CHK2_HUMAN
ID CHK2_HUMAN Reviewed; 543 AA.
AC O96017; A8K3Y9; B7ZBF3; B7ZBF4; B7ZBF5; Q6QA03; Q6QA04; Q6QA05; Q6QA06;
AC Q6QA07; Q6QA08; Q6QA10; Q6QA11; Q6QA12; Q6QA13; Q9HBS5; Q9HCQ8; Q9UGF0;
AC Q9UGF1;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1999, sequence version 1.
DT 03-AUG-2022, entry version 239.
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; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC 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 Cdc25
RT phosphatase.";
RL Curr. Biol. 9:1-10(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND FUNCTION IN PHOSPHORYLATION OF
RP 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 in
RT 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 AND
RP 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-dependent
RT protein kinase and inhibition by cell cycle regulatory 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., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., 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., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA 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., Qiu X.,
RA Zhong F., He L., Yu J., Yao G., Jiang H., Qian L., Yu Y., Shu H., Chen X.,
RA Xu H., Guo M., Pan Z., Chen Y., Ge C., Yang S., 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; MET-436;
RP 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., Clamp M.,
RA Smink L.J., Ainscough R., Almeida J.P., Babbage A.K., Bagguley C.,
RA Bailey J., Barlow K.F., Bates K.N., Beasley O.P., Bird C.P., Blakey S.E.,
RA Bridgeman A.M., Buck D., Burgess J., Burrill W.D., Burton J., Carder C.,
RA Carter N.P., Chen Y., Clark G., Clegg S.M., Cobley V.E., Cole C.G.,
RA Collier R.E., Connor R., Conroy D., Corby N.R., Coville G.J., Cox A.V.,
RA Davis J., Dawson E., Dhami P.D., Dockree C., Dodsworth S.J., Durbin R.M.,
RA Ellington A.G., 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., Hunt S.E.,
RA Jones M.C., Kershaw J., Kimberley A.M., King A., Laird G.K., Langford C.F.,
RA Leversha M.A., Lloyd C., Lloyd D.M., Martyn I.D., Mashreghi-Mohammadi M.,
RA Matthews L.H., Mccann O.T., Mcclay J., Mclaren S., McMurray A.A.,
RA Milne S.A., Mortimore B.J., Odell C.N., Pavitt R., Pearce A.V., Pearson D.,
RA Phillimore B.J.C.T., Phillips S.H., Plumb R.W., Ramsay H., Ramsey Y.,
RA Rogers L., Ross M.T., Scott C.E., Sehra H.K., Skuce C.D., Smalley S.,
RA Smith M.L., Soderlund C., Spragon L., Steward C.A., Sulston J.E.,
RA Swann R.M., 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., Shintani A.,
RA Shibuya K., Yoshizaki Y., Aoki N., Mitsuyama S., Roe B.A., Chen F., Chu L.,
RA Crabtree J., Deschamps S., Do A., Do T., Dorman A., Fang F., Fu Y., Hu P.,
RA Hua A., Kenton S., Lai H., Lao H.I., Lewis J., Lewis S., Lin S.-P., Loh P.,
RA Malaj E., Nguyen T., Pan H., Phan S., Qi S., Qian Y., Ray L., Ren Q.,
RA Shaull S., Sloan D., Song L., Wang Q., Wang Y., Wang Z., White J.,
RA Willingham D., Wu H., Yao Z., Zhan M., Zhang G., Chissoe S., Murray J.,
RA Miller N., Minx P., Fulton R., Johnson D., Bemis G., Bentley D.,
RA Bradshaw H., Bourne S., Cordes M., Du Z., Fulton L., Goela D., Graves T.,
RA Hawkins J., Hinds K., Kemp K., Latreille P., Layman D., Ozersky P.,
RA Rohlfing T., Scheet P., Walker C., Wamsley A., Wohldmann P., Pepin K.,
RA Nelson J., Korf I., Bedell J.A., Hillier L.W., Mardis E., Waterston R.,
RA Wilson R., Emanuel B.S., Shaikh T., Kurahashi H., Saitta S., Budarf M.L.,
RA McDermid H.E., Johnson A., Wong A.C.C., Morrow B.E., Edelmann L., Kim U.J.,
RA Shizuya H., Simon M.I., Dumanski J.P., Peyrard M., Kedra D., Seroussi E.,
RA Fransson I., Tapia I., Bruder C.E., O'Brien K.P., Wilkinson P.,
RA Bodenteich A., Hartman K., Hu X., Khan A.S., Lane L., Tilahun Y.,
RA 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., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., 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 project:
RT 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 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 phosphorylation
RT events on hCds1 that is induced by ionizing 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, CHARACTERIZATION
RP OF VARIANT COLON CANCER TRP-145, AND CHARACTERIZATION 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 DNA
RT 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 familial
RT 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-associated
RT domain.";
RL J. Biol. Chem. 277:19389-19395(2002).
RN [20]
RP FUNCTION IN APOPTOSIS, FUNCTION IN PHOSPHORYLATION OF PML, AND SUBCELLULAR
RP 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 checkpoint
RT 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 FUNCTION
RP 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 ACTIVITY REGULATION, PHOSPHORYLATION AT THR-68 BY MAP3K20, 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 checkpoints
RT 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., Kondo T.,
RA 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 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., Stambrook P.J.;
RT "Priming phosphorylation of Chk2 by polo-like kinase 3 (Plk3) mediates its
RT full activation by ATM and a downstream checkpoint in response to DNA
RT 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 pRB
RT 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 stimulate
RT expression of DNA repair genes.";
RL Mol. Cell. Biol. 27:1007-1016(2007).
RN [33]
RP FUNCTION IN PHOSPHORYLATION OF NEK6.
RX PubMed=18728393; DOI=10.4161/cc.7.17.6551;
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 SER-379,
RP 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 OF
RP BRCA2.
RX PubMed=18317453; DOI=10.1038/onc.2008.17;
RA Bahassi E.M., Ovesen J.L., Riesenberg A.L., Bernstein W.Z., Hasty P.E.,
RA Stambrook P.J.;
RT "The checkpoint kinases Chk1 and Chk2 regulate the functional associations
RT between hBRCA2 and Rad51 in response to DNA damage.";
RL Oncogene 27:3977-3985(2008).
RN [36]
RP PHOSPHORYLATION BY PLK4.
