcsh P., Lee M.K., Ellis N., Offit K., Levy-Lahad E.,
King M.-C.;
"Functional and genomic approaches reveal an ancient CHEK2 allele
associated with breast cancer in the Ashkenazi Jewish population.";
Hum. Mol. Genet. 14:555-563(2005).
[61]
VARIANT THR-157.
PubMed=15810020; DOI=10.1002/ijc.21022;
Bogdanova N., Enbetaen-Dubrowinskaja N., Feshchenko S., Lazjuk G.I.,
Rogov Y.I., Dammann O., Bremer M., Karstens J.H., Sohn C., Doerk T.;
"Association of two mutations in the CHEK2 gene with breast cancer.";
Int. J. Cancer 116:263-266(2005).
[62]
VARIANTS GLY-117; GLN-137; TRP-145; THR-157 AND HIS-180.
PubMed=15818573; DOI=10.1002/path.1764;
van Puijenbroek M., van Asperen C.J., van Mil A., Devilee P.,
van Wezel T., Morreau H.;
"Homozygosity for a CHEK2*1100delC mutation identified in familial
colorectal cancer does not lead to a severe clinical phenotype.";
J. Pathol. 206:198-204(2005).
[63]
VARIANT BC CYS-390, CHARACTERIZATION OF VARIANT BC CYS-390, AND
FUNCTION.
PubMed=25619829; DOI=10.1038/onc.2014.443;
Wang N., Ding H., Liu C., Li X., Wei L., Yu J., Liu M., Ying M.,
Gao W., Jiang H., Wang Y.;
"A novel recurrent CHEK2 Y390C mutation identified in high-risk
Chinese breast cancer patients impairs its activity and is associated
with increased breast cancer risk.";
Oncogene 34:5198-5205(2015).
-!- 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. Promotes the CCAR2-SIRT1 association and is required for
CCAR2-mediated SIRT1 inhibition (PubMed:25361978).
{ECO:0000250|UniProtKB:Q9Z265, ECO:0000269|PubMed:10097108,
ECO:0000269|PubMed:10724175, ECO:0000269|PubMed:11298456,
ECO:0000269|PubMed:12402044, ECO:0000269|PubMed:12607004,
ECO:0000269|PubMed:12717439, ECO:0000269|PubMed:12810724,
ECO:0000269|PubMed:16163388, ECO:0000269|PubMed:17101782,
ECO:0000269|PubMed:17380128, ECO:0000269|PubMed:17715138,
ECO:0000269|PubMed:18317453, ECO:0000269|PubMed:18644861,
ECO:0000269|PubMed:18728393, ECO:0000269|PubMed:20364141,
ECO:0000269|PubMed:25361978, ECO:0000269|PubMed:25619829,
ECO:0000269|PubMed:9836640, ECO:0000269|PubMed:9889122}.
-!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
-!- COFACTOR:
Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
-!- 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.
{ECO:0000269|PubMed:15342622}.
-!- SUBUNIT: 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. Interacts with
CDKN2AIP. Interacts (via protein kinase domain) with CCAR2 (via N-
terminus). Interacts with SIRT1. {ECO:0000269|PubMed:10724175,
ECO:0000269|PubMed:11298456, ECO:0000269|PubMed:12364621,
ECO:0000269|PubMed:12607004, ECO:0000269|PubMed:12810724,
ECO:0000269|PubMed:16794575, ECO:0000269|PubMed:18644861,
ECO:0000269|PubMed:24825908, ECO:0000269|PubMed:25361978}.
-!- INTERACTION:
Self; NbExp=6; IntAct=EBI-1180783, EBI-1180783;
P27958:- (xeno); NbExp=3; IntAct=EBI-1180783, EBI-6904388;
Q9NY61:AATF; NbExp=4; IntAct=EBI-1180783, EBI-372428;
Q9UQ88-1:CDK11A; NbExp=2; IntAct=EBI-1180783, EBI-11579223;
Q96KN1:FAM84B; NbExp=3; IntAct=EBI-1180783, EBI-9057780;
Q9Y248:GINS2; NbExp=2; IntAct=EBI-1180783, EBI-747491;
Q13007:IL24; NbExp=3; IntAct=EBI-1180783, EBI-3915542;
P56645:PER3; NbExp=2; IntAct=EBI-1180783, EBI-2827813;
P53350:PLK1; NbExp=7; IntAct=EBI-1180783, EBI-476768;
Q15172:PPP2R5A; NbExp=2; IntAct=EBI-1180783, EBI-641666;
Q15173:PPP2R5B; NbExp=2; IntAct=EBI-1180783, EBI-1369497;
Q13362-1:PPP2R5C; NbExp=3; IntAct=EBI-1180783, EBI-1266170;
Q13362-2:PPP2R5C; NbExp=2; IntAct=EBI-1180783, EBI-1266173;
Q13362-3:PPP2R5C; NbExp=4; IntAct=EBI-1180783, EBI-1266176;
Q16537:PPP2R5E; NbExp=3; IntAct=EBI-1180783, EBI-968374;
P06400:RB1; NbExp=3; IntAct=EBI-1180783, EBI-491274;
Q5VTR2:RNF20; NbExp=3; IntAct=EBI-1180783, EBI-2372238;
P06725:UL83 (xeno); NbExp=2; IntAct=EBI-1180783, EBI-9545359;
P55072:VCP; NbExp=2; IntAct=EBI-1180783, EBI-355164;
P18887:XRCC1; NbExp=8; IntAct=EBI-1180783, EBI-947466;
-!- SUBCELLULAR LOCATION: Isoform 2: Nucleus. Note=Isoform 10 is
present throughout the cell.
-!- SUBCELLULAR LOCATION: Isoform 4: Nucleus.
-!- SUBCELLULAR LOCATION: Isoform 7: Nucleus.
