CDK12_HUMAN
ID CDK12_HUMAN Reviewed; 1490 AA.
AC Q9NYV4; A7E2B2; B4DYX4; B9EIQ6; O94978;
DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
DT 05-OCT-2010, sequence version 2.
DT 03-AUG-2022, entry version 198.
DE RecName: Full=Cyclin-dependent kinase 12;
DE EC=2.7.11.22;
DE EC=2.7.11.23 {ECO:0000305|PubMed:20952539};
DE AltName: Full=Cdc2-related kinase, arginine/serine-rich;
DE Short=CrkRS;
DE AltName: Full=Cell division cycle 2-related protein kinase 7;
DE Short=CDC2-related protein kinase 7;
DE AltName: Full=Cell division protein kinase 12;
DE Short=hCDK12;
GN Name=CDK12; Synonyms=CRK7, CRKRS, KIAA0904;
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), TISSUE SPECIFICITY, SUBCELLULAR
RP LOCATION, AND FUNCTION.
RX PubMed=11683387; DOI=10.1242/jcs.114.14.2591;
RA Ko T.K., Kelly E., Pines J.;
RT "CrkRS: a novel conserved Cdc2-related protein kinase that colocalises with
RT SC35 speckles.";
RL J. Cell Sci. 114:2591-2603(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain;
RX PubMed=10048485; DOI=10.1093/dnares/5.6.355;
RA Nagase T., Ishikawa K., Suyama M., Kikuno R., Hirosawa M., Miyajima N.,
RA Tanaka A., Kotani H., Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XII. The
RT complete sequences of 100 new cDNA clones from brain which code for large
RT proteins in vitro.";
RL DNA Res. 5:355-364(1998).
RN [3]
RP SEQUENCE REVISION.
RX PubMed=12168954; DOI=10.1093/dnares/9.3.99;
RA Nakajima D., Okazaki N., Yamakawa H., Kikuno R., Ohara O., Nagase T.;
RT "Construction of expression-ready cDNA clones for KIAA genes: manual
RT curation of 330 KIAA cDNA clones.";
RL DNA Res. 9:99-106(2002).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Testis;
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S.,
RA Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E.,
RA Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K.,
RA LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J.,
RA Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A.,
RA Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K.,
RA Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in the
RT human lineage.";
RL Nature 440:1045-1049(2006).
RN [6]
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
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 [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-681 AND SER-685, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT networks.";
RL Cell 127:635-648(2006).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein phosphorylation
RT analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-57; TYR-73; SER-400; SER-423;
RP THR-514; SER-681; SER-685 AND THR-692, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-249; SER-301; SER-303;
RP SER-318; SER-323; SER-325; SER-332; SER-333; SER-334; SER-345; SER-383;
RP SER-385; SER-400; SER-681; SER-685 AND THR-692, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [13]
RP FUNCTION.
RX PubMed=19651820; DOI=10.1093/carcin/bgp187;
RA Iorns E., Martens-de Kemp S.R., Lord C.J., Ashworth A.;
RT "CRK7 modifies the MAPK pathway and influences the response to endocrine
RT therapy.";
RL Carcinogenesis 30:1696-1701(2009).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-420; SER-423; SER-681;
RP SER-685; THR-692 AND SER-1053, AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-236; SER-383; SER-385;
RP SER-681; SER-685 AND THR-1244, AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [16]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=20952539; DOI=10.1101/gad.1968210;
RA Bartkowiak B., Liu P., Phatnani H.P., Fuda N.J., Cooper J.J., Price D.H.,
RA Adelman K., Lis J.T., Greenleaf A.L.;
RT "CDK12 is a transcription elongation-associated CTD kinase, the metazoan
RT ortholog of yeast Ctk1.";
RL Genes Dev. 24:2303-2316(2010).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-236; SER-249; SER-385;
RP SER-400; SER-423; SER-681; SER-685; THR-893 AND SER-1083, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [18]
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 [19]
RP CHROMOSOMAL REARRANGEMENT WITH ERBB2, AND POSSIBLE INVOLVEMENT IN GASTRIC
RP CANCER.