RX PubMed=19164942; DOI=10.4161/cc.8.2.7355;
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 stability in
RT 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., Buerckstuemmer T.,
RA 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., Fan Z.,
RA Fan T., Lin B., Xu X., Xie Y.;
RT "A recurrent CHEK2 p.H371Y mutation is associated with breast cancer risk
RT 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 FUNCTION, AND INTERACTION WITH CCAR2 AND SIRT1.
RX PubMed=25361978; DOI=10.1093/nar/gku1065;
RA Magni M., Ruscica V., Buscemi G., Kim J.E., Nachimuthu B.T., Fontanella E.,
RA Delia D., Zannini L.;
RT "Chk2 and REGgamma-dependent DBC1 regulation in DNA damage induced
RT apoptosis.";
RL Nucleic Acids Res. 42:13150-13160(2014).
RN [42]
RP FUNCTION (MICROBIAL INFECTION).
RX PubMed=32001251; DOI=10.1016/j.jmb.2020.01.021;
RA Hembram D.S.S., Negi H., Biswas P., Tripathi V., Bhushan L., Shet D.,
RA Kumar V., Das R.;
RT "The Viral SUMO-Targeted Ubiquitin Ligase ICP0 is Phosphorylated and
RT Activated by Host Kinase Chk2.";
RL J. Mol. Biol. 432:1952-1977(2020).
RN [43]
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 [44]
RP X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 210-531 IN COMPLEX WITH ADP AND
RP 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., Garrett M.D.,
RA Mittnacht S., Pearl L.H.;
RT "Trans-activation of the DNA-damage signalling protein kinase Chk2 by T-
RT loop exchange.";
RL EMBO J. 25:3179-3190(2006).
RN [45]
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 [46]
RP INTERACTION WITH CDKN2AIP.
RX PubMed=24825908; DOI=10.1074/jbc.m114.547208;
RA Cheung C.T., Singh R., Kalra R.S., Kaul S.C., Wadhwa R.;
RT "Collaborator of ARF (CARF) regulates proliferative fate of human cells by
RT dose-dependent regulation of DNA damage signaling.";
RL J. Biol. Chem. 289:18258-18269(2014).
RN [47]
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 [48]
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 [49]
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., Jorczak M.M.,
RA Sgroi D.C., Garber J.E., Li F.P., Nichols K.E., Varley J.M., Godwin A.K.,
RA Shannon K.M., Harlow E., Haber D.A.;
RT "Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni
RT Syndrome.";
RL Cancer Res. 61:8062-8067(2001).
RN [50]
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 [51]
RP VARIANT BC GLY-117, AND VARIANTS 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., 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 [52]
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 rare
RT in breast, lung, and ovarian tumors.";
RL Genes Chromosomes Cancer 33:17-21(2002).
RN [53]
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 LYS-476,
RP AND VARIANT THR-157.
RX PubMed=12533788; DOI=10.1086/346094;
RA Dong X., Wang L., Taniguchi K., Wang X., Cunningham J.M., McDonnell S.K.,
RA Qian C., Marks A.F., Slager S.L., Peterson B.J., Smith D.I., Cheville J.C.,
RA Blute M.L., Jacobsen S.J., Schaid D.J., Tindall D.J., Thibodeau S.N.,
RA Liu W.;
RT "Mutations in CHEK2 associated with prostate cancer risk.";
RL Am. J. Hum. Genet. 72:270-280(2003).
RN [54]
RP VARIANT BC GLY-117, AND VARIANTS 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., Donaldson A.,
RA Eeles R., Evans G., Gregory H., Gray J., Houlston R., Lalloo F.,
RA Lucassen A., Mackay J., Mitchell G., Morrison P., Murday V., Narod S.,
RA Patterson J., Peretz T., Phelan C.M., Rogers M., Schofield A., Tonin P.,
RA Weber B., Weber W., Futreal P.A., Nathanson K.L., Weber B.L., Easton D.F.,
RA Stratton M.R., Rahman N.;
RT "Variants in CHEK2 other than 1100delC do not make a major contribution to
RT breast cancer susceptibility.";
RL Am. J. Hum. Genet. 72:1023-1028(2003).
RN [55]
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 [56]
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., Witek A.,
RA Narod S.A., Lubinski J.;
RT "CHEK2 is a multiorgan cancer susceptibility gene.";
RL Am. J. Hum. Genet. 75:1131-1135(2004).
RN [57]
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., Ostrander E.A.;
RT "Frequency of CHEK2 mutations in a population based, case-control study of
RT breast cancer in young women.";
RL Breast Cancer Res. 6:R629-R635(2004).
RN [58]
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 [59]
RP VARIANT THR-157.
RX PubMed=15095295; DOI=10.1002/ijc.20073;
RA Dufault M.R., Betz B., Wappenschmidt B., Hofmann W., Bandick K., Golla A.,
RA Pietschmann A., Nestle-Kraemling C., Rhiem K., Huettner C., von Lindern C.,
RA Dall P., Kiechle M., Untch M., Jonat W., Meindl A., Scherneck S.,
RA 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 [60]
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., Holli K.,
RA Blomqvist C., Kallioniemi O.-P., Bartek J., Nevanlinna H.;
RT "CHEK2 variant I157T may be associated with increased breast cancer risk.";
RL Int. J. Cancer 111:543-547(2004).
RN [61]
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 [62]
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 [63]
RP VARIANT BC GLY-117, AND VARIANTS 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., van Wezel T.,
RA 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).
RN [64]
RP VARIANT BC CYS-390, CHARACTERIZATION OF VARIANT BC CYS-390, AND FUNCTION.
RX PubMed=25619829; DOI=10.1038/onc.2014.443;
RA Wang N., Ding H., Liu C., Li X., Wei L., Yu J., Liu M., Ying M., Gao W.,
RA Jiang H., Wang Y.;
RT "A novel recurrent CHEK2 Y390C mutation identified in high-risk Chinese
RT breast cancer patients impairs its activity and is associated with
RT increased breast cancer risk.";
RL Oncogene 34:5198-5205(2015).
