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Database: UniProt
Entry: O96017
LinkDB: O96017
Original site: O96017 
ID   CHK2_HUMAN              Reviewed;         543 AA.
AC   O96017; A8K3Y9; B7ZBF3; B7ZBF4; B7ZBF5; Q6QA03; Q6QA04; Q6QA05;
AC   Q6QA06; Q6QA07; Q6QA08; Q6QA10; Q6QA11; Q6QA12; Q6QA13; Q9HBS5;
AC   Q9HCQ8; Q9UGF0; Q9UGF1;
DT   30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT   01-MAY-1999, sequence version 1.
DT   26-NOV-2014, entry version 177.
DE   RecName: Full=Serine/threonine-protein kinase Chk2;
DE            EC=2.7.11.1;
DE   AltName: Full=CHK2 checkpoint homolog;
DE   AltName: Full=Cds1 homolog;
DE            Short=Hucds1;
DE            Short=hCds1;
DE   AltName: Full=Checkpoint kinase 2;
GN   Name=CHEK2; Synonyms=CDS1, CHK2, RAD53;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC   Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC   Catarrhini; Hominidae; Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION IN PHOSPHORYLATION OF
RP   CDC25C, AND MUTAGENESIS OF ASP-347.
RX   PubMed=9836640; DOI=10.1126/science.282.5395.1893;
RA   Matsuoka S., Huang M., Elledge S.J.;
RT   "Linkage of ATM to cell cycle regulation by the Chk2 protein kinase.";
RL   Science 282:1893-1897(1998).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION IN MITOSIS.
RX   PubMed=9889122; DOI=10.1016/S0960-9822(99)80041-4;
RA   Blasina A., van de Weyer I., Laus M.C., Luyten W.H.M.L., Parker A.E.,
RA   McGowan C.H.;
RT   "A human homologue of the checkpoint kinase Cds1 directly inhibits
RT   Cdc25 phosphatase.";
RL   Curr. Biol. 9:1-10(1999).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND FUNCTION IN
RP   PHOSPHORYLATION OF CDC25C.
RX   PubMed=10097108; DOI=10.1073/pnas.96.7.3745;
RA   Brown A.L., Lee C.-H., Schwarz J.K., Mitiku N., Piwnica-Worms H.,
RA   Chung J.H.;
RT   "A human Cds1-related kinase that functions downstream of ATM protein
RT   in the cellular response to DNA damage.";
RL   Proc. Natl. Acad. Sci. U.S.A. 96:3745-3750(1999).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2; 3; 4; 5; 6; 7; 8; 9; 10; 11
RP   AND 12), AND SUBCELLULAR LOCATION.
RC   TISSUE=Mammary gland;
RX   PubMed=15361853; DOI=10.1038/sj.onc.1207928;
RA   Staalesen V., Falck J., Geisler S., Bartkova J., Boerresen-Dale A.-L.,
RA   Lukas J., Lillehaug J.R., Bartek J., Lonning P.E.;
RT   "Alternative splicing and mutation status of CHEK2 in stage III breast
RT   cancer.";
RL   Oncogene 23:8535-8544(2004).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 9).
RX   PubMed=15461802; DOI=10.1186/gb-2004-5-10-r84;
RA   Collins J.E., Wright C.L., Edwards C.A., Davis M.P., Grinham J.A.,
RA   Cole C.G., Goward M.E., Aguado B., Mallya M., Mokrab Y., Huckle E.J.,
RA   Beare D.M., Dunham I.;
RT   "A genome annotation-driven approach to cloning the human ORFeome.";
RL   Genome Biol. 5:R84.1-R84.11(2004).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC   TISSUE=Colon carcinoma;
RA   Shao R.-G., Zhang H., Yu Q., Pommier Y.;
RT   "Chk2/HuCds1 cell cycle checkpoint protein kinase from human colon
RT   carcinoma HT29 cells: regulation by autophosphorylation and DNA-
RT   dependent protein kinase and inhibition by cell cycle regulatory
RT   drugs.";
RL   Submitted (JUL-1999) to the EMBL/GenBank/DDBJ databases.
RN   [7]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 12).
RC   TISSUE=T-cell;
RA   Ogawa A., Okabe-Nakamura A.;
RT   "An alternative spliced Chk2.";
RL   Submitted (MAR-2000) to the EMBL/GenBank/DDBJ databases.
RN   [8]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA   Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA   Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA   Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA   Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA   Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA   Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA   Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA   Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA   Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA   Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA   Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA   Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA   Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA   Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA   Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA   Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA   Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA   Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA   Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [9]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 13).
RX   PubMed=15498874; DOI=10.1073/pnas.0404089101;
RA   Wan D., Gong Y., Qin W., Zhang P., Li J., Wei L., Zhou X., Li H.,
RA   Qiu X., Zhong F., He L., Yu J., Yao G., Jiang H., Qian L., Yu Y.,
RA   Shu H., Chen X., Xu H., Guo M., Pan Z., Chen Y., Ge C., Yang S.,
RA   Gu J.;
RT   "Large-scale cDNA transfection screening for genes related to cancer
RT   development and progression.";
RL   Proc. Natl. Acad. Sci. U.S.A. 101:15724-15729(2004).
RN   [10]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS LEU-85; THR-157;
RP   MET-436; LYS-446; ILE-447; SER-448; LYS-501 AND VAL-512.
RG   NIEHS SNPs program;
RL   Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN   [11]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=10591208; DOI=10.1038/990031;
RA   Dunham I., Hunt A.R., Collins J.E., Bruskiewich R., Beare D.M.,
RA   Clamp M., Smink L.J., Ainscough R., Almeida J.P., Babbage A.K.,
RA   Bagguley C., Bailey J., Barlow K.F., Bates K.N., Beasley O.P.,
RA   Bird C.P., Blakey S.E., Bridgeman A.M., Buck D., Burgess J.,
RA   Burrill W.D., Burton J., Carder C., Carter N.P., Chen Y., Clark G.,
RA   Clegg S.M., Cobley V.E., Cole C.G., Collier R.E., Connor R.,
RA   Conroy D., Corby N.R., Coville G.J., Cox A.V., Davis J., Dawson E.,
RA   Dhami P.D., Dockree C., Dodsworth S.J., Durbin R.M., Ellington A.G.,
RA   Evans K.L., Fey J.M., Fleming K., French L., Garner A.A.,
RA   Gilbert J.G.R., Goward M.E., Grafham D.V., Griffiths M.N.D., Hall C.,
RA   Hall R.E., Hall-Tamlyn G., Heathcott R.W., Ho S., Holmes S.,
RA   Hunt S.E., Jones M.C., Kershaw J., Kimberley A.M., King A.,
RA   Laird G.K., Langford C.F., Leversha M.A., Lloyd C., Lloyd D.M.,
RA   Martyn I.D., Mashreghi-Mohammadi M., Matthews L.H., Mccann O.T.,
RA   Mcclay J., Mclaren S., McMurray A.A., Milne S.A., Mortimore B.J.,
RA   Odell C.N., Pavitt R., Pearce A.V., Pearson D., Phillimore B.J.C.T.,
RA   Phillips S.H., Plumb R.W., Ramsay H., Ramsey Y., Rogers L., Ross M.T.,
RA   Scott C.E., Sehra H.K., Skuce C.D., Smalley S., Smith M.L.,
RA   Soderlund C., Spragon L., Steward C.A., Sulston J.E., Swann R.M.,
RA   Vaudin M., Wall M., Wallis J.M., Whiteley M.N., Willey D.L.,
RA   Williams L., Williams S.A., Williamson H., Wilmer T.E., Wilming L.,
RA   Wright C.L., Hubbard T., Bentley D.R., Beck S., Rogers J., Shimizu N.,
RA   Minoshima S., Kawasaki K., Sasaki T., Asakawa S., Kudoh J.,
RA   Shintani A., Shibuya K., Yoshizaki Y., Aoki N., Mitsuyama S.,
RA   Roe B.A., Chen F., Chu L., Crabtree J., Deschamps S., Do A., Do T.,
RA   Dorman A., Fang F., Fu Y., Hu P., Hua A., Kenton S., Lai H., Lao H.I.,
RA   Lewis J., Lewis S., Lin S.-P., Loh P., Malaj E., Nguyen T., Pan H.,
RA   Phan S., Qi S., Qian Y., Ray L., Ren Q., Shaull S., Sloan D., Song L.,
RA   Wang Q., Wang Y., Wang Z., White J., Willingham D., Wu H., Yao Z.,
RA   Zhan M., Zhang G., Chissoe S., Murray J., Miller N., Minx P.,
RA   Fulton R., Johnson D., Bemis G., Bentley D., Bradshaw H., Bourne S.,
RA   Cordes M., Du Z., Fulton L., Goela D., Graves T., Hawkins J.,
RA   Hinds K., Kemp K., Latreille P., Layman D., Ozersky P., Rohlfing T.,
RA   Scheet P., Walker C., Wamsley A., Wohldmann P., Pepin K., Nelson J.,
RA   Korf I., Bedell J.A., Hillier L.W., Mardis E., Waterston R.,
RA   Wilson R., Emanuel B.S., Shaikh T., Kurahashi H., Saitta S.,
RA   Budarf M.L., McDermid H.E., Johnson A., Wong A.C.C., Morrow B.E.,
RA   Edelmann L., Kim U.J., Shizuya H., Simon M.I., Dumanski J.P.,
RA   Peyrard M., Kedra D., Seroussi E., Fransson I., Tapia I., Bruder C.E.,
RA   O'Brien K.P., Wilkinson P., Bodenteich A., Hartman K., Hu X.,
RA   Khan A.S., Lane L., Tilahun Y., Wright H.;
RT   "The DNA sequence of human chromosome 22.";
RL   Nature 402:489-495(1999).
RN   [12]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA   Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA   Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA   Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA   Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA   Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA   Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA   Venter J.C.;
RL   Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [13]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Muscle;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA
RT   project: the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [14]
RP   FUNCTION IN PHOSPHORYLATION OF BRCA1, AND INTERACTION WITH BRCA1.
RX   PubMed=10724175; DOI=10.1038/35004614;
RA   Lee J.S., Collins K.M., Brown A.L., Lee C.H., Chung J.H.;
RT   "hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage
RT   response.";
RL   Nature 404:201-204(2000).
RN   [15]
RP   PHOSPHORYLATION AT THR-68 BY ATM.