RX PubMed=21097718; DOI=10.1158/0008-5472.can-10-1749;
RA Zang Z.J., Ong C.K., Cutcutache I., Yu W., Zhang S.L., Huang D., Ler L.D.,
RA Dykema K., Gan A., Tao J., Lim S., Liu Y., Futreal P.A., Grabsch H.,
RA Furge K.A., Goh L.K., Rozen S., Teh B.T., Tan P.;
RT "Genetic and structural variation in the gastric cancer kinome revealed
RT through targeted deep sequencing.";
RL Cancer Res. 71:29-39(2011).
RN [20]
RP FUNCTION, SUBUNIT, AND SUBCELLULAR LOCATION.
RX PubMed=22012619; DOI=10.1101/gad.16962311;
RA Blazek D., Kohoutek J., Bartholomeeusen K., Johansen E., Hulinkova P.,
RA Luo Z., Cimermancic P., Ule J., Peterlin B.M.;
RT "The Cyclin K/Cdk12 complex maintains genomic stability via regulation of
RT expression of DNA damage response genes.";
RL Genes Dev. 25:2158-2172(2011).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-236; SER-249; SER-274;
RP SER-276; SER-301; SER-303; SER-310; SER-312; SER-332; SER-333; SER-334;
RP SER-338; SER-423; SER-681; SER-685; THR-893 AND SER-1083, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-236; SER-249; SER-265;
RP SER-274; SER-276; SER-318; SER-323; SER-325; SER-332; SER-333; SER-334;
RP SER-341; SER-343; SER-345; SER-423; THR-514; SER-614; SER-681; THR-692;
RP SER-889; THR-893; SER-1053 AND SER-1083, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-423; SER-681 AND SER-685, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [24]
RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-263; LYS-509 AND LYS-655, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=28112733; DOI=10.1038/nsmb.3366;
RA Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C.,
RA Nielsen M.L.;
RT "Site-specific mapping of the human SUMO proteome reveals co-modification
RT with phosphorylation.";
RL Nat. Struct. Mol. Biol. 24:325-336(2017).
RN [25]
RP X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF 714-1063 IN COMPLEX WITH THE ATP
RP ANALOG ADP; TRANSITION STATE ANALOG AND CCNK, FUNCTION, CATALYTIC ACTIVITY,
RP SUBUNIT, INTERACTION WITH CCNK, PHOSPHORYLATION AT THR-893, IDENTIFICATION
RP BY MASS SPECTROMETRY, MUTAGENESIS OF ASP-877, AND ACTIVITY REGULATION.
RX PubMed=24662513; DOI=10.1038/ncomms4505;
RA Boesken C.A., Farnung L., Hintermair C., Merzel Schachter M.,
RA Vogel-Bachmayr K., Blazek D., Anand K., Fisher R.P., Eick D., Geyer M.;
RT "The structure and substrate specificity of human Cdk12/Cyclin K.";
RL Nat. Commun. 5:3505-3505(2014).
RN [26]
RP VARIANTS [LARGE SCALE ANALYSIS] ALA-530; HIS-912; GLN-1189 AND LEU-1275.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Cyclin-dependent kinase that phosphorylates the C-terminal
CC domain (CTD) of the large subunit of RNA polymerase II (POLR2A),
CC thereby acting as a key regulator of transcription elongation.
CC Regulates the expression of genes involved in DNA repair and is
CC required for the maintenance of genomic stability. Preferentially
CC phosphorylates 'Ser-5' in CTD repeats that are already phosphorylated
CC at 'Ser-7', but can also phosphorylate 'Ser-2'. Required for RNA
CC splicing, possibly by phosphorylating SRSF1/SF2. Involved in regulation
CC of MAP kinase activity, possibly leading to affect the response to
CC estrogen inhibitors. {ECO:0000269|PubMed:11683387,
CC ECO:0000269|PubMed:19651820, ECO:0000269|PubMed:20952539,
CC ECO:0000269|PubMed:22012619, ECO:0000269|PubMed:24662513}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=[DNA-directed RNA polymerase] + ATP = ADP + H(+) + phospho-
CC [DNA-directed RNA polymerase]; Xref=Rhea:RHEA:10216, Rhea:RHEA-
CC COMP:11321, Rhea:RHEA-COMP:11322, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:43176, ChEBI:CHEBI:68546,
CC ChEBI:CHEBI:456216; EC=2.7.11.23;
CC Evidence={ECO:0000305|PubMed:20952539};
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=2.7.11.22;
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=2.7.11.22;
CC -!- ACTIVITY REGULATION: Inhibited by the ATP analog flavopiridol,
CC purvalanol A, purvalanol B, staurosporine and CR8.