CC -!- FUNCTION: Serine/threonine-protein kinase which is required for
CC checkpoint-mediated cell cycle arrest, activation of DNA repair and
CC apoptosis in response to the presence of DNA double-strand breaks. May
CC also negatively regulate cell cycle progression during unperturbed cell
CC cycles. Following activation, phosphorylates numerous effectors
CC preferentially at the consensus sequence [L-X-R-X-X-S/T]. Regulates
CC cell cycle checkpoint arrest through phosphorylation of CDC25A, CDC25B
CC and CDC25C, inhibiting their activity. Inhibition of CDC25 phosphatase
CC activity leads to increased inhibitory tyrosine phosphorylation of CDK-
CC cyclin 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 the
CC association of RAD51 with chromatin which promotes DNA repair by
CC homologous recombination. Also stimulates the transcription of genes
CC involved in DNA repair (including BRCA2) through the phosphorylation
CC and activation of the transcription factor FOXM1. Regulates apoptosis
CC through the phosphorylation of p53/TP53, MDM4 and PML. Phosphorylation
CC of p53/TP53 at 'Ser-20' by CHEK2 may alleviate inhibition by MDM2,
CC leading to accumulation of active p53/TP53. Phosphorylation of MDM4 may
CC also reduce degradation of p53/TP53. Also controls the transcription of
CC pro-apoptotic genes through phosphorylation of the transcription factor
CC E2F1. Tumor suppressor, it may also have a DNA damage-independent
CC function in mitotic spindle assembly by phosphorylating BRCA1. Its
CC absence may be a cause of the chromosomal instability observed in some
CC cancer cells. Promotes the CCAR2-SIRT1 association and is required for
CC CCAR2-mediated SIRT1 inhibition (PubMed:25361978).
CC {ECO:0000250|UniProtKB:Q9Z265, ECO:0000269|PubMed:10097108,
CC ECO:0000269|PubMed:10724175, ECO:0000269|PubMed:11298456,
CC ECO:0000269|PubMed:12402044, ECO:0000269|PubMed:12607004,
CC ECO:0000269|PubMed:12717439, ECO:0000269|PubMed:12810724,
CC ECO:0000269|PubMed:16163388, ECO:0000269|PubMed:17101782,
CC ECO:0000269|PubMed:17380128, ECO:0000269|PubMed:17715138,
CC ECO:0000269|PubMed:18317453, ECO:0000269|PubMed:18644861,
CC ECO:0000269|PubMed:18728393, ECO:0000269|PubMed:20364141,
CC ECO:0000269|PubMed:25361978, ECO:0000269|PubMed:25619829,
CC ECO:0000269|PubMed:9836640, ECO:0000269|PubMed:9889122}.
CC -!- FUNCTION: (Microbial infection) Phosphorylates herpes simplex virus
CC 1/HHV-1 protein ICP0 and thus activates its SUMO-targeted ubiquitin
CC ligase activity. {ECO:0000269|PubMed:32001251}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.1;
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC -!- ACTIVITY REGULATION: Activated through phosphorylation at Thr-68 by ATM
CC in response to DNA double-strand breaks. Activation is modulated by
CC several mediators including MDC1 and TP53BP1. Induces homodimerization
CC with exchange of the T-loop/activation segment between protomers and
CC transphosphorylation of the protomers. The autophosphorylated kinase
CC dimer is fully active. Negatively regulated by PPM1D through
CC dephosphorylation of Thr-68. {ECO:0000269|PubMed:15342622}.
CC -!- SUBUNIT: Homodimer. Homodimerization is part of the activation process
CC but the dimer may dissociate following activation. Interacts with PML.
CC Interacts with TP53. Interacts with RB1; phosphorylates RB1. Interacts
CC with BRCA1. Interacts (phosphorylated at Thr-68) with MDC1; requires
CC ATM-mediated phosphorylation of CHEK2. Interacts with TP53BP1;
CC modulates CHEK2 phosphorylation at Thr-68 in response to ionizing
CC radiation. Interacts with CDC25A; phosphorylates CDC25A and mediates
CC its degradation in response to ionizing radiation. Interacts with CUL1;
CC mediates CHEK2 ubiquitination and regulation. Interacts with CDKN2AIP.
CC Interacts (via protein kinase domain) with CCAR2 (via N-terminus).
CC Interacts with SIRT1. {ECO:0000269|PubMed:10724175,
CC ECO:0000269|PubMed:11298456, ECO:0000269|PubMed:12364621,
CC ECO:0000269|PubMed:12607004, ECO:0000269|PubMed:12810724,
CC ECO:0000269|PubMed:16794575, ECO:0000269|PubMed:18644861,
CC ECO:0000269|PubMed:24825908, ECO:0000269|PubMed:25361978}.
CC -!- INTERACTION:
CC O96017; Q9NY61: AATF; NbExp=4; IntAct=EBI-1180783, EBI-372428;
CC O96017; Q9UQ88-1: CDK11A; NbExp=2; IntAct=EBI-1180783, EBI-11579223;
CC O96017; O96017: CHEK2; NbExp=6; IntAct=EBI-1180783, EBI-1180783;
CC O96017; Q9Y248: GINS2; NbExp=2; IntAct=EBI-1180783, EBI-747491;
CC O96017; Q13007: IL24; NbExp=3; IntAct=EBI-1180783, EBI-3915542;
CC O96017; Q96KN1: LRATD2; NbExp=3; IntAct=EBI-1180783, EBI-9057780;
CC O96017; P56645: PER3; NbExp=2; IntAct=EBI-1180783, EBI-2827813;
CC O96017; P53350: PLK1; NbExp=7; IntAct=EBI-1180783, EBI-476768;
CC O96017; Q15172: PPP2R5A; NbExp=2; IntAct=EBI-1180783, EBI-641666;
CC O96017; Q15173: PPP2R5B; NbExp=2; IntAct=EBI-1180783, EBI-1369497;
CC O96017; Q13362-1: PPP2R5C; NbExp=3; IntAct=EBI-1180783, EBI-1266170;
CC O96017; Q13362-2: PPP2R5C; NbExp=2; IntAct=EBI-1180783, EBI-1266173;
CC O96017; Q13362-3: PPP2R5C; NbExp=4; IntAct=EBI-1180783, EBI-1266176;
CC O96017; Q16537: PPP2R5E; NbExp=3; IntAct=EBI-1180783, EBI-968374;
CC O96017; P06400: RB1; NbExp=3; IntAct=EBI-1180783, EBI-491274;
CC O96017; Q5VTR2: RNF20; NbExp=3; IntAct=EBI-1180783, EBI-2372238;
CC O96017; P55072: VCP; NbExp=2; IntAct=EBI-1180783, EBI-355164;
CC O96017; P18887: XRCC1; NbExp=8; IntAct=EBI-1180783, EBI-947466;
CC O96017; PRO_0000037319 [P0C6X7]: rep; Xeno; NbExp=2; IntAct=EBI-1180783, EBI-25487926;
CC O96017; P06725: UL83; Xeno; NbExp=2; IntAct=EBI-1180783, EBI-9545359;
CC O96017; PRO_0000037577 [P27958]; Xeno; NbExp=3; IntAct=EBI-1180783, EBI-6904388;
CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Nucleus. Note=Isoform 10 is present
CC 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 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 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 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 Name=10; Synonyms=iso2;
CC IsoId=O96017-10; Sequence=VSP_014560, VSP_014561;
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 Name=13;
CC IsoId=O96017-13; Sequence=VSP_045148;
CC -!- TISSUE SPECIFICITY: High expression is found in testis, spleen, colon
CC and peripheral blood leukocytes. Low expression is found in other
CC tissues.
