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 27-MAR-2024, entry version 248. 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 TPDS4 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 SER-17 AND LEU-85, AND INVOLVEMENT IN OSRC. 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; O15355: PPM1G; NbExp=2; IntAct=EBI-1180783, EBI-725702; CC O96017; Q15172: PPP2R5A; NbExp=3; 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: Tumor predisposition syndrome 4 (TPDS4) [MIM:609265]: A CC disorder characterized by an increased risk for developing various CC types of benign and/or malignant neoplasms that arise at an accelerated CC rate and in different organs. {ECO:0000269|PubMed:11719428}. Note=The CC disease is caused by variants affecting the gene represented in this CC 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. CC {ECO:0000269|PubMed:11746983}. Note=The gene represented in this entry CC 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="https://atlasgeneticsoncology.org/gene/312/CHEK2"; 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. 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; 247. DR CORUM; O96017; -. DR DIP; DIP-24270N; -. DR ELM; O96017; -. DR IntAct; O96017; 136. 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 CPTAC; CPTAC-5892; -. DR CPTAC; CPTAC-5893; -. DR CPTAC; CPTAC-5894; -. DR EPD; O96017; -. DR jPOST; O96017; -. DR MassIVE; O96017; -. DR MaxQB; O96017; -. DR PaxDb; 9606-ENSP00000372023; -. DR PeptideAtlas; 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 Pumba; O96017; -. DR ABCD; O96017; 1 sequenced antibody. DR Antibodypedia; 278; 2290 antibodies from 49 providers. DR CPTC; O96017; 2 antibodies. DR DNASU; 11200; -. DR Ensembl; ENST00000348295.7; ENSP00000329012.5; ENSG00000183765.24. [O96017-12] DR Ensembl; ENST00000382580.6; ENSP00000372023.2; ENSG00000183765.24. [O96017-9] DR Ensembl; ENST00000403642.5; ENSP00000384919.1; ENSG00000183765.24. [O96017-4] DR Ensembl; ENST00000404276.6; ENSP00000385747.1; ENSG00000183765.24. [O96017-1] DR Ensembl; ENST00000405598.5; ENSP00000386087.1; ENSG00000183765.24. [O96017-1] DR Ensembl; ENST00000417588.5; ENSP00000412901.1; ENSG00000183765.24. [O96017-5] DR Ensembl; ENST00000425190.7; ENSP00000390244.2; ENSG00000183765.24. [O96017-13] DR Ensembl; ENST00000433728.5; ENSP00000404400.1; ENSG00000183765.24. [O96017-8] DR Ensembl; ENST00000439346.6; ENSP00000396903.2; ENSG00000183765.24. [O96017-5] DR Ensembl; ENST00000448511.5; ENSP00000404567.1; ENSG00000183765.24. [O96017-6] DR Ensembl; ENST00000649563.1; ENSP00000496928.1; ENSG00000183765.24. [O96017-13] DR Ensembl; ENST00000650281.1; ENSP00000497000.1; ENSG00000183765.24. [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 AGR; HGNC:16627; -. 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. DR MIM; 609265; phenotype. DR neXtProt; NX_O96017; -. DR OpenTargets; ENSG00000183765; -. DR Orphanet; 440437; Familial colorectal cancer Type X. DR Orphanet; 1331; Familial prostate cancer. DR Orphanet; 145; Hereditary breast and/or 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; 20430at2759; -. 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 1201 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 primordial germ cell in gonad and 107 other cell types or tissues. DR ExpressionAtlas; O96017; baseline and differential. 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:0071480; P:cellular response to gamma radiation; IEA:Ensembl. DR GO; GO:0000077; P:DNA damage checkpoint signaling; TAS:UniProtKB. DR GO; GO:0006974; P:DNA damage response; IDA:MGI. 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:0045893; P:positive regulation of DNA-templated transcription; 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:0006355; P:regulation of DNA-templated transcription; 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:0090399; P:replicative senescence; NAS:BHF-UCL. 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; cd22666; FHA_CHK2; 1. DR CDD; cd14084; STKc_Chk2; 1. DR DisProt; DP01797; -. DR Gene3D; 2.60.200.20; -; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. 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 PANTHER; PTHR44167; OVARIAN-SPECIFIC SERINE/THREONINE-PROTEIN KINASE LOK-RELATED; 1. DR PANTHER; PTHR44167:SF9; SERINE_THREONINE-PROTEIN KINASE CHK2; 1. DR Pfam; PF00498; FHA; 1. DR Pfam; PF00069; Pkinase; 1. DR SMART; SM00240; FHA; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR SUPFAM; SSF49879; SMAD/FHA domain; 1. DR PROSITE; PS50006; FHA_DOMAIN; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. DR Genevisible; O96017; HS. 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 (found in an osteogenic sarcoma sample; FT somatic mutation; might influence susceptibility to breast FT cancer; does not cause protein abrogation in familial FT colorectal 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 (found in an osteogenic sarcoma sample; FT somatic mutation; 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 TPDS4; loss of the ability to interact FT with and phosphorylate CDC25A and to promote CDC25A FT degradation in response to ionizing radiation; FT 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; uncertain significance; FT dbSNP:rs587780189)" FT /evidence="ECO:0000269|PubMed:12533788" FT /id="VAR_019111" FT VARIANT 318 FT /note="R -> H (in prostate cancer; uncertain significance; FT 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; uncertain significance; FT 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 //