CC {ECO:0000269|PubMed:24662513}.
CC -!- SUBUNIT: Interacts with CCNL1 and CCNL2 (By similarity). Interacts with
CC CCNK. {ECO:0000250, ECO:0000269|PubMed:22012619,
CC ECO:0000269|PubMed:24662513}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:11683387}. Nucleus
CC speckle {ECO:0000269|PubMed:11683387}. Note=Colocalized with nuclear
CC speckles throughout interphase. {ECO:0000269|PubMed:11683387}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q9NYV4-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9NYV4-2; Sequence=VSP_030284;
CC Name=3;
CC IsoId=Q9NYV4-3; Sequence=VSP_040908, VSP_040909, VSP_040910;
CC -!- TISSUE SPECIFICITY: Widely expressed. {ECO:0000269|PubMed:11683387}.
CC -!- PTM: Phosphorylation at Thr-893 increases kinase activity.
CC {ECO:0000269|PubMed:24662513}.
CC -!- DISEASE: Note=Chromosomal aberrations involving CDK12 may be a cause
CC gastric cancer. Deletions within 17q12 region producing fusion
CC transcripts with ERBB2, leading to CDK12-ERBB2 fusion leading to
CC trunctated CDK12 protein not in-frame with ERBB2.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr
CC protein kinase family. CDC2/CDKX subfamily. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA74927.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AF227198; AAF36401.1; -; mRNA.
DR EMBL; AB020711; BAA74927.2; ALT_INIT; mRNA.
DR EMBL; AK302645; BAG63886.1; -; mRNA.
DR EMBL; AC009283; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471152; EAW60577.1; -; Genomic_DNA.
DR EMBL; BC140854; AAI40855.1; -; mRNA.
DR EMBL; BC150265; AAI50266.1; -; mRNA.
DR CCDS; CCDS11337.1; -. [Q9NYV4-1]
DR CCDS; CCDS45666.1; -. [Q9NYV4-2]
DR RefSeq; NP_055898.1; NM_015083.2. [Q9NYV4-2]
DR RefSeq; NP_057591.2; NM_016507.3. [Q9NYV4-1]
DR PDB; 4CXA; X-ray; 3.15 A; A/C=715-1052.
DR PDB; 4NST; X-ray; 2.20 A; A/C=714-1063.
DR PDB; 4UN0; X-ray; 3.15 A; C/D=715-1038.
DR PDB; 5ACB; X-ray; 2.70 A; C/D=715-1052.
DR PDB; 6B3E; X-ray; 3.06 A; A/C=717-1036.
DR PDB; 6CKX; X-ray; 2.80 A; A/C=714-1063.
DR PDB; 6TD3; X-ray; 3.46 A; B/E/H=712-1051.
DR PDB; 7NXK; X-ray; 3.00 A; A/C=714-1063.
DR PDBsum; 4CXA; -.
DR PDBsum; 4NST; -.
DR PDBsum; 4UN0; -.
DR PDBsum; 5ACB; -.
DR PDBsum; 6B3E; -.
DR PDBsum; 6CKX; -.
DR PDBsum; 6TD3; -.
DR PDBsum; 7NXK; -.
DR AlphaFoldDB; Q9NYV4; -.
DR SMR; Q9NYV4; -.
DR BioGRID; 119715; 217.
DR ComplexPortal; CPX-241; Cyclin K-CDK12 complex.
DR CORUM; Q9NYV4; -.
DR DIP; DIP-39768N; -.
DR IntAct; Q9NYV4; 32.
DR MINT; Q9NYV4; -.
DR STRING; 9606.ENSP00000398880; -.
DR BindingDB; Q9NYV4; -.