CC -!- PTM: Phosphorylated. Phosphorylated at Ser-73 by PLK3 in response to
CC DNA damage, promoting phosphorylation at Thr-68 by ATM and the G2/M
CC transition checkpoint. Phosphorylation at Thr-68 induces
CC homodimerization. Autophosphorylates at Thr-383 and Thr-387 in the T-
CC loop/activation segment upon dimerization to become fully active and
CC phosphorylate its substrates like for instance CDC25C. DNA damage-
CC induced autophosphorylation at Ser-379 induces CUL1-mediated
CC 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 pro-
CC apoptotic function. Ubiquitination may also regulate protein stability.
CC Ubiquitinated by RNF8 via 'Lys-48'-linked ubiquitination.
CC -!- DISEASE: Li-Fraumeni syndrome 2 (LFS2) [MIM:609265]: A highly penetrant
CC familial cancer syndrome that in its classic form is defined by the
CC existence of a proband affected by a sarcoma before 45 years with a
CC first degree relative affected by any tumor before 45 years and another
CC first degree relative with any tumor before 45 years or a sarcoma at
CC any age. Other clinical definitions for LFS have been proposed
CC (PubMed:8118819 and PubMed:8718514) and called Li-Fraumeni like
CC syndrome (LFL). In these families affected relatives develop a diverse
CC set of malignancies at unusually early ages. Four types of cancers
CC account for 80% of tumors occurring in TP53 germline mutation carriers:
CC breast cancers, soft tissue and bone sarcomas, brain tumors
CC (astrocytomas) and adrenocortical carcinomas. Less frequent tumors
CC include choroid plexus carcinoma or papilloma before the age of 15,
CC rhabdomyosarcoma before the age of 5, leukemia, Wilms tumor, malignant
CC phyllodes tumor, colorectal and gastric cancers.
CC {ECO:0000269|PubMed:11719428}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Prostate cancer (PC) [MIM:176807]: A malignancy originating in
CC tissues of the prostate. Most prostate cancers are adenocarcinomas that
CC develop in the acini of the prostatic ducts. Other rare histopathologic
CC types of prostate cancer that occur in approximately 5% of patients
CC include small cell carcinoma, mucinous carcinoma, prostatic ductal
CC carcinoma, transitional cell carcinoma, squamous cell carcinoma, basal
CC cell carcinoma, adenoid cystic carcinoma (basaloid), signet-ring cell
CC carcinoma and neuroendocrine carcinoma. {ECO:0000269|PubMed:12533788}.
CC Note=Disease susceptibility is associated with variants affecting the
CC gene represented in this entry.
CC -!- DISEASE: Osteogenic sarcoma (OSRC) [MIM:259500]: A sarcoma originating
CC in bone-forming cells, affecting the ends of long bones. Note=The gene
CC represented in this entry may be involved in 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 carcinoma is
CC by far the most common type. Breast cancer is etiologically and
CC genetically heterogeneous. Important genetic factors have been
CC indicated by familial occurrence and bilateral involvement. Mutations
CC at more than one locus can be involved in different families or even in
CC the same case. {ECO:0000269|PubMed:12094328,
CC ECO:0000269|PubMed:12454775, ECO:0000269|PubMed:12610780,
CC ECO:0000269|PubMed:15818573, ECO:0000269|PubMed:21618645,
CC ECO:0000269|PubMed:25619829}. Note=Disease susceptibility is associated
CC with variants affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: [Isoform 2]: Lacks enzymatic activity. {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 4]: Lacks enzymatic activity. {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 7]: Lacks enzymatic activity. {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 9]: Retains low level of catalytic activity.
CC {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 10]: Lacks enzymatic activity. {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 12]: Lacks enzymatic activity. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CAMK Ser/Thr
CC protein kinase family. CHK2 subfamily. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/CHEK2ID312.html";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/chek2/";
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
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; AL117330; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL121825; -; NOT_ANNOTATED_CDS; 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 RefSeq; XP_011528147.1; XM_011529845.2. [O96017-13]
DR RefSeq; XP_016884050.1; XM_017028561.1. [O96017-13]
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 AlphaFoldDB; O96017; -.
DR SMR; O96017; -.
DR BioGRID; 116369; 208.
DR CORUM; O96017; -.
DR DIP; DIP-24270N; -.
DR ELM; O96017; -.
DR IntAct; O96017; 115.
DR MINT; O96017; -.
DR STRING; 9606.ENSP00000372023; -.
DR BindingDB; O96017; -.
DR ChEMBL; CHEMBL2527; -.
DR DrugBank; DB06486; Enzastaurin.
DR DrugBank; DB12010; Fostamatinib.
DR DrugBank; DB05149; XL844.
DR DrugCentral; O96017; -.
DR GuidetoPHARMACOLOGY; 1988; -.
DR GlyGen; O96017; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; O96017; -.
DR MetOSite; O96017; -.
DR PhosphoSitePlus; O96017; -.
DR BioMuta; CHEK2; -.
DR EPD; O96017; -.
DR jPOST; O96017; -.
DR MassIVE; O96017; -.
DR MaxQB; O96017; -.
DR PeptideAtlas; O96017; -.
DR PRIDE; O96017; -.