RX   PubMed=10973490; DOI=10.1073/pnas.190030497;
RA   Matsuoka S., Rotman G., Ogawa A., Shiloh Y., Tamai K., Elledge S.J.;
RT   "Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in
RT   vitro.";
RL   Proc. Natl. Acad. Sci. U.S.A. 97:10389-10394(2000).
RN   [16]
RP   PHOSPHORYLATION AT THR-383 AND THR-387, AND MUTAGENESIS OF THR-383 AND
RP   THR-387.
RX   PubMed=11390408; DOI=10.1074/jbc.M104414200;
RA   Lee C.H., Chung J.H.;
RT   "The hCds1 (Chk2)-FHA domain is essential for a chain of
RT   phosphorylation events on hCds1 that is induced by ionizing
RT   radiation.";
RL   J. Biol. Chem. 276:30537-30541(2001).
RN   [17]
RP   FUNCTION IN INTRA S-PHASE CHECKPOINT, FUNCTION IN PHOSPHORYLATION OF
RP   CDC25A, INTERACTION WITH CDC25A, MUTAGENESIS OF ASP-347,
RP   CHARACTERIZATION OF VARIANT COLON CANCER TRP-145, AND CHARACTERIZATION
RP   OF VARIANT THR-157.
RX   PubMed=11298456; DOI=10.1038/35071124;
RA   Falck J., Mailand N., Syljuaasen R.G., Bartek J., Lukas J.;
RT   "The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant
RT   DNA synthesis.";
RL   Nature 410:842-847(2001).
RN   [18]
RP   INVOLVEMENT IN SUSCEPTIBILITY TO BC.
RX   PubMed=12094328; DOI=10.1086/341943;
RA   Vahteristo P., Bartkova J., Eerola H., Syrjakoski K., Ojala S.,
RA   Kilpivaara O., Tamminen A., Kononen J., Aittomaki K., Heikkila P.,
RA   Holli K., Blomqvist C., Bartek J., Kallioniemi O.P., Nevanlinna H.;
RT   "A CHEK2 genetic variant contributing to a substantial fraction of
RT   familial breast cancer.";
RL   Am. J. Hum. Genet. 71:432-438(2002).
RN   [19]
RP   HOMODIMERIZATION, AUTOPHOSPHORYLATION, AND MUTAGENESIS OF THR-68.
RX   PubMed=11901158; DOI=10.1074/jbc.M200822200;
RA   Ahn J.Y., Li X., Davis H.L., Canman C.E.;
RT   "Phosphorylation of threonine 68 promotes oligomerization and
RT   autophosphorylation of the Chk2 protein kinase via the forkhead-
RT   associated domain.";
RL   J. Biol. Chem. 277:19389-19395(2002).
RN   [20]
RP   FUNCTION IN APOPTOSIS, FUNCTION IN PHOSPHORYLATION OF PML, AND
RP   SUBCELLULAR LOCATION.
RX   PubMed=12402044; DOI=10.1038/ncb869;
RA   Yang S., Kuo C., Bisi J.E., Kim M.K.;
RT   "PML-dependent apoptosis after DNA damage is regulated by the
RT   checkpoint kinase hCds1/Chk2.";
RL   Nat. Cell Biol. 4:865-870(2002).
RN   [21]
RP   INTERACTION WITH TP53BP1.
RX   PubMed=12364621; DOI=10.1126/science.1076182;
RA   Wang B., Matsuoka S., Carpenter P.B., Elledge S.J.;
RT   "53BP1, a mediator of the DNA damage checkpoint.";
RL   Science 298:1435-1438(2002).
RN   [22]
RP   FUNCTION, INTERACTION WITH PML AND TP53, AND SUBCELLULAR LOCATION.
RX   PubMed=12810724; DOI=10.1074/jbc.M301264200;
RA   Louria-Hayon I., Grossman T., Sionov R.V., Alsheich O., Pandolfi P.P.,
RA   Haupt Y.;
RT   "The promyelocytic leukemia protein protects p53 from Mdm2-mediated
RT   inhibition and degradation.";
RL   J. Biol. Chem. 278:33134-33141(2003).
RN   [23]
RP   FUNCTION IN TRANSCRIPTION REGULATION, FUNCTION IN APOPTOSIS, AND
RP   FUNCTION IN PHOSPHORYLATION OF E2F1.
RX   PubMed=12717439; DOI=10.1038/ncb974;
RA   Stevens C., Smith L., La Thangue N.B.;
RT   "Chk2 activates E2F-1 in response to DNA damage.";
RL   Nat. Cell Biol. 5:401-409(2003).
RN   [24]
RP   FUNCTION IN DNA DAMAGE RESPONSE, AND INTERACTION WITH MDC1.
RX   PubMed=12607004; DOI=10.1038/nature01447;
RA   Lou Z., Minter-Dykhouse K., Wu X., Chen J.;
RT   "MDC1 is coupled to activated CHK2 in mammalian DNA damage response
RT   pathways.";
RL   Nature 421:957-961(2003).
RN   [25]
RP   REVIEW ON PHOSPHORYLATION OF TP53 AND OTHER SUBSTRATES.
RX   PubMed=15279791; DOI=10.1016/j.dnarep.2004.03.033;
RA   Ahn J., Urist M., Prives C.;
RT   "The Chk2 protein kinase.";
RL   DNA Repair 3:1039-1047(2004).
RN   [26]
RP   ENZYME REGULATION, PHOSPHORYLATION AT THR-68 BY MLTK, AND MUTAGENESIS
RP   OF THR-68 AND ASP-368.
RX   PubMed=15342622; DOI=10.1074/jbc.M409961200;
RA   Tosti E., Waldbaum L., Warshaw G., Gross E.A., Ruggieri R.;
RT   "The stress kinase MRK contributes to regulation of DNA damage
RT   checkpoints through a p38gamma-independent pathway.";
RL   J. Biol. Chem. 279:47652-47660(2004).
RN   [27]
RP   FUNCTION IN TP53 ACTIVATION, AND FUNCTION IN PHOSPHORYLATION OF MDM4.
RX   PubMed=16163388; DOI=10.1038/sj.emboj.7600812;
RA   Chen L., Gilkes D.M., Pan Y., Lane W.S., Chen J.;
RT   "ATM and Chk2-dependent phosphorylation of MDMX contribute to p53
RT   activation after DNA damage.";
RL   EMBO J. 24:3411-3422(2005).
RN   [28]
RP   PHOSPHORYLATION AT THR-68, AND DEPHOSPHORYLATION AT THR-68 BY PPM1D.
RX   PubMed=16311512; DOI=10.1038/sj.cdd.4401801;
RA   Fujimoto H., Onishi N., Kato N., Takekawa M., Xu X.Z., Kosugi A.,
RA   Kondo T., Imamura M., Oishi I., Yoda A., Minami Y.;
RT   "Regulation of the antioncogenic Chk2 kinase by the oncogenic Wip1
RT   phosphatase.";
RL   Cell Death Differ. 13:1170-1180(2006).
RN   [29]
RP   PHOSPHORYLATION AT SER-62; THR-68 AND SER-73, AND MUTAGENESIS OF
RP   SER-73.
RX   PubMed=16481012; DOI=10.1016/j.mrfmmm.2005.12.002;
RA   Bahassi el M., Myer D.L., McKenney R.J., Hennigan R.F.,
RA   Stambrook P.J.;
RT   "Priming phosphorylation of Chk2 by polo-like kinase 3 (Plk3) mediates
RT   its full activation by ATM and a downstream checkpoint in response to
RT   DNA damage.";
RL   Mutat. Res. 596:166-176(2006).
RN   [30]
RP   FUNCTION IN PHOSPHORYLATION OF RB1.
RX   PubMed=17380128; DOI=10.1038/sj.emboj.7601652;
RA   Inoue Y., Kitagawa M., Taya Y.;
RT   "Phosphorylation of pRB at Ser612 by Chk1/2 leads to a complex between
RT   pRB and E2F-1 after DNA damage.";
RL   EMBO J. 26:2083-2093(2007).
RN   [31]
RP   FUNCTION IN APOPTOSIS, PHOSPHORYLATION AT SER-456, UBIQUITINATION, AND
RP   MUTAGENESIS OF SER-456.
RX   PubMed=17715138; DOI=10.1074/jbc.M704642200;
RA   Kass E.M., Ahn J., Tanaka T., Freed-Pastor W.A., Keezer S., Prives C.;
RT   "Stability of checkpoint kinase 2 is regulated via phosphorylation at
RT   serine 456.";
RL   J. Biol. Chem. 282:30311-30321(2007).
RN   [32]
RP   FUNCTION IN DNA REPAIR, AND FUNCTION IN PHOSPHORYLATION OF FOXM1.
RX   PubMed=17101782; DOI=10.1128/MCB.01068-06;
RA   Tan Y., Raychaudhuri P., Costa R.H.;
RT   "Chk2 mediates stabilization of the FoxM1 transcription factor to
RT   stimulate expression of DNA repair genes.";
RL   Mol. Cell. Biol. 27:1007-1016(2007).
RN   [33]
RP   FUNCTION IN PHOSPHORYLATION OF NEK6.
RX   PubMed=18728393;
RA   Lee M.Y., Kim H.J., Kim M.A., Jee H.J., Kim A.J., Bae Y.S., Park J.I.,
RA   Chung J.H., Yun J.;
RT   "Nek6 is involved in G2/M phase cell cycle arrest through DNA damage-
RT   induced phosphorylation.";
RL   Cell Cycle 7:2705-2709(2008).
RN   [34]
RP   FUNCTION IN APOPTOSIS, PHOSPHORYLATION AT SER-379, MUTAGENESIS OF
RP   SER-379, UBIQUITINATION, AND INTERACTION WITH CUL1.
RX   PubMed=18644861; DOI=10.1128/MCB.00821-08;
RA   Lovly C.M., Yan L., Ryan C.E., Takada S., Piwnica-Worms H.;
RT   "Regulation of Chk2 ubiquitination and signaling through
RT   autophosphorylation of serine 379.";
RL   Mol. Cell. Biol. 28:5874-5885(2008).
RN   [35]
RP   FUNCTION IN RAD51-MEDIATED DNA REPAIR, AND FUNCTION IN PHOSPHORYLATION
RP   OF BRCA2.