-!- SUBCELLULAR LOCATION: Isoform 9: Nucleus.
-!- SUBCELLULAR LOCATION: Isoform 12: Nucleus.
-!- SUBCELLULAR LOCATION: Nucleus, PML body. Nucleus, nucleoplasm.
Note=Recruited into PML bodies together with TP53.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=13;
Name=1;
IsoId=O96017-1; Sequence=Displayed;
Name=2; Synonyms=ins2;
IsoId=O96017-2; Sequence=VSP_014564, VSP_014567, VSP_014568;
Note=Lacks enzymatic activity.;
Name=3; Synonyms=del2-12;
IsoId=O96017-3; Sequence=VSP_014559;
Name=4; Synonyms=del2-3;
IsoId=O96017-4; Sequence=VSP_014558;
Note=Lacks enzymatic activity.;
Name=5; Synonyms=del4;
IsoId=O96017-5; Sequence=VSP_014565, VSP_014566;
Name=6; Synonyms=sub3;
IsoId=O96017-6; Sequence=VSP_014562, VSP_014563;
Name=7; Synonyms=del9-12;
IsoId=O96017-7; Sequence=VSP_014572, VSP_014573;
Note=Lacks enzymatic activity.;
Name=8; Synonyms=del7;
IsoId=O96017-8; Sequence=VSP_014569, VSP_014570;
Name=9; Synonyms=insx;
IsoId=O96017-9; Sequence=VSP_014557;
Note=Retains low level of catalytic activity.;
Name=10; Synonyms=iso2;
IsoId=O96017-10; Sequence=VSP_014560, VSP_014561;
Note=Lacks enzymatic activity.;
Name=11; Synonyms=iso1;
IsoId=O96017-11; Sequence=VSP_014556;
Name=12; Synonyms=del9;
IsoId=O96017-12; Sequence=VSP_014571;
Note=Lacks enzymatic activity.;
Name=13;
IsoId=O96017-13; Sequence=VSP_045148;
-!- TISSUE SPECIFICITY: High expression is found in testis, spleen,
colon and peripheral blood leukocytes. Low expression is found in
other tissues.
-!- PTM: Phosphorylated. Phosphorylated at Ser-73 by PLK3 in response
to DNA damage, promoting phosphorylation at Thr-68 by ATM and the
G2/M transition checkpoint. 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. {ECO:0000269|PubMed:10973490,
ECO:0000269|PubMed:11390408, ECO:0000269|PubMed:15342622,
ECO:0000269|PubMed:16311512, ECO:0000269|PubMed:16481012,
ECO:0000269|PubMed:17715138, ECO:0000269|PubMed:18644861,
ECO:0000269|PubMed:19164942}.
-!- PTM: Ubiquitinated. CUL1-mediated ubiquitination regulates the
pro-apoptotic function. Ubiquitination may also regulate protein
stability. Ubiquitinated by RNF8 via 'Lys-48'-linked
ubiquitination.
-!- DISEASE: Li-Fraumeni syndrome 2 (LFS2) [MIM:609265]: A highly
penetrant familial cancer syndrome that in its classic form is
defined by the existence of a proband affected by a sarcoma before
45 years with a first degree relative affected by any tumor before
45 years and another first degree relative with any tumor before
45 years or a sarcoma at any age. Other clinical definitions for
LFS have been proposed (PubMed:8118819 and PubMed:8718514) and
called Li-Fraumeni like syndrome (LFL). In these families affected
relatives develop a diverse set of malignancies at unusually early
ages. Four types of cancers account for 80% of tumors occurring in
TP53 germline mutation carriers: breast cancers, soft tissue and
bone sarcomas, brain tumors (astrocytomas) and adrenocortical
carcinomas. Less frequent tumors include choroid plexus carcinoma
or papilloma before the age of 15, rhabdomyosarcoma before the age
of 5, leukemia, Wilms tumor, malignant phyllodes tumor, colorectal
and gastric cancers. {ECO:0000269|PubMed:11719428}. Note=The
disease is caused by mutations affecting the gene represented in
this entry.
-!- DISEASE: Prostate cancer (PC) [MIM:176807]: A malignancy
originating in tissues of the prostate. Most prostate cancers are
adenocarcinomas that develop in the acini of the prostatic ducts.
Other rare histopathologic types of prostate cancer that occur in
approximately 5% of patients include small cell carcinoma,
mucinous carcinoma, prostatic ductal carcinoma, transitional cell
carcinoma, squamous cell carcinoma, basal cell carcinoma, adenoid
cystic carcinoma (basaloid), signet-ring cell carcinoma and
neuroendocrine carcinoma. {ECO:0000269|PubMed:12533788}.
Note=Disease susceptibility is associated with variations
affecting the gene represented in this entry.
-!- DISEASE: Osteogenic sarcoma (OSRC) [MIM:259500]: A sarcoma
originating in bone-forming cells, affecting the ends of long
bones. Note=The gene represented in this entry may be involved in
disease pathogenesis.
-!- DISEASE: Breast cancer (BC) [MIM:114480]: A common malignancy
originating from breast epithelial tissue. Breast neoplasms can be
distinguished by their histologic pattern. Invasive ductal
carcinoma is by far the most common type. Breast cancer is
etiologically and genetically heterogeneous. Important genetic
factors have been indicated by familial occurrence and bilateral
involvement. Mutations at more than one locus can be involved in
different families or even in the same case.
{ECO:0000269|PubMed:12094328, ECO:0000269|PubMed:21618645,
ECO:0000269|PubMed:25619829}. Note=Disease susceptibility is
associated with variations affecting the gene represented in this
entry. {ECO:0000269|PubMed:12094328}.
-!- SIMILARITY: Belongs to the protein kinase superfamily. CAMK
Ser/Thr protein kinase family. CHK2 subfamily. {ECO:0000305}.