DR ProteomicsDB; 51198; -. [O96017-1]
DR ProteomicsDB; 51199; -. [O96017-10]
DR ProteomicsDB; 51200; -. [O96017-11]
DR ProteomicsDB; 51201; -. [O96017-12]
DR ProteomicsDB; 51202; -. [O96017-2]
DR ProteomicsDB; 51203; -. [O96017-3]
DR ProteomicsDB; 51204; -. [O96017-4]
DR ProteomicsDB; 51205; -. [O96017-5]
DR ProteomicsDB; 51206; -. [O96017-6]
DR ProteomicsDB; 51207; -. [O96017-7]
DR ProteomicsDB; 51208; -. [O96017-8]
DR ProteomicsDB; 51209; -. [O96017-9]
DR ProteomicsDB; 81589; -.
DR ABCD; O96017; 1 sequenced antibody.
DR Antibodypedia; 278; 2059 antibodies from 49 providers.
DR CPTC; O96017; 2 antibodies.
DR DNASU; 11200; -.
DR Ensembl; ENST00000348295.7; ENSP00000329012.5; ENSG00000183765.23. [O96017-12]
DR Ensembl; ENST00000382580.6; ENSP00000372023.2; ENSG00000183765.23. [O96017-9]
DR Ensembl; ENST00000403642.5; ENSP00000384919.1; ENSG00000183765.23. [O96017-4]
DR Ensembl; ENST00000404276.6; ENSP00000385747.1; ENSG00000183765.23. [O96017-1]
DR Ensembl; ENST00000405598.5; ENSP00000386087.1; ENSG00000183765.23. [O96017-1]
DR Ensembl; ENST00000417588.5; ENSP00000412901.1; ENSG00000183765.23. [O96017-5]
DR Ensembl; ENST00000425190.7; ENSP00000390244.2; ENSG00000183765.23. [O96017-13]
DR Ensembl; ENST00000433728.5; ENSP00000404400.1; ENSG00000183765.23. [O96017-8]
DR Ensembl; ENST00000448511.5; ENSP00000404567.1; ENSG00000183765.23. [O96017-6]
DR Ensembl; ENST00000649563.1; ENSP00000496928.1; ENSG00000183765.23. [O96017-13]
DR Ensembl; ENST00000650281.1; ENSP00000497000.1; ENSG00000183765.23. [O96017-1]
DR GeneID; 11200; -.
DR KEGG; hsa:11200; -.
DR MANE-Select; ENST00000404276.6; ENSP00000385747.1; NM_007194.4; NP_009125.1.
DR UCSC; uc003adt.2; human. [O96017-1]
DR CTD; 11200; -.
DR DisGeNET; 11200; -.
DR GeneCards; CHEK2; -.
DR HGNC; HGNC:16627; CHEK2.
DR HPA; ENSG00000183765; Low tissue specificity.
DR MalaCards; CHEK2; -.
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 OpenTargets; ENSG00000183765; -.
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 VEuPathDB; HostDB:ENSG00000183765; -.
DR eggNOG; KOG0615; Eukaryota.
DR GeneTree; ENSGT00800000124190; -.
DR HOGENOM; CLU_070593_1_0_1; -.
DR InParanoid; O96017; -.
DR OMA; MLCAVQY; -.
DR OrthoDB; 1510589at2759; -.
DR PhylomeDB; O96017; -.
DR TreeFam; TF101082; -.
DR BRENDA; 2.7.11.1; 2681.
DR PathwayCommons; O96017; -.
DR Reactome; R-HSA-5693565; Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks.
DR Reactome; R-HSA-6804756; Regulation of TP53 Activity through Phosphorylation.
DR Reactome; R-HSA-6804757; Regulation of TP53 Degradation.
DR Reactome; R-HSA-6804760; Regulation of TP53 Activity through Methylation.
DR Reactome; R-HSA-69473; G2/M DNA damage checkpoint.
DR Reactome; R-HSA-69541; Stabilization of p53.
DR Reactome; R-HSA-69601; Ubiquitin Mediated Degradation of Phosphorylated Cdc25A.
DR Reactome; R-HSA-75035; Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex.
DR SignaLink; O96017; -.
DR SIGNOR; O96017; -.
DR BioGRID-ORCS; 11200; 24 hits in 1116 CRISPR screens.
DR ChiTaRS; CHEK2; human.
DR EvolutionaryTrace; O96017; -.
DR GeneWiki; CHEK2; -.
DR GenomeRNAi; 11200; -.
DR Pharos; O96017; Tchem.
DR PRO; PR:O96017; -.
DR Proteomes; UP000005640; Chromosome 22.
DR RNAct; O96017; protein.
DR Bgee; ENSG00000183765; Expressed in lower esophagus mucosa and 106 other tissues.
DR ExpressionAtlas; O96017; baseline and differential.
DR Genevisible; O96017; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
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:0106310; F:protein serine kinase activity; IEA:RHEA.
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:0051301; P:cell division; IEA:UniProtKB-KW.
DR GO; GO:1903926; P:cellular response to bisphenol A; IEA:Ensembl.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IDA:MGI.
DR GO; GO:0071480; P:cellular response to gamma radiation; IEA:Ensembl.
DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; IEA:Ensembl.
DR GO; GO:0000077; P:DNA damage checkpoint signaling; TAS:UniProtKB.
DR GO; GO:0006975; P:DNA damage induced protein phosphorylation; IMP:UniProtKB.
DR GO; GO:0006977; P:DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest; TAS:Reactome.
DR GO; GO:0006978; P:DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator; IEA:Ensembl.
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:0042771; P:intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator; IEA:Ensembl.
DR GO; GO:0044773; P:mitotic DNA damage checkpoint signaling; IBA:GO_Central.
DR GO; GO:0031573; P:mitotic intra-S DNA damage checkpoint signaling; IMP:UniProtKB.
DR GO; GO:0090307; P:mitotic spindle assembly; IMP:UniProtKB.
DR GO; GO:2000002; P:negative regulation of DNA damage checkpoint; IEA:Ensembl.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IEA:Ensembl.
DR GO; GO:2000210; P:positive regulation of anoikis; IEA:Ensembl.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IEA:Ensembl.
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:0030163; P:protein catabolic process; IMP: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:1901796; P:regulation of signal transduction by p53 class mediator; TAS:Reactome.
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:1903416; P:response to glycoside; IEA:Ensembl.
DR GO; GO:0042770; P:signal transduction in response to DNA damage; IDA:MGI.
DR GO; GO:0070242; P:thymocyte apoptotic process; IEA:Ensembl.
DR CDD; cd00060; FHA; 1.
DR DisProt; DP01797; -.