RX   PubMed=18317453; DOI=10.1038/onc.2008.17;
RA   Bahassi E.M., Ovesen J.L., Riesenberg A.L., Bernstein W.Z.,
RA   Hasty P.E., Stambrook P.J.;
RT   "The checkpoint kinases Chk1 and Chk2 regulate the functional
RT   associations between hBRCA2 and Rad51 in response to DNA damage.";
RL   Oncogene 27:3977-3985(2008).
RN   [36]
RP   PHOSPHORYLATION BY PLK4.
RX   PubMed=19164942;
RA   Petrinac S., Ganuelas M.L., Bonni S., Nantais J., Hudson J.W.;
RT   "Polo-like kinase 4 phosphorylates Chk2.";
RL   Cell Cycle 8:327-329(2009).
RN   [37]
RP   FUNCTION IN PHOSPHORYLATION OF BRCA1, AND FUNCTION IN CHROMOSOMAL
RP   STABILITY.
RX   PubMed=20364141; DOI=10.1038/ncb2051;
RA   Stolz A., Ertych N., Kienitz A., Vogel C., Schneider V., Fritz B.,
RA   Jacob R., Dittmar G., Weichert W., Petersen I., Bastians H.;
RT   "The CHK2-BRCA1 tumour suppressor pathway ensures chromosomal
RT   stability in human somatic cells.";
RL   Nat. Cell Biol. 12:492-499(2010).
RN   [38]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA   Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [39]
RP   INVOLVEMENT IN SUSCEPTIBILITY TO BC, VARIANTS CYS-180 AND TYR-371, AND
RP   CHARACTERIZATION OF VARIANT TYR-371.
RX   PubMed=21618645; DOI=10.1002/humu.21538;
RA   Liu Y., Liao J., Xu Y., Chen W., Liu D., Ouyang T., Li J., Wang T.,
RA   Fan Z., Fan T., Lin B., Xu X., Xie Y.;
RT   "A recurrent CHEK2 p.H371Y mutation is associated with breast cancer
RT   risk in Chinese women.";
RL   Hum. Mutat. 32:1000-1003(2011).
RN   [40]
RP   UBIQUITINATION BY RNF8.
RX   PubMed=22266820; DOI=10.1038/nsmb.2211;
RA   Feng L., Chen J.;
RT   "The E3 ligase RNF8 regulates KU80 removal and NHEJ repair.";
RL   Nat. Struct. Mol. Biol. 19:201-206(2012).
RN   [41]
RP   X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 64-212.
RX   PubMed=12049740; DOI=10.1016/S1097-2765(02)00527-0;
RA   Li J., Williams B.L., Haire L.F., Goldberg M., Wilker E., Durocher D.,
RA   Yaffe M.B., Jackson S.P., Smerdon S.J.;
RT   "Structural and functional versatility of the FHA domain in DNA-damage
RT   signaling by the tumor suppressor kinase Chk2.";
RL   Mol. Cell 9:1045-1054(2002).
RN   [42]
RP   X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 210-531 IN COMPLEX WITH ADP
RP   AND INHIBITOR, HOMODIMERIZATION, AND AUTOPHOSPHORYLATION.
RX   PubMed=16794575; DOI=10.1038/sj.emboj.7601209;
RA   Oliver A.W., Paul A., Boxall K.J., Barrie S.E., Aherne G.W.,
RA   Garrett M.D., Mittnacht S., Pearl L.H.;
RT   "Trans-activation of the DNA-damage signalling protein kinase Chk2 by
RT   T-loop exchange.";
RL   EMBO J. 25:3179-3190(2006).
RN   [43]
RP   X-RAY CRYSTALLOGRAPHY (3.00 ANGSTROMS) OF 84-502 OF HOMODIMER.
RX   PubMed=19782031; DOI=10.1016/j.molcel.2009.09.007;
RA   Cai Z., Chehab N.H., Pavletich N.P.;
RT   "Structure and activation mechanism of the CHK2 DNA damage checkpoint
RT   kinase.";
RL   Mol. Cell 35:818-829(2009).
RN   [44]
RP   VARIANT THR-157, AND VARIANT COLON CANCER TRP-145.
RX   PubMed=10617473; DOI=10.1126/science.286.5449.2528;
RA   Bell D.W., Varley J.M., Szydlo T.E., Kang D.H., Wahrer D.C.R.,
RA   Shannon K.E., Lubratovich M., Versalis S.J., Isselbacher K.J.,
RA   Fraumeni J.F. Jr., Birch J.M., Li F.P., Garber J.E., Haber D.A.;
RT   "Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome.";
RL   Science 286:2528-2531(1999).
RN   [45]
RP   VARIANT THR-157.
RX   PubMed=11461078; DOI=10.1054/bjoc.2001.1858;
RA   Allinen M., Huusko P., Maentyniemi S., Launonen V., Winqvist R.;
RT   "Mutation analysis of the CHK2 gene in families with hereditary breast
RT   cancer.";
RL   Br. J. Cancer 85:209-212(2001).
RN   [46]
RP   VARIANT LFS2 TRP-145.
RX   PubMed=11719428;
RA   Lee S.B., Kim S.H., Bell D.W., Wahrer D.C.R., Schiripo T.A.,
RA   Jorczak M.M., Sgroi D.C., Garber J.E., Li F.P., Nichols K.E.,
RA   Varley J.M., Godwin A.K., Shannon K.M., Harlow E., Haber D.A.;
RT   "Destabilization of CHK2 by a missense mutation associated with Li-
RT   Fraumeni Syndrome.";
RL   Cancer Res. 61:8062-8067(2001).
RN   [47]
RP   VARIANT MULTIPLE CANCERS LYS-59.
RX   PubMed=12052256; DOI=10.1186/bcr435;
RA   Ingvarsson S., Sigbjornsdottir B.I., Huiping C., Hafsteinsdottir S.H.,
RA   Ragnarsson G., Barkardottir R.B., Arason A., Egilsson V.,
RA   Bergthorsson J.T.;
RT   "Mutation analysis of the CHK2 gene in breast carcinoma and other
RT   cancers.";
RL   Breast Cancer Res. 4:R4-R4(2002).
RN   [48]
RP   VARIANTS GLY-117; GLN-137 AND HIS-180.
RX   PubMed=12454775; DOI=10.1038/sj.bjc.6600637;
RA   Sodha N., Bullock S., Taylor R., Mitchell G., Guertl-Lackner B.,
RA   Williams R.D., Bevan S., Bishop K., McGuire S., Houlston R.S.,
RA   Eeles R.A.;
RT   "CHEK2 variants in susceptibility to breast cancer and evidence of
RT   retention of the wild type allele in tumours.";
RL   Br. J. Cancer 87:1445-1448(2002).
RN   [49]
RP   VARIANTS OSTEOSARCOMA SER-17 AND LEU-85.
RX   PubMed=11746983; DOI=10.1002/gcc.1207;
RA   Miller C.W., Ikezoe T., Krug U., Hofmann W.K., Tavor S., Vegesna V.,
RA   Tsukasaki K., Takeuchi S., Koeffler H.P.;
RT   "Mutations of the CHK2 gene are found in some osteosarcomas, but are
RT   rare in breast, lung, and ovarian tumors.";
RL   Genes Chromosomes Cancer 33:17-21(2002).
RN   [50]
RP   VARIANTS PROSTATE CANCER LYS-64; PRO-145; ARG-167; CYS-180; HIS-180;
RP   CYS-181; HIS-181; LYS-239; PHE-251; HIS-318; PRO-323; CYS-327 AND
RP   LYS-476, AND VARIANT THR-157.
RX   PubMed=12533788; DOI=10.1086/346094;
RA   Dong X., Wang L., Taniguchi K., Wang X., Cunningham J.M.,
RA   McDonnell S.K., Qian C., Marks A.F., Slager S.L., Peterson B.J.,
RA   Smith D.I., Cheville J.C., Blute M.L., Jacobsen S.J., Schaid D.J.,
RA   Tindall D.J., Thibodeau S.N., Liu W.;
RT   "Mutations in CHEK2 associated with prostate cancer risk.";
RL   Am. J. Hum. Genet. 72:270-280(2003).
RN   [51]
RP   VARIANTS GLY-117; TRP-145 AND THR-157.
RX   PubMed=12610780; DOI=10.1086/373965;
RA   Schutte M., Seal S., Barfoot R., Meijers-Heijboer H., Wasielewski M.,
RA   Evans D.G., Eccles D., Meijers C., Lohman F., Klijn J.,
RA   van den Ouweland A., Brady A., Cole T., Collins A., Cox H.,
RA   Donaldson A., Eeles R., Evans G., Gregory H., Gray J., Houlston R.,
RA   Lalloo F., Lucassen A., Mackay J., Mitchell G., Morrison P.,
RA   Murday V., Narod S., Patterson J., Peretz T., Phelan C.M., Rogers M.,
RA   Schofield A., Tonin P., Weber B., Weber W., Futreal P.A.,
RA   Nathanson K.L., Weber B.L., Easton D.F., Stratton M.R., Rahman N.;
RT   "Variants in CHEK2 other than 1100delC do not make a major
RT   contribution to breast cancer susceptibility.";
RL   Am. J. Hum. Genet. 72:1023-1028(2003).
RN   [52]
RP   VARIANT THR-157.
RX   PubMed=14612911; DOI=10.1038/sj.bjc.6601425;
RA   Seppaelae E.H., Ikonen T., Mononen N., Autio V., Roekman A.,
RA   Matikainen M.P., Tammela T.L.J., Schleutker J.;
RT   "CHEK2 variants associate with hereditary prostate cancer.";
RL   Br. J. Cancer 89:1966-1970(2003).
RN   [53]
RP   VARIANT THR-157.
RX   PubMed=15492928; DOI=10.1086/426403;
RA   Cybulski C., Gorski B., Huzarski T., Masojc B., Mierzejewski M.,
RA   Debniak T., Teodorczyk U., Byrski T., Gronwald J., Matyjasik J.,
RA   Zlowocka E., Lenner M., Grabowska E., Nej K., Castaneda J., Medrek K.,
RA   Szymanska A., Szymanska J., Kurzawski G., Suchy J., Oszurek O.,
RA   Witek A., Narod S.A., Lubinski J.;
RT   "CHEK2 is a multiorgan cancer susceptibility gene.";
RL   Am. J. Hum. Genet. 75:1131-1135(2004).