DR ChEMBL; CHEMBL3559692; -.
DR GuidetoPHARMACOLOGY; 1965; -.
DR CarbonylDB; Q9NYV4; -.
DR GlyConnect; 2877; 1 O-Linked glycan (2 sites).
DR GlyGen; Q9NYV4; 6 sites, 1 O-linked glycan (6 sites).
DR iPTMnet; Q9NYV4; -.
DR PhosphoSitePlus; Q9NYV4; -.
DR BioMuta; CDK12; -.
DR DMDM; 308153421; -.
DR EPD; Q9NYV4; -.
DR jPOST; Q9NYV4; -.
DR MassIVE; Q9NYV4; -.
DR MaxQB; Q9NYV4; -.
DR PaxDb; Q9NYV4; -.
DR PeptideAtlas; Q9NYV4; -.
DR PRIDE; Q9NYV4; -.
DR ProteomicsDB; 83279; -. [Q9NYV4-1]
DR ProteomicsDB; 83280; -. [Q9NYV4-2]
DR ProteomicsDB; 83281; -. [Q9NYV4-3]
DR Antibodypedia; 2096; 244 antibodies from 32 providers.
DR DNASU; 51755; -.
DR Ensembl; ENST00000430627.6; ENSP00000407720.2; ENSG00000167258.15. [Q9NYV4-2]
DR Ensembl; ENST00000447079.6; ENSP00000398880.4; ENSG00000167258.15. [Q9NYV4-1]
DR GeneID; 51755; -.
DR KEGG; hsa:51755; -.
DR MANE-Select; ENST00000447079.6; ENSP00000398880.4; NM_016507.4; NP_057591.2.
DR UCSC; uc002hrw.6; human. [Q9NYV4-1]
DR CTD; 51755; -.
DR DisGeNET; 51755; -.
DR GeneCards; CDK12; -.
DR HGNC; HGNC:24224; CDK12.
DR HPA; ENSG00000167258; Low tissue specificity.
DR MIM; 615514; gene.
DR neXtProt; NX_Q9NYV4; -.
DR OpenTargets; ENSG00000167258; -.
DR PharmGKB; PA165431656; -.
DR VEuPathDB; HostDB:ENSG00000167258; -.
DR eggNOG; KOG0600; Eukaryota.
DR GeneTree; ENSGT00940000157595; -.
DR InParanoid; Q9NYV4; -.
DR OMA; STKHNRE; -.
DR OrthoDB; 925637at2759; -.
DR PhylomeDB; Q9NYV4; -.
DR TreeFam; TF101060; -.
DR BRENDA; 2.7.11.22; 2681.
DR BRENDA; 2.7.11.23; 2681.
DR PathwayCommons; Q9NYV4; -.
DR Reactome; R-HSA-6796648; TP53 Regulates Transcription of DNA Repair Genes.
DR SignaLink; Q9NYV4; -.
DR SIGNOR; Q9NYV4; -.
DR BioGRID-ORCS; 51755; 318 hits in 1118 CRISPR screens.
DR ChiTaRS; CDK12; human.
DR GeneWiki; CRKRS; -.
DR GenomeRNAi; 51755; -.
DR Pharos; Q9NYV4; Tchem.
DR PRO; PR:Q9NYV4; -.
DR Proteomes; UP000005640; Chromosome 17.
DR RNAct; Q9NYV4; protein.
DR Bgee; ENSG00000167258; Expressed in buccal mucosa cell and 173 other tissues.
DR ExpressionAtlas; Q9NYV4; baseline and differential.
DR Genevisible; Q9NYV4; HS.
DR GO; GO:0002944; C:cyclin K-CDK12 complex; IPI:MGI.
DR GO; GO:0000307; C:cyclin-dependent protein kinase holoenzyme complex; IBA:GO_Central.
DR GO; GO:0008024; C:cyclin/CDK positive transcription elongation factor complex; IBA:GO_Central.
DR GO; GO:0019908; C:nuclear cyclin-dependent protein kinase holoenzyme complex; ISS:UniProtKB.
DR GO; GO:0016607; C:nuclear speck; IDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0030332; F:cyclin binding; IPI:MGI.