DR InterPro; IPR000253; FHA_dom.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR InterPro; IPR008984; SMAD_FHA_dom_sf.
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; Cell cycle;
KW Cell division; Disease variant; DNA damage; DNA repair;
KW Host-virus interaction; Kinase; Li-Fraumeni syndrome; Magnesium;
KW Metal-binding; Mitosis; Nucleotide-binding; Nucleus; Phosphoprotein;
KW Reference proteome; Serine/threonine-protein kinase; Transcription;
KW Transcription regulation; Transferase; Tumor suppressor; Ubl conjugation.
FT CHAIN 1..543
FT /note="Serine/threonine-protein kinase Chk2"
FT /id="PRO_0000085858"
FT DOMAIN 113..175
FT /note="FHA"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00086"
FT DOMAIN 220..486
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1..66
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 368..394
FT /note="T-loop/activation segment"
FT REGION 506..538
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 7..66
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 347
FT /note="Proton acceptor"
FT BINDING 227..234
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT BINDING 249
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT BINDING 302..308
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT BINDING 351..352
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT BINDING 368
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT MOD_RES 62
FT /note="Phosphoserine; by PLK3"
FT /evidence="ECO:0000269|PubMed:16481012"
FT MOD_RES 68
FT /note="Phosphothreonine; by ATM and MAP3K20"
FT /evidence="ECO:0000269|PubMed:10973490,
FT ECO:0000269|PubMed:15342622, ECO:0000269|PubMed:16311512,
FT ECO:0000269|PubMed:16481012"
FT MOD_RES 73
FT /note="Phosphoserine; by PLK3"
FT /evidence="ECO:0000269|PubMed:16481012"
FT MOD_RES 379
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:18644861"
FT MOD_RES 383
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:11390408"
FT MOD_RES 387
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:11390408"
FT MOD_RES 456
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:17715138"
FT VAR_SEQ 1..221
FT /note="Missing (in isoform 13)"
FT /evidence="ECO:0000303|PubMed:15498874"
FT /id="VSP_045148"
FT VAR_SEQ 75..392
FT /note="Missing (in isoform 11)"
FT /evidence="ECO:0000303|PubMed:15361853"
FT /id="VSP_014556"
FT VAR_SEQ 107..487
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15361853"
FT /id="VSP_014559"
FT VAR_SEQ 107..197
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:15361853"
FT /id="VSP_014558"
FT VAR_SEQ 107
FT /note="E -> ETESGHVTQSDLELLLSSDPPASASQSAGIRGVRHHPRPVCSLK
FT (in isoform 9)"
FT /evidence="ECO:0000303|PubMed:15361853,
FT ECO:0000303|PubMed:15461802"
FT /id="VSP_014557"
FT VAR_SEQ 131..147
FT /note="KRTDKYRTYSKKHFRIF -> EFRSYSFYLP (in isoform 10)"
FT /evidence="ECO:0000303|PubMed:15361853"
FT /id="VSP_014560"
FT VAR_SEQ 148..543
FT /note="Missing (in isoform 10)"
FT /evidence="ECO:0000303|PubMed:15361853"
FT /id="VSP_014561"
FT VAR_SEQ 150..165
FT /note="VGPKNSYIAYIEDHSG -> ENLSCPYRIWFNFCLF (in isoform 6)"
FT /evidence="ECO:0000303|PubMed:15361853"
FT /id="VSP_014562"
FT VAR_SEQ 166..543
FT /note="Missing (in isoform 6)"
FT /evidence="ECO:0000303|PubMed:15361853"
FT /id="VSP_014563"
FT VAR_SEQ 198..224
FT /note="VFVFFDLTVDDQSVYPKALRDEYIMSK -> EKILKIYSLSRFSKIRRGAVA
FT HVFNPS (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:10097108,
FT ECO:0000303|PubMed:15361853"
FT /id="VSP_014564"
FT VAR_SEQ 199..203
FT /note="FVFFD -> VPVER (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:15361853"
FT /id="VSP_014565"
FT VAR_SEQ 204..543
FT /note="Missing (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:15361853"
FT /id="VSP_014566"
FT VAR_SEQ 228..234
FT /note="SGACGEV -> GRGWQIT (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:10097108,
FT ECO:0000303|PubMed:15361853"
FT /id="VSP_014567"
FT VAR_SEQ 235..543
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:10097108,
FT ECO:0000303|PubMed:15361853"
FT /id="VSP_014568"
FT VAR_SEQ 283..289
FT /note="PCIIKIK -> DGRGRAV (in isoform 8)"
FT /evidence="ECO:0000303|PubMed:15361853"
FT /id="VSP_014569"
FT VAR_SEQ 290..543
FT /note="Missing (in isoform 8)"
FT /evidence="ECO:0000303|PubMed:15361853"
FT /id="VSP_014570"
FT VAR_SEQ 337..365
FT /note="Missing (in isoform 12)"
FT /evidence="ECO:0000303|PubMed:15361853, ECO:0000303|Ref.7"
FT /id="VSP_014571"
FT VAR_SEQ 337..339
FT /note="YLH -> MKT (in isoform 7)"
FT /evidence="ECO:0000303|PubMed:15361853"
FT /id="VSP_014572"
FT VAR_SEQ 340..543
FT /note="Missing (in isoform 7)"
FT /evidence="ECO:0000303|PubMed:15361853"
FT /id="VSP_014573"
FT VARIANT 17
FT /note="A -> S (in an osteogenic sarcoma sample; somatic
FT mutation; might influence susceptibility to breast cancer;
FT does not cause protein abrogation in familial colorectal
FT cancer; dbSNP:rs137853008)"
FT /evidence="ECO:0000269|PubMed:11746983"
FT /id="VAR_019101"
FT VARIANT 59
FT /note="T -> K (in multiple cancers; dbSNP:rs149991239)"
FT /evidence="ECO:0000269|PubMed:12052256"
FT /id="VAR_026630"
FT VARIANT 64
FT /note="E -> K (in prostate cancer; somatic mutation;
FT dbSNP:rs141568342)"
FT /evidence="ECO:0000269|PubMed:12533788"
FT /id="VAR_019107"
FT VARIANT 85
FT /note="P -> L (in an osteogenic sarcoma sample; neutral
FT allele among Ashkenazi Jewish women; dbSNP:rs17883862)"