RN   [54]
RP   VARIANTS TRP-145 AND THR-157.
RX   PubMed=15535844; DOI=10.1186/bcr933;
RA   Friedrichsen D.M., Malone K.E., Doody D.R., Daling J.R.,
RA   Ostrander E.A.;
RT   "Frequency of CHEK2 mutations in a population based, case-control
RT   study of breast cancer in young women.";
RL   Breast Cancer Res. 6:R629-R635(2004).
RN   [55]
RP   VARIANT THR-157.
RX   PubMed=15087378; DOI=10.1158/0008-5472.CAN-04-0341;
RA   Cybulski C., Huzarski T., Gorski B., Masojc B., Mierzejewski M.,
RA   Debniak T., Gliniewicz B., Matyjasik J., Zlowocka E., Kurzawski G.,
RA   Sikorski A., Posmyk M., Szwiec M., Czajka R., Narod S.A., Lubinski J.;
RT   "A novel founder CHEK2 mutation is associated with increased prostate
RT   cancer risk.";
RL   Cancer Res. 64:2677-2679(2004).
RN   [56]
RP   VARIANT THR-157.
RX   PubMed=15095295; DOI=10.1002/ijc.20073;
RA   Dufault M.R., Betz B., Wappenschmidt B., Hofmann W., Bandick K.,
RA   Golla A., Pietschmann A., Nestle-Kraemling C., Rhiem K., Huettner C.,
RA   von Lindern C., Dall P., Kiechle M., Untch M., Jonat W., Meindl A.,
RA   Scherneck S., Niederacher D., Schmutzler R.K., Arnold N.;
RT   "Limited relevance of the CHEK2 gene in hereditary breast cancer.";
RL   Int. J. Cancer 110:320-325(2004).
RN   [57]
RP   VARIANT THR-157.
RX   PubMed=15239132; DOI=10.1002/ijc.20299;
RA   Kilpivaara O., Vahteristo P., Falck J., Syrjaekoski K., Eerola H.,
RA   Easton D., Bartkova J., Lukas J., Heikkilae P., Aittomaeki K.,
RA   Holli K., Blomqvist C., Kallioniemi O.-P., Bartek J., Nevanlinna H.;
RT   "CHEK2 variant I157T may be associated with increased breast cancer
RT   risk.";
RL   Int. J. Cancer 111:543-547(2004).
RN   [58]
RP   VARIANTS LEU-85 AND PHE-428.
RX   PubMed=15649950; DOI=10.1093/hmg/ddi052;
RA   Shaag A., Walsh T., Renbaum P., Kirchhoff T., Nafa K., Shiovitz S.,
RA   Mandell J.B., Welcsh P., Lee M.K., Ellis N., Offit K., Levy-Lahad E.,
RA   King M.-C.;
RT   "Functional and genomic approaches reveal an ancient CHEK2 allele
RT   associated with breast cancer in the Ashkenazi Jewish population.";
RL   Hum. Mol. Genet. 14:555-563(2005).
RN   [59]
RP   VARIANT THR-157.
RX   PubMed=15810020; DOI=10.1002/ijc.21022;
RA   Bogdanova N., Enbetaen-Dubrowinskaja N., Feshchenko S., Lazjuk G.I.,
RA   Rogov Y.I., Dammann O., Bremer M., Karstens J.H., Sohn C., Doerk T.;
RT   "Association of two mutations in the CHEK2 gene with breast cancer.";
RL   Int. J. Cancer 116:263-266(2005).
RN   [60]
RP   VARIANTS GLY-117; GLN-137; TRP-145; THR-157 AND HIS-180.
RX   PubMed=15818573; DOI=10.1002/path.1764;
RA   van Puijenbroek M., van Asperen C.J., van Mil A., Devilee P.,
RA   van Wezel T., Morreau H.;
RT   "Homozygosity for a CHEK2*1100delC mutation identified in familial
RT   colorectal cancer does not lead to a severe clinical phenotype.";
RL   J. Pathol. 206:198-204(2005).
CC   -!- FUNCTION: Serine/threonine-protein kinase which is required for
CC       checkpoint-mediated cell cycle arrest, activation of DNA repair
CC       and apoptosis in response to the presence of DNA double-strand
CC       breaks. May also negatively regulate cell cycle progression during
CC       unperturbed cell cycles. Following activation, phosphorylates
CC       numerous effectors preferentially at the consensus sequence [L-X-
CC       R-X-X-S/T]. Regulates cell cycle checkpoint arrest through
CC       phosphorylation of CDC25A, CDC25B and CDC25C, inhibiting their
CC       activity. Inhibition of CDC25 phosphatase activity leads to
CC       increased inhibitory tyrosine phosphorylation of CDK-cyclin
CC       complexes and blocks cell cycle progression. May also
CC       phosphorylate NEK6 which is involved in G2/M cell cycle arrest.
CC       Regulates DNA repair through phosphorylation of BRCA2, enhancing
CC       the association of RAD51 with chromatin which promotes DNA repair
CC       by homologous recombination. Also stimulates the transcription of
CC       genes involved in DNA repair (including BRCA2) through the
CC       phosphorylation and activation of the transcription factor FOXM1.
CC       Regulates apoptosis through the phosphorylation of p53/TP53, MDM4
CC       and PML. Phosphorylation of p53/TP53 at 'Ser-20' by CHEK2 may
CC       alleviate inhibition by MDM2, leading to accumulation of active
CC       p53/TP53. Phosphorylation of MDM4 may also reduce degradation of
CC       p53/TP53. Also controls the transcription of pro-apoptotic genes
CC       through phosphorylation of the transcription factor E2F1. Tumor
CC       suppressor, it may also have a DNA damage-independent function in
CC       mitotic spindle assembly by phosphorylating BRCA1. Its absence may
CC       be a cause of the chromosomal instability observed in some cancer
CC       cells. {ECO:0000269|PubMed:10097108, ECO:0000269|PubMed:10724175,
CC       ECO:0000269|PubMed:11298456, ECO:0000269|PubMed:12402044,
CC       ECO:0000269|PubMed:12607004, ECO:0000269|PubMed:12717439,
CC       ECO:0000269|PubMed:12810724, ECO:0000269|PubMed:16163388,
CC       ECO:0000269|PubMed:17101782, ECO:0000269|PubMed:17380128,
CC       ECO:0000269|PubMed:17715138, ECO:0000269|PubMed:18317453,
CC       ECO:0000269|PubMed:18644861, ECO:0000269|PubMed:18728393,
CC       ECO:0000269|PubMed:20364141, ECO:0000269|PubMed:9836640,
CC       ECO:0000269|PubMed:9889122}.
CC   -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC   -!- COFACTOR:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC   -!- ENZYME REGULATION: Activated through phosphorylation at Thr-68 by
CC       ATM in response to DNA double-strand breaks. Activation is
CC       modulated by several mediators including MDC1 and TP53BP1. Induces
CC       homodimerization with exchange of the T-loop/activation segment
CC       between protomers and transphosphorylation of the protomers. The
CC       autophosphorylated kinase dimer is fully active. Negatively
CC       regulated by PPM1D through dephosphorylation of Thr-68.
CC       {ECO:0000269|PubMed:15342622}.
CC   -!- SUBUNIT: Homodimer. Homodimerization is part of the activation
CC       process but the dimer may dissociate following activation.
CC       Interacts with PML. Interacts with TP53. Interacts with RB1;
CC       phosphorylates RB1. Interacts with BRCA1. Interacts
CC       (phosphorylated at Thr-68) with MDC1; requires ATM-mediated
CC       phosphorylation of CHEK2. Interacts with TP53BP1; modulates CHEK2
CC       phosphorylation at Thr-68 in response to ionizing radiation.
CC       Interacts with CDC25A; phosphorylates CDC25A and mediates its
CC       degradation in response to ionizing radiation. Interacts with
CC       CUL1; mediates CHEK2 ubiquitination and regulation.
CC       {ECO:0000269|PubMed:10724175, ECO:0000269|PubMed:11298456,
CC       ECO:0000269|PubMed:12364621, ECO:0000269|PubMed:12607004,
CC       ECO:0000269|PubMed:12810724, ECO:0000269|PubMed:16794575,
CC       ECO:0000269|PubMed:18644861}.
CC   -!- INTERACTION:
CC       Self; NbExp=6; IntAct=EBI-1180783, EBI-1180783;
CC       P27958:- (xeno); NbExp=3; IntAct=EBI-1180783, EBI-6904388;
CC       Q9NY61:AATF; NbExp=4; IntAct=EBI-1180783, EBI-372428;
CC       Q9Y248:GINS2; NbExp=2; IntAct=EBI-1180783, EBI-747491;
CC       P56645:PER3; NbExp=2; IntAct=EBI-1180783, EBI-2827813;
CC       P53350:PLK1; NbExp=6; IntAct=EBI-1180783, EBI-476768;
CC       Q15172:PPP2R5A; NbExp=2; IntAct=EBI-1180783, EBI-641666;
CC       Q15173:PPP2R5B; NbExp=2; IntAct=EBI-1180783, EBI-1369497;
CC       Q13362-1:PPP2R5C; NbExp=3; IntAct=EBI-1180783, EBI-1266170;
CC       Q13362-2:PPP2R5C; NbExp=2; IntAct=EBI-1180783, EBI-1266173;
CC       Q13362-3:PPP2R5C; NbExp=4; IntAct=EBI-1180783, EBI-1266176;
CC       Q16537:PPP2R5E; NbExp=3; IntAct=EBI-1180783, EBI-968374;
CC       P06400:RB1; NbExp=3; IntAct=EBI-1180783, EBI-491274;
CC       P55072:VCP; NbExp=2; IntAct=EBI-1180783, EBI-355164;
CC       P18887:XRCC1; NbExp=8; IntAct=EBI-1180783, EBI-947466;
CC   -!- SUBCELLULAR LOCATION: Isoform 2: Nucleus. Note=Isoform 10 is
CC       present throughout the cell.
CC   -!- SUBCELLULAR LOCATION: Isoform 4: Nucleus.
CC   -!- SUBCELLULAR LOCATION: Isoform 7: Nucleus.
CC   -!- SUBCELLULAR LOCATION: Isoform 9: Nucleus.