-!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
and Haematology;
URL="http://atlasgeneticsoncology.org/Genes/CHEK2ID312.html";
-!- WEB RESOURCE: Name=NIEHS-SNPs;
URL="http://egp.gs.washington.edu/data/chek2/";
-----------------------------------------------------------------------
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EMBL; AF086904; AAC83693.1; -; mRNA.
EMBL; AJ131197; CAA10319.1; -; mRNA.
EMBL; AF096279; AAD11784.1; -; mRNA.
EMBL; AY551295; AAS58456.1; -; mRNA.
EMBL; AY551296; AAS58457.1; -; mRNA.
EMBL; AY551297; AAS58458.1; -; mRNA.
EMBL; AY551298; AAS58459.1; -; mRNA.
EMBL; AY551299; AAS58460.1; -; mRNA.
EMBL; AY551300; AAS58461.1; -; mRNA.
EMBL; AY551301; AAS58462.1; -; mRNA.
EMBL; AY551302; AAS58463.1; -; mRNA.
EMBL; AY551303; AAS58464.1; -; mRNA.
EMBL; AY551304; AAS58465.1; -; mRNA.
EMBL; AY551305; AAS58466.1; -; mRNA.
EMBL; CR456418; CAG30304.1; -; mRNA.
EMBL; AF174135; AAD48504.1; -; mRNA.
EMBL; AB040105; BAB17231.1; -; mRNA.
EMBL; AK290754; BAF83443.1; -; mRNA.
EMBL; AF217975; AAG17218.1; -; mRNA.
EMBL; AY800241; AAV41895.1; -; Genomic_DNA.
EMBL; AL121825; CAH73823.1; -; Genomic_DNA.
EMBL; AL117330; CAH73823.1; JOINED; Genomic_DNA.
EMBL; AL117330; CAH73875.1; -; Genomic_DNA.
EMBL; AL121825; CAH73875.1; JOINED; Genomic_DNA.
EMBL; AL121825; CAX11957.1; -; Genomic_DNA.
EMBL; AL117330; CAX11957.1; JOINED; Genomic_DNA.
EMBL; AL121825; CAX11958.1; -; Genomic_DNA.
EMBL; AL117330; CAX11958.1; JOINED; Genomic_DNA.
EMBL; AL121825; CAX11959.1; -; Genomic_DNA.
EMBL; AL117330; CAX11959.1; JOINED; Genomic_DNA.
EMBL; AL117330; CAX14026.1; -; Genomic_DNA.
EMBL; AL121825; CAX14026.1; JOINED; Genomic_DNA.
EMBL; AL117330; CAX14027.1; -; Genomic_DNA.
EMBL; AL121825; CAX14027.1; JOINED; Genomic_DNA.
EMBL; AL117330; CAX14028.1; -; Genomic_DNA.
EMBL; AL121825; CAX14028.1; JOINED; Genomic_DNA.
EMBL; CH471095; EAW59755.1; -; Genomic_DNA.
EMBL; BC004207; AAH04207.1; -; mRNA.
CCDS; CCDS13843.1; -. [O96017-1]
CCDS; CCDS13844.1; -. [O96017-12]
CCDS; CCDS33629.1; -. [O96017-9]
RefSeq; NP_001005735.1; NM_001005735.1. [O96017-9]
RefSeq; NP_001244316.1; NM_001257387.1. [O96017-13]
RefSeq; NP_009125.1; NM_007194.3. [O96017-1]
RefSeq; NP_665861.1; NM_145862.2. [O96017-12]
RefSeq; XP_011528147.1; XM_011529845.2. [O96017-13]
RefSeq; XP_016884050.1; XM_017028561.1. [O96017-13]
UniGene; Hs.291363; -.
UniGene; Hs.505297; -.
PDB; 1GXC; X-ray; 2.70 A; A/D/G/J=64-212.
PDB; 2CN5; X-ray; 2.25 A; A=210-531.
PDB; 2CN8; X-ray; 2.70 A; A=210-531.
PDB; 2W0J; X-ray; 2.05 A; A=210-531.
PDB; 2W7X; X-ray; 2.07 A; A=210-531.
PDB; 2WTC; X-ray; 3.00 A; A=210-531.
PDB; 2WTD; X-ray; 2.75 A; A=210-531.
PDB; 2WTI; X-ray; 2.50 A; A=210-531.
PDB; 2WTJ; X-ray; 2.10 A; A=210-531.
PDB; 2XBJ; X-ray; 2.30 A; A=210-531.
PDB; 2XK9; X-ray; 2.35 A; A=210-531.
PDB; 2XM8; X-ray; 3.40 A; A=210-531.
PDB; 2XM9; X-ray; 2.50 A; A=210-531.
PDB; 2YCF; X-ray; 1.77 A; A=210-530.
PDB; 2YCQ; X-ray; 2.05 A; A=210-531.
PDB; 2YCR; X-ray; 2.20 A; A=210-531.
PDB; 2YCS; X-ray; 2.35 A; A=210-531.
PDB; 2YIQ; X-ray; 1.89 A; A=210-531.
PDB; 2YIR; X-ray; 2.10 A; A=210-531.
PDB; 2YIT; X-ray; 2.20 A; A=210-531.
PDB; 3I6U; X-ray; 3.00 A; A/B=84-502.
PDB; 3I6W; X-ray; 3.25 A; A/B/C/D/E/F/G/H=70-512.
PDB; 3VA4; X-ray; 1.54 A; C=63-73.
PDB; 4A9R; X-ray; 2.85 A; A=210-531.
PDB; 4A9S; X-ray; 2.66 A; A=210-531.
PDB; 4A9T; X-ray; 2.70 A; A=210-531.
PDB; 4A9U; X-ray; 2.48 A; A=210-531.
PDB; 4BDA; X-ray; 2.60 A; A=210-531.