FT /evidence="ECO:0000269|PubMed:11746983,
FT ECO:0000269|PubMed:15649950, ECO:0000269|Ref.10"
FT /id="VAR_019102"
FT VARIANT 117
FT /note="R -> G (in BC; dbSNP:rs28909982)"
FT /evidence="ECO:0000269|PubMed:12454775,
FT ECO:0000269|PubMed:12610780, ECO:0000269|PubMed:15818573"
FT /id="VAR_022461"
FT VARIANT 137
FT /note="R -> Q (might influence susceptibility to breast
FT cancer; does not cause protein abrogation in familial
FT colorectal cancer; dbSNP:rs368570187)"
FT /evidence="ECO:0000269|PubMed:12454775,
FT ECO:0000269|PubMed:15818573"
FT /id="VAR_022462"
FT VARIANT 145
FT /note="R -> P (in prostate cancer; somatic mutation;
FT dbSNP:rs587781667)"
FT /evidence="ECO:0000269|PubMed:12533788"
FT /id="VAR_019108"
FT VARIANT 145
FT /note="R -> W (in colon cancer and LFS2; does not cause
FT protein abrogation in familial colorectal cancer; loss of
FT the ability to interact with and phosphorylate CDC25A and
FT to promote CDC25A degradation in response to ionizing
FT radiation; dbSNP:rs137853007)"
FT /evidence="ECO:0000269|PubMed:10617473,
FT ECO:0000269|PubMed:11298456, ECO:0000269|PubMed:11719428,
FT ECO:0000269|PubMed:12610780, ECO:0000269|PubMed:15535844,
FT ECO:0000269|PubMed:15818573"
FT /id="VAR_008554"
FT VARIANT 157
FT /note="I -> T (might influence susceptibility to different
FT types of cancer; does not cause protein abrogation in
FT familial colorectal cancer; loss of the ability to interact
FT with and phosphorylate CDC25A and to promote CDC25A
FT degradation in response to ionizing radiation;
FT dbSNP:rs17879961)"
FT /evidence="ECO:0000269|PubMed:10617473,
FT ECO:0000269|PubMed:11298456, ECO:0000269|PubMed:11461078,
FT ECO:0000269|PubMed:12533788, ECO:0000269|PubMed:12610780,
FT ECO:0000269|PubMed:14612911, ECO:0000269|PubMed:15087378,
FT ECO:0000269|PubMed:15095295, ECO:0000269|PubMed:15239132,
FT ECO:0000269|PubMed:15492928, ECO:0000269|PubMed:15535844,
FT ECO:0000269|PubMed:15810020, ECO:0000269|PubMed:15818573,
FT ECO:0000269|Ref.10"
FT /id="VAR_008555"
FT VARIANT 167
FT /note="G -> R (in prostate cancer; somatic mutation;
FT dbSNP:rs72552322)"
FT /evidence="ECO:0000269|PubMed:12533788"
FT /id="VAR_019109"
FT VARIANT 180
FT /note="R -> C (in prostate cancer; somatic mutation;
FT dbSNP:rs77130927)"
FT /evidence="ECO:0000269|PubMed:12533788,
FT ECO:0000269|PubMed:21618645"
FT /id="VAR_019103"
FT VARIANT 180
FT /note="R -> H (in prostate cancer; somatic mutation;
FT dbSNP:rs137853009)"
FT /evidence="ECO:0000269|PubMed:12454775,
FT ECO:0000269|PubMed:12533788, ECO:0000269|PubMed:15818573"
FT /id="VAR_019110"
FT VARIANT 181
FT /note="R -> C (in prostate cancer; somatic mutation;
FT dbSNP:rs137853010)"
FT /evidence="ECO:0000269|PubMed:12533788"
FT /id="VAR_019104"
FT VARIANT 181
FT /note="R -> H (in prostate cancer; somatic mutation;
FT dbSNP:rs121908701)"
FT /evidence="ECO:0000269|PubMed:12533788"
FT /id="VAR_019105"
FT VARIANT 239
FT /note="E -> K (in prostate cancer; germline mutation;
FT dbSNP:rs121908702)"
FT /evidence="ECO:0000269|PubMed:12533788"
FT /id="VAR_019106"
FT VARIANT 251
FT /note="I -> F (in prostate cancer; unknown pathological
FT significance; dbSNP:rs587780189)"
FT /evidence="ECO:0000269|PubMed:12533788"
FT /id="VAR_019111"
FT VARIANT 318
FT /note="R -> H (in prostate cancer; unknown pathological
FT significance; somatic mutation; dbSNP:rs143611747)"
FT /evidence="ECO:0000269|PubMed:12533788"
FT /id="VAR_019112"
FT VARIANT 323
FT /note="T -> P (in prostate cancer; somatic mutation;
FT dbSNP:rs750984976)"
FT /evidence="ECO:0000269|PubMed:12533788"
FT /id="VAR_019113"
FT VARIANT 327
FT /note="Y -> C (in prostate cancer; unknown pathological
FT significance; somatic mutation; dbSNP:rs587780194)"
FT /evidence="ECO:0000269|PubMed:12533788"
FT /id="VAR_019114"
FT VARIANT 347
FT /note="D -> N (in dbSNP:rs28909980)"
FT /id="VAR_029154"
FT VARIANT 371
FT /note="H -> Y (confers a moderate risk of breast cancer;
FT partially reduces kinase activity; dbSNP:rs531398630)"
FT /evidence="ECO:0000269|PubMed:21618645"
FT /id="VAR_066012"
FT VARIANT 390
FT /note="Y -> C (in BC; does not phosphorylate p53/TP53;
FT dbSNP:rs200928781)"
FT /evidence="ECO:0000269|PubMed:25619829"
FT /id="VAR_073020"
FT VARIANT 406
FT /note="R -> H (in dbSNP:rs200649225)"
FT /id="VAR_024572"
FT VARIANT 428
FT /note="S -> F (may increase breast cancer risk;
FT dbSNP:rs137853011)"
FT /evidence="ECO:0000269|PubMed:15649950"
FT /id="VAR_022463"
FT VARIANT 436
FT /note="L -> M (in dbSNP:rs17882922)"
FT /evidence="ECO:0000269|Ref.10"
FT /id="VAR_021117"
FT VARIANT 446
FT /note="N -> K (in dbSNP:rs17880867)"
FT /evidence="ECO:0000269|Ref.10"
FT /id="VAR_021118"
FT VARIANT 447
FT /note="F -> I (in dbSNP:rs17881473)"
FT /evidence="ECO:0000269|Ref.10"
FT /id="VAR_021119"
FT VARIANT 448
FT /note="I -> S (in dbSNP:rs17886163)"
FT /evidence="ECO:0000269|Ref.10"
FT /id="VAR_021120"
FT VARIANT 476
FT /note="T -> K (in prostate cancer; somatic mutation)"
FT /evidence="ECO:0000269|PubMed:12533788"
FT /id="VAR_019115"
FT VARIANT 500
FT /note="S -> C (in dbSNP:rs28909981)"
FT /id="VAR_029155"
FT VARIANT 501
FT /note="E -> K (in dbSNP:rs17883172)"
FT /evidence="ECO:0000269|Ref.10"
FT /id="VAR_021121"
FT VARIANT 512
FT /note="L -> V (in dbSNP:rs17882942)"
FT /evidence="ECO:0000269|Ref.10"
FT /id="VAR_021122"
FT MUTAGEN 68
FT /note="T->A: Loss of activation and phosphorylation."