CC   -!- SUBCELLULAR LOCATION: Isoform 12: Nucleus.
CC   -!- SUBCELLULAR LOCATION: Nucleus, PML body. Nucleus, nucleoplasm.
CC       Note=Recruited into PML bodies together with TP53.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=13;
CC       Name=1;
CC         IsoId=O96017-1; Sequence=Displayed;
CC       Name=2; Synonyms=ins2;
CC         IsoId=O96017-2; Sequence=VSP_014564, VSP_014567, VSP_014568;
CC         Note=Lacks enzymatic activity.;
CC       Name=3; Synonyms=del2-12;
CC         IsoId=O96017-3; Sequence=VSP_014559;
CC       Name=4; Synonyms=del2-3;
CC         IsoId=O96017-4; Sequence=VSP_014558;
CC         Note=Lacks enzymatic activity.;
CC       Name=5; Synonyms=del4;
CC         IsoId=O96017-5; Sequence=VSP_014565, VSP_014566;
CC       Name=6; Synonyms=sub3;
CC         IsoId=O96017-6; Sequence=VSP_014562, VSP_014563;
CC       Name=7; Synonyms=del9-12;
CC         IsoId=O96017-7; Sequence=VSP_014572, VSP_014573;
CC         Note=Lacks enzymatic activity.;
CC       Name=8; Synonyms=del7;
CC         IsoId=O96017-8; Sequence=VSP_014569, VSP_014570;
CC       Name=9; Synonyms=insx;
CC         IsoId=O96017-9; Sequence=VSP_014557;
CC         Note=Retains low level of catalytic activity.;
CC       Name=10; Synonyms=iso2;
CC         IsoId=O96017-10; Sequence=VSP_014560, VSP_014561;
CC         Note=Lacks enzymatic activity.;
CC       Name=11; Synonyms=iso1;
CC         IsoId=O96017-11; Sequence=VSP_014556;
CC       Name=12; Synonyms=del9;
CC         IsoId=O96017-12; Sequence=VSP_014571;
CC         Note=Lacks enzymatic activity.;
CC       Name=13;
CC         IsoId=O96017-13; Sequence=VSP_045148;
CC   -!- TISSUE SPECIFICITY: High expression is found in testis, spleen,
CC       colon and peripheral blood leukocytes. Low expression is found in
CC       other tissues.
CC   -!- PTM: Phosphorylated. Phosphorylated at Ser-73 by PLK3 in response
CC       to DNA damage, promoting phosphorylation at Thr-68 by ATM and the
CC       G2/M transition checkpoint. Phosphorylation at Thr-68 induces
CC       homodimerization. Autophosphorylates at Thr-383 and Thr-387 in the
CC       T-loop/activation segment upon dimerization to become fully active
CC       and phosphorylate its substrates like for instance CDC25C. DNA
CC       damage-induced autophosphorylation at Ser-379 induces CUL1-
CC       mediated ubiquitination and regulates the pro-apoptotic function.
CC       Phosphorylation at Ser-456 also regulates ubiquitination.
CC       Phosphorylated by PLK4. {ECO:0000269|PubMed:10973490,
CC       ECO:0000269|PubMed:11390408, ECO:0000269|PubMed:15342622,
CC       ECO:0000269|PubMed:16311512, ECO:0000269|PubMed:16481012,
CC       ECO:0000269|PubMed:17715138, ECO:0000269|PubMed:18644861,
CC       ECO:0000269|PubMed:19164942}.
CC   -!- PTM: Ubiquitinated. CUL1-mediated ubiquitination regulates the
CC       pro-apoptotic function. Ubiquitination may also regulate protein
CC       stability. Ubiquitinated by RNF8 via 'Lys-48'-linked
CC       ubiquitination.
CC   -!- DISEASE: Li-Fraumeni syndrome 2 (LFS2) [MIM:609265]: A highly
CC       penetrant familial cancer syndrome that in its classic form is
CC       defined by the existence of a proband affected by a sarcoma before
CC       45 years with a first degree relative affected by any tumor before
CC       45 years and another first degree relative with any tumor before
CC       45 years or a sarcoma at any age. Other clinical definitions for
CC       LFS have been proposed (PubMed:8118819 and PubMed:8718514) and
CC       called Li-Fraumeni like syndrome (LFL). In these families affected
CC       relatives develop a diverse set of malignancies at unusually early
CC       ages. Four types of cancers account for 80% of tumors occurring in
CC       TP53 germline mutation carriers: breast cancers, soft tissue and
CC       bone sarcomas, brain tumors (astrocytomas) and adrenocortical
CC       carcinomas. Less frequent tumors include choroid plexus carcinoma
CC       or papilloma before the age of 15, rhabdomyosarcoma before the age
CC       of 5, leukemia, Wilms tumor, malignant phyllodes tumor, colorectal
CC       and gastric cancers. {ECO:0000269|PubMed:11719428}. Note=The
CC       disease is caused by mutations affecting the gene represented in
CC       this entry.
CC   -!- DISEASE: Prostate cancer (PC) [MIM:176807]: A malignancy
CC       originating in tissues of the prostate. Most prostate cancers are
CC       adenocarcinomas that develop in the acini of the prostatic ducts.
CC       Other rare histopathologic types of prostate cancer that occur in
CC       approximately 5% of patients include small cell carcinoma,
CC       mucinous carcinoma, prostatic ductal carcinoma, transitional cell
CC       carcinoma, squamous cell carcinoma, basal cell carcinoma, adenoid
CC       cystic carcinoma (basaloid), signet-ring cell carcinoma and
CC       neuroendocrine carcinoma. {ECO:0000269|PubMed:12533788}.
CC       Note=Disease susceptibility is associated with variations
CC       affecting the gene represented in this entry.
CC   -!- DISEASE: Osteogenic sarcoma (OSRC) [MIM:259500]: A sarcoma
CC       originating in bone-forming cells, affecting the ends of long
CC       bones. Note=The gene represented in this entry may be involved in
CC       disease pathogenesis.
CC   -!- DISEASE: Breast cancer (BC) [MIM:114480]: A common malignancy
CC       originating from breast epithelial tissue. Breast neoplasms can be
CC       distinguished by their histologic pattern. Invasive ductal
CC       carcinoma is by far the most common type. Breast cancer is
CC       etiologically and genetically heterogeneous. Important genetic
CC       factors have been indicated by familial occurrence and bilateral
CC       involvement. Mutations at more than one locus can be involved in
CC       different families or even in the same case.
CC       {ECO:0000269|PubMed:12094328, ECO:0000269|PubMed:21618645}.
CC       Note=Disease susceptibility is associated with variations
CC       affecting the gene represented in this entry.
CC       {ECO:0000269|PubMed:12094328}.
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. CAMK
CC       Ser/Thr protein kinase family. CHK2 subfamily. {ECO:0000305}.
CC   -!- SIMILARITY: Contains 1 FHA domain. {ECO:0000255|PROSITE-
CC       ProRule:PRU00086}.
CC   -!- SIMILARITY: Contains 1 protein kinase domain.
CC       {ECO:0000255|PROSITE-ProRule:PRU00159}.
CC   -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC       and Haematology;
CC       URL="http://atlasgeneticsoncology.org/Genes/CHEK2ID312.html";
CC   -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC       URL="http://egp.gs.washington.edu/data/chek2/";
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CC   -----------------------------------------------------------------------
DR   EMBL; AF086904; AAC83693.1; -; mRNA.
DR   EMBL; AJ131197; CAA10319.1; -; mRNA.
DR   EMBL; AF096279; AAD11784.1; -; mRNA.
DR   EMBL; AY551295; AAS58456.1; -; mRNA.
DR   EMBL; AY551296; AAS58457.1; -; mRNA.
DR   EMBL; AY551297; AAS58458.1; -; mRNA.
DR   EMBL; AY551298; AAS58459.1; -; mRNA.
DR   EMBL; AY551299; AAS58460.1; -; mRNA.
DR   EMBL; AY551300; AAS58461.1; -; mRNA.
DR   EMBL; AY551301; AAS58462.1; -; mRNA.
DR   EMBL; AY551302; AAS58463.1; -; mRNA.
DR   EMBL; AY551303; AAS58464.1; -; mRNA.
DR   EMBL; AY551304; AAS58465.1; -; mRNA.
DR   EMBL; AY551305; AAS58466.1; -; mRNA.
DR   EMBL; CR456418; CAG30304.1; -; mRNA.
DR   EMBL; AF174135; AAD48504.1; -; mRNA.
DR   EMBL; AB040105; BAB17231.1; -; mRNA.
DR   EMBL; AK290754; BAF83443.1; -; mRNA.
DR   EMBL; AF217975; AAG17218.1; -; mRNA.
DR   EMBL; AY800241; AAV41895.1; -; Genomic_DNA.
DR   EMBL; AL121825; CAH73823.1; -; Genomic_DNA.
DR   EMBL; AL117330; CAH73823.1; JOINED; Genomic_DNA.
DR   EMBL; AL117330; CAH73875.1; -; Genomic_DNA.
DR   EMBL; AL121825; CAH73875.1; JOINED; Genomic_DNA.
DR   EMBL; AL121825; CAX11957.1; -; Genomic_DNA.
DR   EMBL; AL117330; CAX11957.1; JOINED; Genomic_DNA.
DR   EMBL; AL121825; CAX11958.1; -; Genomic_DNA.
DR   EMBL; AL117330; CAX11958.1; JOINED; Genomic_DNA.
DR   EMBL; AL121825; CAX11959.1; -; Genomic_DNA.
DR   EMBL; AL117330; CAX11959.1; JOINED; Genomic_DNA.
DR   EMBL; AL117330; CAX14026.1; -; Genomic_DNA.
DR   EMBL; AL121825; CAX14026.1; JOINED; Genomic_DNA.
DR   EMBL; AL117330; CAX14027.1; -; Genomic_DNA.
DR   EMBL; AL121825; CAX14027.1; JOINED; Genomic_DNA.
DR   EMBL; AL117330; CAX14028.1; -; Genomic_DNA.
DR   EMBL; AL121825; CAX14028.1; JOINED; Genomic_DNA.
DR   EMBL; CH471095; EAW59755.1; -; Genomic_DNA.
DR   EMBL; BC004207; AAH04207.1; -; mRNA.