PDB; 4BDB; X-ray; 2.50 A; A=210-531.
PDB; 4BDC; X-ray; 3.00 A; A=210-531.
PDB; 4BDD; X-ray; 2.67 A; A=210-531.
PDB; 4BDE; X-ray; 2.55 A; A=210-531.
PDB; 4BDF; X-ray; 2.70 A; A=210-531.
PDB; 4BDG; X-ray; 2.84 A; A=210-531.
PDB; 4BDH; X-ray; 2.70 A; A=210-531.
PDB; 4BDI; X-ray; 2.32 A; A=210-531.
PDB; 4BDJ; X-ray; 3.01 A; A=210-531.
PDB; 4BDK; X-ray; 3.30 A; A=210-531.
PDBsum; 1GXC; -.
PDBsum; 2CN5; -.
PDBsum; 2CN8; -.
PDBsum; 2W0J; -.
PDBsum; 2W7X; -.
PDBsum; 2WTC; -.
PDBsum; 2WTD; -.
PDBsum; 2WTI; -.
PDBsum; 2WTJ; -.
PDBsum; 2XBJ; -.
PDBsum; 2XK9; -.
PDBsum; 2XM8; -.
PDBsum; 2XM9; -.
PDBsum; 2YCF; -.
PDBsum; 2YCQ; -.
PDBsum; 2YCR; -.
PDBsum; 2YCS; -.
PDBsum; 2YIQ; -.
PDBsum; 2YIR; -.
PDBsum; 2YIT; -.
PDBsum; 3I6U; -.
PDBsum; 3I6W; -.
PDBsum; 3VA4; -.
PDBsum; 4A9R; -.
PDBsum; 4A9S; -.
PDBsum; 4A9T; -.
PDBsum; 4A9U; -.
PDBsum; 4BDA; -.
PDBsum; 4BDB; -.
PDBsum; 4BDC; -.
PDBsum; 4BDD; -.
PDBsum; 4BDE; -.
PDBsum; 4BDF; -.
PDBsum; 4BDG; -.
PDBsum; 4BDH; -.
PDBsum; 4BDI; -.
PDBsum; 4BDJ; -.
PDBsum; 4BDK; -.
ProteinModelPortal; O96017; -.
SMR; O96017; -.
BioGrid; 116369; 98.
CORUM; O96017; -.
DIP; DIP-24270N; -.
ELM; O96017; -.
IntAct; O96017; 109.
MINT; MINT-124588; -.
BindingDB; O96017; -.
ChEMBL; CHEMBL2527; -.
DrugBank; DB05149; XL844.
GuidetoPHARMACOLOGY; 1988; -.
iPTMnet; O96017; -.
PhosphoSitePlus; O96017; -.
BioMuta; CHEK2; -.
EPD; O96017; -.
MaxQB; O96017; -.
PeptideAtlas; O96017; -.
PRIDE; O96017; -.
DNASU; 11200; -.
Ensembl; ENST00000328354; ENSP00000329178; ENSG00000183765. [O96017-1]
Ensembl; ENST00000348295; ENSP00000329012; ENSG00000183765. [O96017-12]
Ensembl; ENST00000382580; ENSP00000372023; ENSG00000183765. [O96017-9]
Ensembl; ENST00000402731; ENSP00000384835; ENSG00000183765. [O96017-12]
Ensembl; ENST00000403642; ENSP00000384919; ENSG00000183765. [O96017-4]
Ensembl; ENST00000404276; ENSP00000385747; ENSG00000183765. [O96017-1]
Ensembl; ENST00000405598; ENSP00000386087; ENSG00000183765. [O96017-1]
Ensembl; ENST00000417588; ENSP00000412901; ENSG00000183765. [O96017-5]
Ensembl; ENST00000433728; ENSP00000404400; ENSG00000183765. [O96017-8]
Ensembl; ENST00000448511; ENSP00000404567; ENSG00000183765. [O96017-6]
GeneID; 11200; -.
KEGG; hsa:11200; -.
UCSC; uc003adt.2; human. [O96017-1]
CTD; 11200; -.
DisGeNET; 11200; -.
EuPathDB; HostDB:ENSG00000183765.20; -.
GeneCards; CHEK2; -.
HGNC; HGNC:16627; CHEK2.
HPA; CAB002030; -.
HPA; HPA001878; -.
MalaCards; CHEK2; -.
MIM; 114480; phenotype.
MIM; 176807; phenotype.
MIM; 259500; phenotype.
MIM; 604373; gene+phenotype.
MIM; 609265; phenotype.
neXtProt; NX_O96017; -.
OpenTargets; ENSG00000183765; -.
Orphanet; 1331; Familial prostate cancer.
Orphanet; 145; Hereditary breast and ovarian cancer syndrome.
Orphanet; 524; Li-Fraumeni syndrome.
Orphanet; 668; Osteosarcoma.
PharmGKB; PA404; -.
GeneTree; ENSGT00800000124190; -.
HOGENOM; HOG000233016; -.
HOVERGEN; HBG108055; -.
InParanoid; O96017; -.
KO; K06641; -.
OMA; NLSHPCV; -.
OrthoDB; EOG091G0DVW; -.
PhylomeDB; O96017; -.
TreeFam; TF101082; -.
BRENDA; 2.7.11.1; 2681.
Reactome; R-HSA-5693565; Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks.
Reactome; R-HSA-6804756; Regulation of TP53 Activity through Phosphorylation.
Reactome; R-HSA-6804757; Regulation of TP53 Degradation.
Reactome; R-HSA-6804760; Regulation of TP53 Activity through Methylation.
Reactome; R-HSA-69473; G2/M DNA damage checkpoint.
Reactome; R-HSA-69541; Stabilization of p53.
Reactome; R-HSA-69601; Ubiquitin Mediated Degradation of Phosphorylated Cdc25A.