DR GO; GO:0004693; F:cyclin-dependent protein serine/threonine kinase activity; IBA:GO_Central.
DR GO; GO:0004672; F:protein kinase activity; IDA:HGNC-UCL.
DR GO; GO:0019901; F:protein kinase binding; IEA:Ensembl.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0008353; F:RNA polymerase II CTD heptapeptide repeat kinase activity; IMP:UniProtKB.
DR GO; GO:0006397; P:mRNA processing; IEA:UniProtKB-KW.
DR GO; GO:2000737; P:negative regulation of stem cell differentiation; IEA:Ensembl.
DR GO; GO:0070816; P:phosphorylation of RNA polymerase II C-terminal domain; IDA:ComplexPortal.
DR GO; GO:0032968; P:positive regulation of transcription elongation from RNA polymerase II promoter; IBA:GO_Central.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:HGNC-UCL.
DR GO; GO:0006468; P:protein phosphorylation; IBA:GO_Central.
DR GO; GO:0043405; P:regulation of MAP kinase activity; IMP:UniProtKB.
DR GO; GO:0043484; P:regulation of RNA splicing; IEA:Ensembl.
DR GO; GO:0008380; P:RNA splicing; ISS:UniProtKB.
DR GO; GO:0006368; P:transcription elongation from RNA polymerase II promoter; IBA:GO_Central.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 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; ATP-binding; Chromosomal rearrangement;
KW Isopeptide bond; Kinase; mRNA processing; mRNA splicing;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Transferase; Ubl conjugation.
FT CHAIN 1..1490
FT /note="Cyclin-dependent kinase 12"
FT /id="PRO_0000085715"
FT DOMAIN 727..1020
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1..703
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1047..1098
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1161..1189
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1220..1348
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1441..1460
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1466..1490
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 17..33
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 36..50
FT /note="Basic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 85..105
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 106..121
FT /note="Basic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 122..139
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 149..163
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 173..194
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 233..364
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 365..379
FT /note="Basic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 398..412
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 432..456
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 462..476
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 477..523
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 528..572
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 573..621
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 640..665
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 675..695
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1066..1081
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1220..1243
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1259..1284
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1333..1348
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 859
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 733..741
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT BINDING 756
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT BINDING 814..819
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT BINDING 1040
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT MOD_RES 57
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:18691976"
FT MOD_RES 73
FT /note="Phosphotyrosine"
FT /evidence="ECO:0007744|PubMed:18691976"
FT MOD_RES 236
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19690332,
FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 249
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 265
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 274
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21406692,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 276
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21406692,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 301
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:21406692"
FT MOD_RES 303
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:21406692"
FT MOD_RES 310
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21406692"
FT MOD_RES 312
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21406692"
FT MOD_RES 318
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 323
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 325
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 332
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"
FT MOD_RES 333
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"
FT MOD_RES 334
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"
FT MOD_RES 338
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21406692"
FT MOD_RES 341
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 343
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 345
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 383
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:19690332"
FT MOD_RES 385
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231"
FT MOD_RES 400
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:20068231"
FT MOD_RES 420
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19369195"
FT MOD_RES 423
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18691976,
FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163,
FT ECO:0007744|PubMed:24275569"
FT MOD_RES 514
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:18691976,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 614
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 644
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q3MJK5"
FT MOD_RES 681
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17081983,
FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:18691976,
FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:19690332,
FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692,
FT ECO:0007744|PubMed:23186163, ECO:0007744|PubMed:24275569"
FT MOD_RES 685
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17081983,
FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:18691976,
FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:19690332,
FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692,
FT ECO:0007744|PubMed:24275569"
FT MOD_RES 692
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:19369195,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 889
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 893
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:24662513,
FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 1053
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19369195,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 1083
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"
FT MOD_RES 1244
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:19690332"
FT MOD_RES 1246
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q14AX6"
FT CROSSLNK 263
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0007744|PubMed:28112733"
FT CROSSLNK 509
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0007744|PubMed:28112733"
FT CROSSLNK 655
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0007744|PubMed:28112733"
FT VAR_SEQ 349
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_040908"
FT VAR_SEQ 1205..1274
FT /note="DMQNILAVLLSQLMKTQEPAGSLEENNSDKNSGPQGPRRTPTMPQEEAAACP
FT PHILPPEKRPPEPPGPPP -> ILWYMQRPNCKTMGSWGQEPLGPAAQEQAFTGGAQLS
FT LLLMENSIGGLQESHQEGEEGEEFLTNPETSVS (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_040909"
FT VAR_SEQ 1254..1262
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:10048485,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_030284"
FT VAR_SEQ 1275..1490
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_040910"
FT VARIANT 530
FT /note="P -> A (in dbSNP:rs56121596)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041968"
FT VARIANT 912
FT /note="R -> H (in a colorectal adenocarcinoma sample;
FT somatic mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041969"
FT VARIANT 1189
FT /note="L -> Q (in dbSNP:rs56362165)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041970"
FT VARIANT 1275
FT /note="P -> L (in dbSNP:rs34070318)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041971"
FT MUTAGEN 877
FT /note="D->N: Abolishes kinase activity."