DR   CCDS; CCDS13843.1; -. [O96017-1]
DR   CCDS; CCDS13844.1; -. [O96017-12]
DR   CCDS; CCDS33629.1; -. [O96017-9]
DR   RefSeq; NP_001005735.1; NM_001005735.1. [O96017-9]
DR   RefSeq; NP_001244316.1; NM_001257387.1. [O96017-13]
DR   RefSeq; NP_009125.1; NM_007194.3. [O96017-1]
DR   RefSeq; NP_665861.1; NM_145862.2. [O96017-12]
DR   UniGene; Hs.291363; -.
DR   UniGene; Hs.505297; -.
DR   PDB; 1GXC; X-ray; 2.70 A; A/D/G/J=64-212.
DR   PDB; 2CN5; X-ray; 2.25 A; A=210-531.
DR   PDB; 2CN8; X-ray; 2.70 A; A=210-531.
DR   PDB; 2W0J; X-ray; 2.05 A; A=210-531.
DR   PDB; 2W7X; X-ray; 2.07 A; A=210-531.
DR   PDB; 2WTC; X-ray; 3.00 A; A=210-531.
DR   PDB; 2WTD; X-ray; 2.75 A; A=210-531.
DR   PDB; 2WTI; X-ray; 2.50 A; A=210-531.
DR   PDB; 2WTJ; X-ray; 2.10 A; A=210-531.
DR   PDB; 2XBJ; X-ray; 2.30 A; A=210-531.
DR   PDB; 2XK9; X-ray; 2.35 A; A=210-531.
DR   PDB; 2XM8; X-ray; 3.40 A; A=210-531.
DR   PDB; 2XM9; X-ray; 2.50 A; A=210-531.
DR   PDB; 2YCF; X-ray; 1.77 A; A=210-530.
DR   PDB; 2YCQ; X-ray; 2.05 A; A=210-531.
DR   PDB; 2YCR; X-ray; 2.20 A; A=210-531.
DR   PDB; 2YCS; X-ray; 2.35 A; A=210-531.
DR   PDB; 2YIQ; X-ray; 1.89 A; A=210-531.
DR   PDB; 2YIR; X-ray; 2.10 A; A=210-531.
DR   PDB; 2YIT; X-ray; 2.20 A; A=210-531.
DR   PDB; 3I6U; X-ray; 3.00 A; A/B=84-502.
DR   PDB; 3I6W; X-ray; 3.25 A; A/B/C/D/E/F/G/H=70-512.
DR   PDB; 3VA4; X-ray; 1.54 A; C=63-73.
DR   PDB; 4A9R; X-ray; 2.85 A; A=210-531.
DR   PDB; 4A9S; X-ray; 2.66 A; A=210-531.
DR   PDB; 4A9T; X-ray; 2.70 A; A=210-531.
DR   PDB; 4A9U; X-ray; 2.48 A; A=210-531.
DR   PDB; 4BDA; X-ray; 2.60 A; A=210-531.
DR   PDB; 4BDB; X-ray; 2.50 A; A=210-531.
DR   PDB; 4BDC; X-ray; 3.00 A; A=210-531.
DR   PDB; 4BDD; X-ray; 2.67 A; A=210-531.
DR   PDB; 4BDE; X-ray; 2.55 A; A=210-531.
DR   PDB; 4BDF; X-ray; 2.70 A; A=210-531.
DR   PDB; 4BDG; X-ray; 2.84 A; A=210-531.
DR   PDB; 4BDH; X-ray; 2.70 A; A=210-531.
DR   PDB; 4BDI; X-ray; 2.32 A; A=210-531.
DR   PDB; 4BDJ; X-ray; 3.01 A; A=210-531.
DR   PDB; 4BDK; X-ray; 3.30 A; A=210-531.
DR   PDBsum; 1GXC; -.
DR   PDBsum; 2CN5; -.
DR   PDBsum; 2CN8; -.
DR   PDBsum; 2W0J; -.
DR   PDBsum; 2W7X; -.
DR   PDBsum; 2WTC; -.
DR   PDBsum; 2WTD; -.
DR   PDBsum; 2WTI; -.
DR   PDBsum; 2WTJ; -.
DR   PDBsum; 2XBJ; -.
DR   PDBsum; 2XK9; -.
DR   PDBsum; 2XM8; -.
DR   PDBsum; 2XM9; -.
DR   PDBsum; 2YCF; -.
DR   PDBsum; 2YCQ; -.
DR   PDBsum; 2YCR; -.
DR   PDBsum; 2YCS; -.
DR   PDBsum; 2YIQ; -.
DR   PDBsum; 2YIR; -.
DR   PDBsum; 2YIT; -.
DR   PDBsum; 3I6U; -.
DR   PDBsum; 3I6W; -.
DR   PDBsum; 3VA4; -.
DR   PDBsum; 4A9R; -.
DR   PDBsum; 4A9S; -.
DR   PDBsum; 4A9T; -.
DR   PDBsum; 4A9U; -.
DR   PDBsum; 4BDA; -.
DR   PDBsum; 4BDB; -.
DR   PDBsum; 4BDC; -.
DR   PDBsum; 4BDD; -.
DR   PDBsum; 4BDE; -.
DR   PDBsum; 4BDF; -.
DR   PDBsum; 4BDG; -.
DR   PDBsum; 4BDH; -.
DR   PDBsum; 4BDI; -.
DR   PDBsum; 4BDJ; -.
DR   PDBsum; 4BDK; -.
DR   ProteinModelPortal; O96017; -.
DR   SMR; O96017; 89-525.
DR   BioGrid; 116369; 61.
DR   DIP; DIP-24270N; -.
DR   IntAct; O96017; 25.
DR   MINT; MINT-124588; -.
DR   BindingDB; O96017; -.
DR   ChEMBL; CHEMBL2527; -.
DR   GuidetoPHARMACOLOGY; 1988; -.
DR   PhosphoSite; O96017; -.
DR   MaxQB; O96017; -.
DR   PaxDb; O96017; -.
DR   PRIDE; O96017; -.
DR   DNASU; 11200; -.
DR   Ensembl; ENST00000328354; ENSP00000329178; ENSG00000183765. [O96017-1]
DR   Ensembl; ENST00000348295; ENSP00000329012; ENSG00000183765. [O96017-12]
DR   Ensembl; ENST00000382580; ENSP00000372023; ENSG00000183765. [O96017-9]
DR   Ensembl; ENST00000402731; ENSP00000384835; ENSG00000183765. [O96017-12]
DR   Ensembl; ENST00000403642; ENSP00000384919; ENSG00000183765. [O96017-4]
DR   Ensembl; ENST00000404276; ENSP00000385747; ENSG00000183765. [O96017-1]
DR   Ensembl; ENST00000405598; ENSP00000386087; ENSG00000183765. [O96017-1]
DR   Ensembl; ENST00000417588; ENSP00000412901; ENSG00000183765. [O96017-5]
DR   Ensembl; ENST00000433728; ENSP00000404400; ENSG00000183765. [O96017-8]
DR   Ensembl; ENST00000448511; ENSP00000404567; ENSG00000183765. [O96017-6]
DR   GeneID; 11200; -.
DR   KEGG; hsa:11200; -.
DR   UCSC; uc003ads.1; human. [O96017-1]
DR   UCSC; uc003adt.1; human. [O96017-9]
DR   UCSC; uc003adv.1; human. [O96017-12]
DR   UCSC; uc010gvh.1; human. [O96017-4]
DR   CTD; 11200; -.
DR   GeneCards; GC22M029083; -.
DR   HGNC; HGNC:16627; CHEK2.
DR   HPA; CAB002030; -.
DR   HPA; HPA001878; -.
DR   MIM; 114480; phenotype.
DR   MIM; 176807; phenotype.
DR   MIM; 259500; phenotype.
DR   MIM; 604373; gene+phenotype.
DR   MIM; 609265; phenotype.
DR   neXtProt; NX_O96017; -.
DR   Orphanet; 1331; Familial prostate cancer.
DR   Orphanet; 145; Hereditary breast and ovarian cancer syndrome.
DR   Orphanet; 524; Li-Fraumeni syndrome.
DR   Orphanet; 668; Osteosarcoma.
DR   PharmGKB; PA404; -.
DR   eggNOG; COG0515; -.
DR   GeneTree; ENSGT00710000106821; -.
DR   HOVERGEN; HBG108055; -.
DR   InParanoid; O96017; -.
DR   KO; K06641; -.
DR   OMA; KFAIGSE; -.
DR   OrthoDB; EOG7C5M7Z; -.
DR   PhylomeDB; O96017; -.
DR   TreeFam; TF101082; -.
DR   BRENDA; 2.7.11.1; 2681.
DR   Reactome; REACT_1614; Ubiquitin Mediated Degradation of Phosphorylated Cdc25A.
DR   Reactome; REACT_897; G2/M DNA damage checkpoint.
DR   SignaLink; O96017; -.
DR   EvolutionaryTrace; O96017; -.
DR   GeneWiki; CHEK2; -.
DR   GenomeRNAi; 11200; -.
DR   NextBio; 42629; -.
DR   PRO; PR:O96017; -.
DR   Bgee; O96017; -.
DR   ExpressionAtlas; O96017; baseline and differential.
DR   Genevestigator; O96017; -.
DR   GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR   GO; GO:0016605; C:PML body; IDA:UniProtKB.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR   GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB.
DR   GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR   GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB.
DR   GO; GO:0044257; P:cellular protein catabolic process; IMP:UniProtKB.
DR   GO; GO:0006974; P:cellular response to DNA damage stimulus; IMP:UniProtKB.
DR   GO; GO:0000077; P:DNA damage checkpoint; TAS:UniProtKB.
DR   GO; GO:0006975; P:DNA damage induced protein phosphorylation; IMP:UniProtKB.
DR   GO; GO:0006302; P:double-strand break repair; IMP:UniProtKB.
DR   GO; GO:0000086; P:G2/M transition of mitotic cell cycle; IMP:UniProtKB.
DR   GO; GO:0008630; P:intrinsic apoptotic signaling pathway in response to DNA damage; IDA:UniProtKB.
DR   GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:UniProtKB.
DR   GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
DR   GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR   GO; GO:0050821; P:protein stabilization; IDA:UniProtKB.
DR   GO; GO:0042176; P:regulation of protein catabolic process; IMP:UniProtKB.