Reactome; R-HSA-75035; Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex.
SignaLink; O96017; -.
SIGNOR; O96017; -.
EvolutionaryTrace; O96017; -.
GeneWiki; CHEK2; -.
GenomeRNAi; 11200; -.
PRO; PR:O96017; -.
Proteomes; UP000005640; Chromosome 22.
Bgee; ENSG00000183765; -.
ExpressionAtlas; O96017; baseline and differential.
Genevisible; O96017; HS.
GO; GO:0005794; C:Golgi apparatus; IDA:HPA.
GO; GO:0005654; C:nucleoplasm; IDA:HPA.
GO; GO:0016605; C:PML body; IDA:UniProtKB.
GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
GO; GO:0042802; F:identical protein binding; IPI:IntAct.
GO; GO:0016301; F:kinase activity; TAS:Reactome.
GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB.
GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB.
GO; GO:0051301; P:cell division; IEA:UniProtKB-KW.
GO; GO:0044257; P:cellular protein catabolic process; IMP:UniProtKB.
GO; GO:1903926; P:cellular response to bisphenol A; IEA:Ensembl.
GO; GO:0006974; P:cellular response to DNA damage stimulus; IDA:MGI.
GO; GO:0035690; P:cellular response to drug; IEA:Ensembl.
GO; GO:0071480; P:cellular response to gamma radiation; IEA:Ensembl.
GO; GO:0000077; P:DNA damage checkpoint; TAS:UniProtKB.
GO; GO:0006975; P:DNA damage induced protein phosphorylation; IMP:UniProtKB.
GO; GO:0006977; P:DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest; TAS:Reactome.
GO; GO:0006978; P:DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator; IEA:Ensembl.
GO; GO:0006302; P:double-strand break repair; IMP:UniProtKB.
GO; GO:0000086; P:G2/M transition of mitotic cell cycle; IMP:UniProtKB.
GO; GO:0008630; P:intrinsic apoptotic signaling pathway in response to DNA damage; IDA:UniProtKB.
GO; GO:0042771; P:intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator; IEA:Ensembl.
GO; GO:0090307; P:mitotic spindle assembly; IMP:UniProtKB.
GO; GO:0071157; P:negative regulation of cell cycle arrest; IEA:Ensembl.
GO; GO:2000002; P:negative regulation of DNA damage checkpoint; IEA:Ensembl.
GO; GO:0018105; P:peptidyl-serine phosphorylation; IBA:GO_Central.
GO; GO:0018107; P:peptidyl-threonine phosphorylation; IBA:GO_Central.
GO; GO:2000210; P:positive regulation of anoikis; IEA:Ensembl.
GO; GO:0001934; P:positive regulation of protein phosphorylation; IEA:Ensembl.
GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:UniProtKB.
GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
GO; GO:0050821; P:protein stabilization; IDA:UniProtKB.
GO; GO:0042981; P:regulation of apoptotic process; IBA:GO_Central.
GO; GO:0042176; P:regulation of protein catabolic process; IMP:UniProtKB.
GO; GO:1901796; P:regulation of signal transduction by p53 class mediator; TAS:Reactome.
GO; GO:0006355; P:regulation of transcription, DNA-templated; IDA:UniProtKB.
GO; GO:0001302; P:replicative cell aging; IMP:CACAO.
GO; GO:0090399; P:replicative senescence; NAS:BHF-UCL.
GO; GO:1903416; P:response to glycoside; IEA:Ensembl.
GO; GO:0042770; P:signal transduction in response to DNA damage; IDA:MGI.
GO; GO:0072428; P:signal transduction involved in intra-S DNA damage checkpoint; IMP:UniProtKB.
GO; GO:0006351; P:transcription, DNA-templated; IEA:UniProtKB-KW.
CDD; cd00060; FHA; 1.
InterPro; IPR000253; FHA_dom.
InterPro; IPR011009; Kinase-like_dom_sf.
InterPro; IPR000719; Prot_kinase_dom.
InterPro; IPR008271; Ser/Thr_kinase_AS.
InterPro; IPR008984; SMAD_FHA_dom_sf.
Pfam; PF00498; FHA; 1.
Pfam; PF00069; Pkinase; 1.
SMART; SM00240; FHA; 1.
SMART; SM00220; S_TKc; 1.
SUPFAM; SSF49879; SSF49879; 1.
SUPFAM; SSF56112; SSF56112; 1.
PROSITE; PS50006; FHA_DOMAIN; 1.
PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
1: Evidence at protein level;
3D-structure; Alternative splicing; Apoptosis; ATP-binding;
Cell cycle; Cell division; Complete proteome; Disease mutation;
DNA damage; DNA repair; Kinase; Li-Fraumeni syndrome; Magnesium;
Metal-binding; Mitosis; Nucleotide-binding; Nucleus; Phosphoprotein;
Polymorphism; Reference proteome; Serine/threonine-protein kinase;
Transcription; Transcription regulation; Transferase;
Tumor suppressor; Ubl conjugation.
CHAIN 1 543 Serine/threonine-protein kinase Chk2.
/FTId=PRO_0000085858.
DOMAIN 113 175 FHA. {ECO:0000255|PROSITE-
ProRule:PRU00086}.
DOMAIN 220 486 Protein kinase. {ECO:0000255|PROSITE-
ProRule:PRU00159}.
NP_BIND 227 234 ATP.
NP_BIND 302 308 ATP.
NP_BIND 351 352 ATP.
REGION 368 394 T-loop/activation segment.
ACT_SITE 347 347 Proton acceptor.
BINDING 249 249 ATP.
BINDING 368 368 ATP.
MOD_RES 62 62 Phosphoserine; by PLK3.
{ECO:0000269|PubMed:16481012}.
MOD_RES 68 68 Phosphothreonine; by ATM and MAP3K20.