FT /evidence="ECO:0000269|PubMed:11901158,
FT ECO:0000269|PubMed:15342622"
FT MUTAGEN 73
FT /note="S->A: Impaired activation, phosphorylation by ATM
FT and G2/M transition checkpoint."
FT /evidence="ECO:0000269|PubMed:16481012"
FT MUTAGEN 347
FT /note="D->A: Loss of kinase activity and of the ability to
FT phosphorylate CDC25A."
FT /evidence="ECO:0000269|PubMed:11298456,
FT ECO:0000269|PubMed:9836640"
FT MUTAGEN 368
FT /note="D->N: Loss of autophosphorylation activity."
FT /evidence="ECO:0000269|PubMed:15342622"
FT MUTAGEN 379
FT /note="S->A: Abrogates autophosphorylation at Ser-379 and
FT prevents ubiquitination."
FT /evidence="ECO:0000269|PubMed:18644861"
FT MUTAGEN 383
FT /note="T->A: Loss of phosphorylation in response to
FT ionizing radiation."
FT /evidence="ECO:0000269|PubMed:11390408"
FT MUTAGEN 387
FT /note="T->A: Loss of phosphorylation in response to
FT ionizing radiation."
FT /evidence="ECO:0000269|PubMed:11390408"
FT MUTAGEN 456
FT /note="S->A: Increased ubiquitination and degradation by
FT the proteasome."
FT /evidence="ECO:0000269|PubMed:17715138"
FT STRAND 94..98
FT /evidence="ECO:0007829|PDB:1GXC"
FT STRAND 100..103
FT /evidence="ECO:0007829|PDB:3I6U"
FT STRAND 106..108
FT /evidence="ECO:0007829|PDB:1GXC"
FT STRAND 110..118
FT /evidence="ECO:0007829|PDB:1GXC"
FT STRAND 122..124
FT /evidence="ECO:0007829|PDB:1GXC"
FT HELIX 128..132
FT /evidence="ECO:0007829|PDB:1GXC"
FT HELIX 135..138
FT /evidence="ECO:0007829|PDB:1GXC"
FT STRAND 144..150
FT /evidence="ECO:0007829|PDB:1GXC"
FT STRAND 154..162
FT /evidence="ECO:0007829|PDB:1GXC"
FT STRAND 168..170
FT /evidence="ECO:0007829|PDB:1GXC"
FT STRAND 180..182
FT /evidence="ECO:0007829|PDB:1GXC"
FT STRAND 187..193
FT /evidence="ECO:0007829|PDB:1GXC"
FT STRAND 197..203
FT /evidence="ECO:0007829|PDB:1GXC"
FT HELIX 209..211
FT /evidence="ECO:0007829|PDB:3I6U"
FT HELIX 214..219
FT /evidence="ECO:0007829|PDB:2YCF"
FT STRAND 220..228
FT /evidence="ECO:0007829|PDB:2YCF"
FT STRAND 230..239
FT /evidence="ECO:0007829|PDB:2YCF"
FT TURN 240..243
FT /evidence="ECO:0007829|PDB:2YCF"
FT STRAND 244..251
FT /evidence="ECO:0007829|PDB:2YCF"
FT HELIX 253..256
FT /evidence="ECO:0007829|PDB:3I6U"
FT HELIX 270..279
FT /evidence="ECO:0007829|PDB:2YCF"
FT STRAND 288..302
FT /evidence="ECO:0007829|PDB:2YCF"
FT STRAND 307..309
FT /evidence="ECO:0007829|PDB:4BDD"
FT HELIX 310..313
FT /evidence="ECO:0007829|PDB:2YCF"
FT HELIX 314..316
FT /evidence="ECO:0007829|PDB:2W7X"
FT HELIX 321..340
FT /evidence="ECO:0007829|PDB:2YCF"
FT HELIX 350..352
FT /evidence="ECO:0007829|PDB:2YCF"
FT STRAND 353..361
FT /evidence="ECO:0007829|PDB:2YCF"
FT STRAND 364..366
FT /evidence="ECO:0007829|PDB:2YCF"
FT HELIX 369..371
FT /evidence="ECO:0007829|PDB:4BDE"
FT HELIX 379..385
FT /evidence="ECO:0007829|PDB:2YCF"
FT HELIX 388..390
FT /evidence="ECO:0007829|PDB:2WTJ"
FT HELIX 393..398
FT /evidence="ECO:0007829|PDB:2YCF"
FT TURN 399..403
FT /evidence="ECO:0007829|PDB:2YCF"
FT HELIX 407..422
FT /evidence="ECO:0007829|PDB:2YCF"
FT STRAND 429..431
FT /evidence="ECO:0007829|PDB:2CN5"
FT HELIX 436..442
FT /evidence="ECO:0007829|PDB:2YCF"
FT HELIX 449..452
FT /evidence="ECO:0007829|PDB:2YCF"
FT HELIX 457..466
FT /evidence="ECO:0007829|PDB:2YCF"
FT TURN 471..473
FT /evidence="ECO:0007829|PDB:2YCF"
FT HELIX 477..481
FT /evidence="ECO:0007829|PDB:2YCF"
FT HELIX 484..486
FT /evidence="ECO:0007829|PDB:2YCF"
FT HELIX 489..502
FT /evidence="ECO:0007829|PDB:2YCF"
FT TURN 504..506
FT /evidence="ECO:0007829|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