DR   GO; GO:0006355; P:regulation of transcription, DNA-templated; IDA:UniProtKB.
DR   GO; GO:0090399; P:replicative senescence; NAS:BHF-UCL.
DR   GO; GO:0010332; P:response to gamma radiation; IEA:Ensembl.
DR   GO; GO:0042770; P:signal transduction in response to DNA damage; IDA:MGI.
DR   GO; GO:0072428; P:signal transduction involved in intra-S DNA damage checkpoint; IMP:UniProtKB.
DR   GO; GO:0090307; P:spindle assembly involved in mitosis; IMP:UniProtKB.
DR   GO; GO:0006351; P:transcription, DNA-templated; IEA:UniProtKB-KW.
DR   Gene3D; 2.60.200.20; -; 1.
DR   InterPro; IPR000253; FHA_dom.
DR   InterPro; IPR011009; Kinase-like_dom.
DR   InterPro; IPR000719; Prot_kinase_dom.
DR   InterPro; IPR002290; Ser/Thr_dual-sp_kinase.
DR   InterPro; IPR008271; Ser/Thr_kinase_AS.
DR   InterPro; IPR008984; SMAD_FHA_domain.
DR   Pfam; PF00498; FHA; 1.
DR   Pfam; PF00069; Pkinase; 1.
DR   SMART; SM00240; FHA; 1.
DR   SMART; SM00220; S_TKc; 1.
DR   SUPFAM; SSF49879; SSF49879; 1.
DR   SUPFAM; SSF56112; SSF56112; 1.
DR   PROSITE; PS50006; FHA_DOMAIN; 1.
DR   PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR   PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; Apoptosis; ATP-binding;
KW   Cell cycle; Cell division; Complete proteome; Disease mutation;
KW   DNA damage; DNA repair; Kinase; Li-Fraumeni syndrome; Magnesium;
KW   Metal-binding; Mitosis; Nucleotide-binding; Nucleus; Phosphoprotein;
KW   Polymorphism; Reference proteome; Serine/threonine-protein kinase;
KW   Transcription; Transcription regulation; Transferase;
KW   Tumor suppressor; Ubl conjugation.
FT   CHAIN         1    543       Serine/threonine-protein kinase Chk2.
FT                                /FTId=PRO_0000085858.
FT   DOMAIN      113    175       FHA. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00086}.
FT   DOMAIN      220    486       Protein kinase. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00159}.
FT   NP_BIND     227    234       ATP.
FT   NP_BIND     302    308       ATP.
FT   NP_BIND     351    352       ATP.
FT   REGION      368    394       T-loop/activation segment.
FT   ACT_SITE    347    347       Proton acceptor.
FT   BINDING     249    249       ATP.
FT   BINDING     368    368       ATP.
FT   MOD_RES      62     62       Phosphoserine; by PLK3.
FT                                {ECO:0000269|PubMed:16481012}.
FT   MOD_RES      68     68       Phosphothreonine; by ATM and MLTK.
FT                                {ECO:0000269|PubMed:10973490,
FT                                ECO:0000269|PubMed:15342622,
FT                                ECO:0000269|PubMed:16311512,
FT                                ECO:0000269|PubMed:16481012}.
FT   MOD_RES      73     73       Phosphoserine; by PLK3.
FT                                {ECO:0000269|PubMed:16481012}.
FT   MOD_RES     379    379       Phosphoserine; by autocatalysis.
FT                                {ECO:0000269|PubMed:18644861}.
FT   MOD_RES     383    383       Phosphothreonine; by autocatalysis.
FT                                {ECO:0000269|PubMed:11390408}.
FT   MOD_RES     387    387       Phosphothreonine; by autocatalysis.
FT                                {ECO:0000269|PubMed:11390408}.
FT   MOD_RES     456    456       Phosphoserine.
FT                                {ECO:0000269|PubMed:17715138}.
FT   VAR_SEQ       1    221       Missing (in isoform 13).
FT                                {ECO:0000303|PubMed:15498874}.
FT                                /FTId=VSP_045148.
FT   VAR_SEQ      75    392       Missing (in isoform 11).
FT                                {ECO:0000303|PubMed:15361853}.
FT                                /FTId=VSP_014556.
FT   VAR_SEQ     107    487       Missing (in isoform 3).
FT                                {ECO:0000303|PubMed:15361853}.
FT                                /FTId=VSP_014559.
FT   VAR_SEQ     107    197       Missing (in isoform 4).
FT                                {ECO:0000303|PubMed:15361853}.
FT                                /FTId=VSP_014558.
FT   VAR_SEQ     107    107       E -> ETESGHVTQSDLELLLSSDPPASASQSAGIRGVRHH
FT                                PRPVCSLK (in isoform 9).
FT                                {ECO:0000303|PubMed:15361853,
FT                                ECO:0000303|PubMed:15461802}.
FT                                /FTId=VSP_014557.
FT   VAR_SEQ     131    147       KRTDKYRTYSKKHFRIF -> EFRSYSFYLP (in
FT                                isoform 10).
FT                                {ECO:0000303|PubMed:15361853}.
FT                                /FTId=VSP_014560.
FT   VAR_SEQ     148    543       Missing (in isoform 10).
FT                                {ECO:0000303|PubMed:15361853}.
FT                                /FTId=VSP_014561.
FT   VAR_SEQ     150    165       VGPKNSYIAYIEDHSG -> ENLSCPYRIWFNFCLF (in
FT                                isoform 6).
FT                                {ECO:0000303|PubMed:15361853}.
FT                                /FTId=VSP_014562.
FT   VAR_SEQ     166    543       Missing (in isoform 6).
FT                                {ECO:0000303|PubMed:15361853}.
FT                                /FTId=VSP_014563.
FT   VAR_SEQ     198    224       VFVFFDLTVDDQSVYPKALRDEYIMSK -> EKILKIYSLS
FT                                RFSKIRRGAVAHVFNPS (in isoform 2).
FT                                {ECO:0000303|PubMed:10097108,
FT                                ECO:0000303|PubMed:15361853}.
FT                                /FTId=VSP_014564.
FT   VAR_SEQ     199    203       FVFFD -> VPVER (in isoform 5).
FT                                {ECO:0000303|PubMed:15361853}.
FT                                /FTId=VSP_014565.
FT   VAR_SEQ     204    543       Missing (in isoform 5).
FT                                {ECO:0000303|PubMed:15361853}.
FT                                /FTId=VSP_014566.
FT   VAR_SEQ     228    234       SGACGEV -> GRGWQIT (in isoform 2).
FT                                {ECO:0000303|PubMed:10097108,
FT                                ECO:0000303|PubMed:15361853}.
FT                                /FTId=VSP_014567.
FT   VAR_SEQ     235    543       Missing (in isoform 2).
FT                                {ECO:0000303|PubMed:10097108,
FT                                ECO:0000303|PubMed:15361853}.
FT                                /FTId=VSP_014568.
FT   VAR_SEQ     283    289       PCIIKIK -> DGRGRAV (in isoform 8).
FT                                {ECO:0000303|PubMed:15361853}.
FT                                /FTId=VSP_014569.
FT   VAR_SEQ     290    543       Missing (in isoform 8).
FT                                {ECO:0000303|PubMed:15361853}.
FT                                /FTId=VSP_014570.
FT   VAR_SEQ     337    365       Missing (in isoform 12).
FT                                {ECO:0000303|PubMed:15361853,
FT                                ECO:0000303|Ref.7}.
FT                                /FTId=VSP_014571.
FT   VAR_SEQ     337    339       YLH -> MKT (in isoform 7).
FT                                {ECO:0000303|PubMed:15361853}.
FT                                /FTId=VSP_014572.
FT   VAR_SEQ     340    543       Missing (in isoform 7).
FT                                {ECO:0000303|PubMed:15361853}.
FT                                /FTId=VSP_014573.
FT   VARIANT      17     17       A -> S (in an osteogenic sarcoma sample;
FT                                somatic mutation; might influence
FT                                susceptibility to breast cancer; does not
FT                                cause protein abrogation in familial
FT                                colorectal cancer).
FT                                {ECO:0000269|PubMed:11746983}.
FT                                /FTId=VAR_019101.
FT   VARIANT      59     59       T -> K (in multiple cancers).
FT                                {ECO:0000269|PubMed:12052256}.
FT                                /FTId=VAR_026630.
FT   VARIANT      64     64       E -> K (in prostate cancer; somatic
FT                                mutation). {ECO:0000269|PubMed:12533788}.
FT                                /FTId=VAR_019107.
FT   VARIANT      85     85       P -> L (in an osteogenic sarcoma sample;
FT                                neutral allele among Ashkenazi Jewish
FT                                women; dbSNP:rs17883862).
FT                                {ECO:0000269|PubMed:11746983,
FT                                ECO:0000269|PubMed:15649950,
FT                                ECO:0000269|Ref.10}.
FT                                /FTId=VAR_019102.
FT   VARIANT     117    117       R -> G (in dbSNP:rs28909982).
FT                                {ECO:0000269|PubMed:12454775,
FT                                ECO:0000269|PubMed:12610780,
FT                                ECO:0000269|PubMed:15818573}.
FT                                /FTId=VAR_022461.
FT   VARIANT     137    137       R -> Q (might influence susceptibility to
FT                                breast cancer; does not cause protein
FT                                abrogation in familial colorectal
FT                                cancer). {ECO:0000269|PubMed:12454775,
FT                                ECO:0000269|PubMed:15818573}.
FT                                /FTId=VAR_022462.
FT   VARIANT     145    145       R -> P (in prostate cancer; somatic
FT                                mutation). {ECO:0000269|PubMed:12533788}.
FT                                /FTId=VAR_019108.
FT   VARIANT     145    145       R -> W (in colon cancer and LFS2; does
FT                                not cause protein abrogation in familial
FT                                colorectal cancer; loss of the ability to
FT                                interact with and phosphorylate CDC25A
FT                                and to promote CDC25A degradation in
FT                                response to ionizing radiation).
FT                                {ECO:0000269|PubMed:10617473,
FT                                ECO:0000269|PubMed:11719428,
FT                                ECO:0000269|PubMed:12610780,
FT                                ECO:0000269|PubMed:15535844,
FT                                ECO:0000269|PubMed:15818573}.
FT                                /FTId=VAR_008554.