{ECO:0000269|PubMed:10973490,
ECO:0000269|PubMed:15342622,
ECO:0000269|PubMed:16311512,
ECO:0000269|PubMed:16481012}.
MOD_RES 73 73 Phosphoserine; by PLK3.
{ECO:0000269|PubMed:16481012}.
MOD_RES 379 379 Phosphoserine; by autocatalysis.
{ECO:0000269|PubMed:18644861}.
MOD_RES 383 383 Phosphothreonine; by autocatalysis.
{ECO:0000269|PubMed:11390408}.
MOD_RES 387 387 Phosphothreonine; by autocatalysis.
{ECO:0000269|PubMed:11390408}.
MOD_RES 456 456 Phosphoserine.
{ECO:0000269|PubMed:17715138}.
VAR_SEQ 1 221 Missing (in isoform 13).
{ECO:0000303|PubMed:15498874}.
/FTId=VSP_045148.
VAR_SEQ 75 392 Missing (in isoform 11).
{ECO:0000303|PubMed:15361853}.
/FTId=VSP_014556.
VAR_SEQ 107 487 Missing (in isoform 3).
{ECO:0000303|PubMed:15361853}.
/FTId=VSP_014559.
VAR_SEQ 107 197 Missing (in isoform 4).
{ECO:0000303|PubMed:15361853}.
/FTId=VSP_014558.
VAR_SEQ 107 107 E -> ETESGHVTQSDLELLLSSDPPASASQSAGIRGVRHH
PRPVCSLK (in isoform 9).
{ECO:0000303|PubMed:15361853,
ECO:0000303|PubMed:15461802}.
/FTId=VSP_014557.
VAR_SEQ 131 147 KRTDKYRTYSKKHFRIF -> EFRSYSFYLP (in
isoform 10).
{ECO:0000303|PubMed:15361853}.
/FTId=VSP_014560.
VAR_SEQ 148 543 Missing (in isoform 10).
{ECO:0000303|PubMed:15361853}.
/FTId=VSP_014561.
VAR_SEQ 150 165 VGPKNSYIAYIEDHSG -> ENLSCPYRIWFNFCLF (in
isoform 6).
{ECO:0000303|PubMed:15361853}.
/FTId=VSP_014562.
VAR_SEQ 166 543 Missing (in isoform 6).
{ECO:0000303|PubMed:15361853}.
/FTId=VSP_014563.
VAR_SEQ 198 224 VFVFFDLTVDDQSVYPKALRDEYIMSK -> EKILKIYSLS
RFSKIRRGAVAHVFNPS (in isoform 2).
{ECO:0000303|PubMed:10097108,
ECO:0000303|PubMed:15361853}.
/FTId=VSP_014564.
VAR_SEQ 199 203 FVFFD -> VPVER (in isoform 5).
{ECO:0000303|PubMed:15361853}.
/FTId=VSP_014565.
VAR_SEQ 204 543 Missing (in isoform 5).
{ECO:0000303|PubMed:15361853}.
/FTId=VSP_014566.
VAR_SEQ 228 234 SGACGEV -> GRGWQIT (in isoform 2).
{ECO:0000303|PubMed:10097108,
ECO:0000303|PubMed:15361853}.
/FTId=VSP_014567.
VAR_SEQ 235 543 Missing (in isoform 2).
{ECO:0000303|PubMed:10097108,
ECO:0000303|PubMed:15361853}.
/FTId=VSP_014568.
VAR_SEQ 283 289 PCIIKIK -> DGRGRAV (in isoform 8).
{ECO:0000303|PubMed:15361853}.
/FTId=VSP_014569.
VAR_SEQ 290 543 Missing (in isoform 8).
{ECO:0000303|PubMed:15361853}.
/FTId=VSP_014570.
VAR_SEQ 337 365 Missing (in isoform 12).
{ECO:0000303|PubMed:15361853,
ECO:0000303|Ref.7}.
/FTId=VSP_014571.
VAR_SEQ 337 339 YLH -> MKT (in isoform 7).
{ECO:0000303|PubMed:15361853}.
/FTId=VSP_014572.
VAR_SEQ 340 543 Missing (in isoform 7).
{ECO:0000303|PubMed:15361853}.
/FTId=VSP_014573.
VARIANT 17 17 A -> S (in an osteogenic sarcoma sample;
somatic mutation; might influence
susceptibility to breast cancer; does not
cause protein abrogation in familial
colorectal cancer; dbSNP:rs137853008).
{ECO:0000269|PubMed:11746983}.
/FTId=VAR_019101.
VARIANT 59 59 T -> K (in multiple cancers;
dbSNP:rs149991239).
{ECO:0000269|PubMed:12052256}.
/FTId=VAR_026630.
VARIANT 64 64 E -> K (in prostate cancer; somatic
mutation; dbSNP:rs141568342).
{ECO:0000269|PubMed:12533788}.
/FTId=VAR_019107.
VARIANT 85 85 P -> L (in an osteogenic sarcoma sample;
neutral allele among Ashkenazi Jewish
women; dbSNP:rs17883862).
{ECO:0000269|PubMed:11746983,
ECO:0000269|PubMed:15649950,
ECO:0000269|Ref.10}.
/FTId=VAR_019102.
VARIANT 117 117 R -> G (in dbSNP:rs28909982).
{ECO:0000269|PubMed:12454775,
ECO:0000269|PubMed:12610780,
ECO:0000269|PubMed:15818573}.
/FTId=VAR_022461.
VARIANT 137 137 R -> Q (might influence susceptibility to
breast cancer; does not cause protein
abrogation in familial colorectal cancer;
dbSNP:rs368570187).
{ECO:0000269|PubMed:12454775,
ECO:0000269|PubMed:15818573}.
/FTId=VAR_022462.
VARIANT 145 145 R -> P (in prostate cancer; somatic
mutation; dbSNP:rs587781667).
{ECO:0000269|PubMed:12533788}.
/FTId=VAR_019108.
VARIANT 145 145 R -> W (in colon cancer and LFS2; does
not cause protein abrogation in familial
colorectal cancer; loss of the ability to
interact with and phosphorylate CDC25A
and to promote CDC25A degradation in
response to ionizing radiation;
dbSNP:rs137853007).
{ECO:0000269|PubMed:10617473,
ECO:0000269|PubMed:11298456,
ECO:0000269|PubMed:11719428,
ECO:0000269|PubMed:12610780,
ECO:0000269|PubMed:15535844,
ECO:0000269|PubMed:15818573}.
/FTId=VAR_008554.
VARIANT 157 157 I -> T (might influence susceptibility to
different types of cancer; does not cause
protein abrogation in familial colorectal
cancer; loss of the ability to interact
with and phosphorylate CDC25A and to
promote CDC25A degradation in response to
ionizing radiation; dbSNP:rs17879961).
{ECO:0000269|PubMed:10617473,
ECO:0000269|PubMed:11298456,
ECO:0000269|PubMed:11461078,
ECO:0000269|PubMed:12533788,
ECO:0000269|PubMed:12610780,
ECO:0000269|PubMed:14612911,
ECO:0000269|PubMed:15087378,
ECO:0000269|PubMed:15095295,
ECO:0000269|PubMed:15239132,
ECO:0000269|PubMed:15492928,
ECO:0000269|PubMed:15535844,
ECO:0000269|PubMed:15810020,
ECO:0000269|PubMed:15818573,
ECO:0000269|Ref.10}.
/FTId=VAR_008555.
VARIANT 167 167 G -> R (in prostate cancer; somatic
mutation; dbSNP:rs72552322).
{ECO:0000269|PubMed:12533788}.
/FTId=VAR_019109.
VARIANT 180 180 R -> C (in prostate cancer; somatic
mutation; dbSNP:rs77130927).
{ECO:0000269|PubMed:12533788,
ECO:0000269|PubMed:21618645}.
/FTId=VAR_019103.
VARIANT 180 180 R -> H (in prostate cancer; somatic
mutation; dbSNP:rs137853009).
{ECO:0000269|PubMed:12454775,
ECO:0000269|PubMed:12533788,
ECO:0000269|PubMed:15818573}.
/FTId=VAR_019110.
VARIANT 181 181 R -> C (in prostate cancer; somatic
mutation; dbSNP:rs137853010).
{ECO:0000269|PubMed:12533788}.
/FTId=VAR_019104.
VARIANT 181 181 R -> H (in prostate cancer; somatic
mutation; dbSNP:rs121908701).
{ECO:0000269|PubMed:12533788}.
/FTId=VAR_019105.
VARIANT 239 239 E -> K (in prostate cancer; germline
mutation; dbSNP:rs121908702).
{ECO:0000269|PubMed:12533788}.
/FTId=VAR_019106.
VARIANT 251 251 I -> F (in prostate cancer; germline
mutation; dbSNP:rs587780189).
{ECO:0000269|PubMed:12533788}.
/FTId=VAR_019111.
VARIANT 318 318 R -> H (in prostate cancer; somatic
mutation; dbSNP:rs143611747).
{ECO:0000269|PubMed:12533788}.
/FTId=VAR_019112.
VARIANT 323 323 T -> P (in prostate cancer; somatic
mutation). {ECO:0000269|PubMed:12533788}.
/FTId=VAR_019113.
VARIANT 327 327 Y -> C (in prostate cancer; somatic
mutation; dbSNP:rs587780194).
{ECO:0000269|PubMed:12533788}.
/FTId=VAR_019114.
VARIANT 347 347 D -> N (in dbSNP:rs28909980).
/FTId=VAR_029154.
VARIANT 371 371 H -> Y (confers a moderate risk of breast
cancer; partially reduces kinase
activity; dbSNP:rs531398630).
{ECO:0000269|PubMed:21618645}.
/FTId=VAR_066012.
VARIANT 390 390 Y -> C (in BC; does not phosphorylate
p53/TP53; dbSNP:rs200928781).
{ECO:0000269|PubMed:25619829}.
/FTId=VAR_073020.
VARIANT 406 406 R -> H (in dbSNP:rs200649225).
/FTId=VAR_024572.
VARIANT 428 428 S -> F (may increase breast cancer risk;
dbSNP:rs137853011).
{ECO:0000269|PubMed:15649950}.
/FTId=VAR_022463.
VARIANT 436 436 L -> M (in dbSNP:rs17882922).
{ECO:0000269|Ref.10}.
/FTId=VAR_021117.
VARIANT 446 446 N -> K (in dbSNP:rs17880867).
{ECO:0000269|Ref.10}.
/FTId=VAR_021118.
VARIANT 447 447 F -> I (in dbSNP:rs17881473).
{ECO:0000269|Ref.10}.
/FTId=VAR_021119.
VARIANT 448 448 I -> S (in dbSNP:rs17886163).
{ECO:0000269|Ref.10}.
/FTId=VAR_021120.
VARIANT 476 476 T -> K (in prostate cancer; somatic
mutation). {ECO:0000269|PubMed:12533788}.
/FTId=VAR_019115.
VARIANT 500 500 S -> C (in dbSNP:rs28909981).
/FTId=VAR_029155.
VARIANT 501 501 E -> K (in dbSNP:rs17883172).
{ECO:0000269|Ref.10}.
/FTId=VAR_021121.
VARIANT 512 512 L -> V (in dbSNP:rs17882942).
{ECO:0000269|Ref.10}.
/FTId=VAR_021122.
MUTAGEN 68 68 T->A: Loss of activation and
phosphorylation.