FT   VARIANT     157    157       I -> T (might influence susceptibility to
FT                                different types of cancer; does not cause
FT                                protein abrogation in familial colorectal
FT                                cancer; loss of the ability to interact
FT                                with and phosphorylate CDC25A and to
FT                                promote CDC25A degradation in response to
FT                                ionizing radiation; dbSNP:rs17879961).
FT                                {ECO:0000269|PubMed:10617473,
FT                                ECO:0000269|PubMed:11461078,
FT                                ECO:0000269|PubMed:12533788,
FT                                ECO:0000269|PubMed:12610780,
FT                                ECO:0000269|PubMed:14612911,
FT                                ECO:0000269|PubMed:15087378,
FT                                ECO:0000269|PubMed:15095295,
FT                                ECO:0000269|PubMed:15239132,
FT                                ECO:0000269|PubMed:15492928,
FT                                ECO:0000269|PubMed:15535844,
FT                                ECO:0000269|PubMed:15810020,
FT                                ECO:0000269|PubMed:15818573,
FT                                ECO:0000269|Ref.10}.
FT                                /FTId=VAR_008555.
FT   VARIANT     167    167       G -> R (in prostate cancer; somatic
FT                                mutation). {ECO:0000269|PubMed:12533788}.
FT                                /FTId=VAR_019109.
FT   VARIANT     180    180       R -> C (in prostate cancer; somatic
FT                                mutation; dbSNP:rs77130927).
FT                                {ECO:0000269|PubMed:12533788,
FT                                ECO:0000269|PubMed:21618645}.
FT                                /FTId=VAR_019103.
FT   VARIANT     180    180       R -> H (in prostate cancer; somatic
FT                                mutation; dbSNP:rs137853009).
FT                                {ECO:0000269|PubMed:12454775,
FT                                ECO:0000269|PubMed:12533788,
FT                                ECO:0000269|PubMed:15818573}.
FT                                /FTId=VAR_019110.
FT   VARIANT     181    181       R -> C (in prostate cancer; somatic
FT                                mutation; dbSNP:rs137853010).
FT                                {ECO:0000269|PubMed:12533788}.
FT                                /FTId=VAR_019104.
FT   VARIANT     181    181       R -> H (in prostate cancer; somatic
FT                                mutation; dbSNP:rs121908701).
FT                                {ECO:0000269|PubMed:12533788}.
FT                                /FTId=VAR_019105.
FT   VARIANT     239    239       E -> K (in prostate cancer; germline
FT                                mutation). {ECO:0000269|PubMed:12533788}.
FT                                /FTId=VAR_019106.
FT   VARIANT     251    251       I -> F (in prostate cancer; germline
FT                                mutation). {ECO:0000269|PubMed:12533788}.
FT                                /FTId=VAR_019111.
FT   VARIANT     318    318       R -> H (in prostate cancer; somatic
FT                                mutation; dbSNP:rs143611747).
FT                                {ECO:0000269|PubMed:12533788}.
FT                                /FTId=VAR_019112.
FT   VARIANT     323    323       T -> P (in prostate cancer; somatic
FT                                mutation). {ECO:0000269|PubMed:12533788}.
FT                                /FTId=VAR_019113.
FT   VARIANT     327    327       Y -> C (in prostate cancer; somatic
FT                                mutation). {ECO:0000269|PubMed:12533788}.
FT                                /FTId=VAR_019114.
FT   VARIANT     347    347       D -> N (in dbSNP:rs28909980).
FT                                /FTId=VAR_029154.
FT   VARIANT     371    371       H -> Y (confers a moderate risk of breast
FT                                cancer; partially reduces kinase
FT                                activity). {ECO:0000269|PubMed:21618645}.
FT                                /FTId=VAR_066012.
FT   VARIANT     406    406       R -> H (in dbSNP:rs299671).
FT                                /FTId=VAR_024572.
FT   VARIANT     428    428       S -> F (may increase breast cancer risk;
FT                                dbSNP:rs137853011).
FT                                {ECO:0000269|PubMed:15649950}.
FT                                /FTId=VAR_022463.
FT   VARIANT     436    436       L -> M (in dbSNP:rs17882922).
FT                                {ECO:0000269|Ref.10}.
FT                                /FTId=VAR_021117.
FT   VARIANT     446    446       N -> K (in dbSNP:rs17880867).
FT                                {ECO:0000269|Ref.10}.
FT                                /FTId=VAR_021118.
FT   VARIANT     447    447       F -> I (in dbSNP:rs17881473).
FT                                {ECO:0000269|Ref.10}.
FT                                /FTId=VAR_021119.
FT   VARIANT     448    448       I -> S (in dbSNP:rs17886163).
FT                                {ECO:0000269|Ref.10}.
FT                                /FTId=VAR_021120.
FT   VARIANT     476    476       T -> K (in prostate cancer; somatic
FT                                mutation). {ECO:0000269|PubMed:12533788}.
FT                                /FTId=VAR_019115.
FT   VARIANT     500    500       S -> C (in dbSNP:rs28909981).
FT                                /FTId=VAR_029155.
FT   VARIANT     501    501       E -> K (in dbSNP:rs17883172).
FT                                {ECO:0000269|Ref.10}.
FT                                /FTId=VAR_021121.
FT   VARIANT     512    512       L -> V (in dbSNP:rs17882942).
FT                                {ECO:0000269|Ref.10}.
FT                                /FTId=VAR_021122.
FT   MUTAGEN      68     68       T->A: Loss of activation and
FT                                phosphorylation.
FT                                {ECO:0000269|PubMed:11901158,
FT                                ECO:0000269|PubMed:15342622}.
FT   MUTAGEN      73     73       S->A: Impaired activation,
FT                                phosphorylation by ATM and G2/M
FT                                transition checkpoint.
FT                                {ECO:0000269|PubMed:16481012}.
FT   MUTAGEN     347    347       D->A: Loss of kinase activity and of the
FT                                ability to phosphorylate CDC25A.
FT                                {ECO:0000269|PubMed:11298456,
FT                                ECO:0000269|PubMed:9836640}.
FT   MUTAGEN     368    368       D->N: Loss of autophosphorylation
FT                                activity. {ECO:0000269|PubMed:15342622}.
FT   MUTAGEN     379    379       S->A: Abrogates autophosphorylation at
FT                                Ser-379 and prevents ubiquitination.
FT                                {ECO:0000269|PubMed:18644861}.
FT   MUTAGEN     383    383       T->A: Loss of phosphorylation in response
FT                                to ionizing radiation.
FT                                {ECO:0000269|PubMed:11390408}.
FT   MUTAGEN     387    387       T->A: Loss of phosphorylation in response
FT                                to ionizing radiation.
FT                                {ECO:0000269|PubMed:11390408}.
FT   MUTAGEN     456    456       S->A: Increased ubiquitination and
FT                                degradation by the proteasome.
FT                                {ECO:0000269|PubMed:17715138}.
FT   STRAND       94     98       {ECO:0000244|PDB:1GXC}.
FT   STRAND      100    103       {ECO:0000244|PDB:3I6U}.
FT   STRAND      106    108       {ECO:0000244|PDB:1GXC}.
FT   STRAND      110    118       {ECO:0000244|PDB:1GXC}.
FT   STRAND      122    124       {ECO:0000244|PDB:1GXC}.
FT   HELIX       128    132       {ECO:0000244|PDB:1GXC}.
FT   HELIX       135    138       {ECO:0000244|PDB:1GXC}.
FT   STRAND      144    150       {ECO:0000244|PDB:1GXC}.
FT   STRAND      154    162       {ECO:0000244|PDB:1GXC}.
FT   STRAND      168    170       {ECO:0000244|PDB:1GXC}.
FT   STRAND      180    182       {ECO:0000244|PDB:1GXC}.
FT   STRAND      187    193       {ECO:0000244|PDB:1GXC}.
FT   STRAND      197    203       {ECO:0000244|PDB:1GXC}.
FT   HELIX       209    211       {ECO:0000244|PDB:3I6U}.
FT   HELIX       214    219       {ECO:0000244|PDB:2YCF}.
FT   STRAND      220    228       {ECO:0000244|PDB:2YCF}.
FT   STRAND      230    239       {ECO:0000244|PDB:2YCF}.
FT   TURN        240    243       {ECO:0000244|PDB:2YCF}.
FT   STRAND      244    251       {ECO:0000244|PDB:2YCF}.
FT   HELIX       253    256       {ECO:0000244|PDB:3I6U}.
FT   HELIX       270    279       {ECO:0000244|PDB:2YCF}.
FT   STRAND      288    302       {ECO:0000244|PDB:2YCF}.
FT   STRAND      307    309       {ECO:0000244|PDB:4BDD}.
FT   HELIX       310    313       {ECO:0000244|PDB:2YCF}.
FT   HELIX       314    316       {ECO:0000244|PDB:2W7X}.
FT   HELIX       321    340       {ECO:0000244|PDB:2YCF}.
FT   HELIX       350    352       {ECO:0000244|PDB:2YCF}.
FT   STRAND      353    361       {ECO:0000244|PDB:2YCF}.
FT   STRAND      364    366       {ECO:0000244|PDB:2YCF}.
FT   HELIX       369    371       {ECO:0000244|PDB:4BDE}.
FT   HELIX       379    385       {ECO:0000244|PDB:2YCF}.
FT   HELIX       388    390       {ECO:0000244|PDB:2WTJ}.
FT   HELIX       393    398       {ECO:0000244|PDB:2YCF}.
FT   TURN        399    403       {ECO:0000244|PDB:2YCF}.
FT   HELIX       407    422       {ECO:0000244|PDB:2YCF}.
FT   STRAND      429    431       {ECO:0000244|PDB:2CN5}.
FT   HELIX       436    442       {ECO:0000244|PDB:2YCF}.
FT   HELIX       449    452       {ECO:0000244|PDB:2YCF}.
FT   HELIX       457    466       {ECO:0000244|PDB:2YCF}.
FT   TURN        471    473       {ECO:0000244|PDB:2YCF}.
FT   HELIX       477    481       {ECO:0000244|PDB:2YCF}.
FT   HELIX       484    486       {ECO:0000244|PDB:2YCF}.
FT   HELIX       489    502       {ECO:0000244|PDB:2YCF}.
FT   TURN        504    506       {ECO:0000244|PDB:2WTJ}.
SQ   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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