{ECO:0000269|PubMed:11901158,
ECO:0000269|PubMed:15342622}.
MUTAGEN 73 73 S->A: Impaired activation,
phosphorylation by ATM and G2/M
transition checkpoint.
{ECO:0000269|PubMed:16481012}.
MUTAGEN 347 347 D->A: Loss of kinase activity and of the
ability to phosphorylate CDC25A.
{ECO:0000269|PubMed:11298456,
ECO:0000269|PubMed:9836640}.
MUTAGEN 368 368 D->N: Loss of autophosphorylation
activity. {ECO:0000269|PubMed:15342622}.
MUTAGEN 379 379 S->A: Abrogates autophosphorylation at
Ser-379 and prevents ubiquitination.
{ECO:0000269|PubMed:18644861}.
MUTAGEN 383 383 T->A: Loss of phosphorylation in response
to ionizing radiation.
{ECO:0000269|PubMed:11390408}.
MUTAGEN 387 387 T->A: Loss of phosphorylation in response
to ionizing radiation.
{ECO:0000269|PubMed:11390408}.
MUTAGEN 456 456 S->A: Increased ubiquitination and
degradation by the proteasome.
{ECO:0000269|PubMed:17715138}.
STRAND 94 98 {ECO:0000244|PDB:1GXC}.
STRAND 100 103 {ECO:0000244|PDB:3I6U}.
STRAND 106 108 {ECO:0000244|PDB:1GXC}.
STRAND 110 118 {ECO:0000244|PDB:1GXC}.
STRAND 122 124 {ECO:0000244|PDB:1GXC}.
HELIX 128 132 {ECO:0000244|PDB:1GXC}.
HELIX 135 138 {ECO:0000244|PDB:1GXC}.
STRAND 144 150 {ECO:0000244|PDB:1GXC}.
STRAND 154 162 {ECO:0000244|PDB:1GXC}.
STRAND 168 170 {ECO:0000244|PDB:1GXC}.
STRAND 180 182 {ECO:0000244|PDB:1GXC}.
STRAND 187 193 {ECO:0000244|PDB:1GXC}.
STRAND 197 203 {ECO:0000244|PDB:1GXC}.
HELIX 209 211 {ECO:0000244|PDB:3I6U}.
HELIX 214 219 {ECO:0000244|PDB:2YCF}.
STRAND 220 228 {ECO:0000244|PDB:2YCF}.
STRAND 230 239 {ECO:0000244|PDB:2YCF}.
TURN 240 243 {ECO:0000244|PDB:2YCF}.
STRAND 244 251 {ECO:0000244|PDB:2YCF}.
HELIX 253 256 {ECO:0000244|PDB:3I6U}.
HELIX 270 279 {ECO:0000244|PDB:2YCF}.
STRAND 288 302 {ECO:0000244|PDB:2YCF}.
STRAND 307 309 {ECO:0000244|PDB:4BDD}.
HELIX 310 313 {ECO:0000244|PDB:2YCF}.
HELIX 314 316 {ECO:0000244|PDB:2W7X}.
HELIX 321 340 {ECO:0000244|PDB:2YCF}.
HELIX 350 352 {ECO:0000244|PDB:2YCF}.
STRAND 353 361 {ECO:0000244|PDB:2YCF}.
STRAND 364 366 {ECO:0000244|PDB:2YCF}.
HELIX 369 371 {ECO:0000244|PDB:4BDE}.
HELIX 379 385 {ECO:0000244|PDB:2YCF}.
HELIX 388 390 {ECO:0000244|PDB:2WTJ}.
HELIX 393 398 {ECO:0000244|PDB:2YCF}.
TURN 399 403 {ECO:0000244|PDB:2YCF}.
HELIX 407 422 {ECO:0000244|PDB:2YCF}.
STRAND 429 431 {ECO:0000244|PDB:2CN5}.
HELIX 436 442 {ECO:0000244|PDB:2YCF}.
HELIX 449 452 {ECO:0000244|PDB:2YCF}.
HELIX 457 466 {ECO:0000244|PDB:2YCF}.
TURN 471 473 {ECO:0000244|PDB:2YCF}.
HELIX 477 481 {ECO:0000244|PDB:2YCF}.
HELIX 484 486 {ECO:0000244|PDB:2YCF}.
HELIX 489 502 {ECO:0000244|PDB:2YCF}.
TURN 504 506 {ECO:0000244|PDB:2WTJ}.
SEQUENCE 543 AA; 60915 MW; 28890ACF3C1F3408 CRC64;
MSRESDVEAQ QSHGSSACSQ PHGSVTQSQG SSSQSQGISS SSTSTMPNSS QSSHSSSGTL
SSLETVSTQE LYSIPEDQEP EDQEPEEPTP APWARLWALQ DGFANLECVN DNYWFGRDKS
CEYCFDEPLL KRTDKYRTYS KKHFRIFREV GPKNSYIAYI EDHSGNGTFV NTELVGKGKR
RPLNNNSEIA LSLSRNKVFV FFDLTVDDQS VYPKALRDEY IMSKTLGSGA CGEVKLAFER
KTCKKVAIKI ISKRKFAIGS AREADPALNV ETEIEILKKL NHPCIIKIKN FFDAEDYYIV
LELMEGGELF DKVVGNKRLK EATCKLYFYQ MLLAVQYLHE NGIIHRDLKP ENVLLSSQEE
DCLIKITDFG HSKILGETSL MRTLCGTPTY LAPEVLVSVG TAGYNRAVDC WSLGVILFIC
LSGYPPFSEH RTQVSLKDQI TSGKYNFIPE VWAEVSEKAL DLVKKLLVVD PKARFTTEEA
LRHPWLQDED MKRKFQDLLS EENESTALPQ VLAQPSTSRK RPREGEAEGA ETTKRPAVCA
AVL


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