FT /evidence="ECO:0000269|PubMed:24662513"
FT CONFLICT 133
FT /note="S -> G (in Ref. 4; BAG63886)"
FT /evidence="ECO:0000305"
FT CONFLICT 268
FT /note="S -> G (in Ref. 4; BAG63886)"
FT /evidence="ECO:0000305"
FT CONFLICT 639
FT /note="D -> G (in Ref. 1; AAF36401)"
FT /evidence="ECO:0000305"
FT CONFLICT 737
FT /note="T -> I (in Ref. 4; BAG63886)"
FT /evidence="ECO:0000305"
FT CONFLICT 745
FT /note="K -> R (in Ref. 1; AAF36401)"
FT /evidence="ECO:0000305"
FT CONFLICT 822
FT /note="G -> V (in Ref. 4; BAG63886)"
FT /evidence="ECO:0000305"
FT CONFLICT 1195
FT /note="T -> M (in Ref. 1; AAF36401, 2; BAA74927 and 6;
FT AAI50266)"
FT /evidence="ECO:0000305"
FT HELIX 724..726
FT /evidence="ECO:0007829|PDB:4NST"
FT STRAND 727..735
FT /evidence="ECO:0007829|PDB:4NST"
FT STRAND 737..746
FT /evidence="ECO:0007829|PDB:4NST"
FT TURN 747..749
FT /evidence="ECO:0007829|PDB:4NST"
FT STRAND 752..758
FT /evidence="ECO:0007829|PDB:4NST"
FT STRAND 761..763
FT /evidence="ECO:0007829|PDB:5ACB"
FT STRAND 764..767
FT /evidence="ECO:0007829|PDB:6CKX"
FT HELIX 769..778
FT /evidence="ECO:0007829|PDB:4NST"
FT STRAND 789..794
FT /evidence="ECO:0007829|PDB:4NST"
FT TURN 802..804
FT /evidence="ECO:0007829|PDB:5ACB"
FT STRAND 809..814
FT /evidence="ECO:0007829|PDB:4NST"
FT STRAND 817..819
FT /evidence="ECO:0007829|PDB:4NST"
FT HELIX 820..826
FT /evidence="ECO:0007829|PDB:4NST"
FT HELIX 833..852
FT /evidence="ECO:0007829|PDB:4NST"
FT HELIX 862..864
FT /evidence="ECO:0007829|PDB:4NST"
FT STRAND 865..867
FT /evidence="ECO:0007829|PDB:4NST"
FT STRAND 873..875
FT /evidence="ECO:0007829|PDB:4NST"
FT HELIX 878..880
FT /evidence="ECO:0007829|PDB:6TD3"
FT STRAND 886..888
FT /evidence="ECO:0007829|PDB:4NST"
FT HELIX 899..901
FT /evidence="ECO:0007829|PDB:4NST"
FT HELIX 904..907
FT /evidence="ECO:0007829|PDB:4NST"
FT HELIX 916..931
FT /evidence="ECO:0007829|PDB:4NST"
FT HELIX 941..952
FT /evidence="ECO:0007829|PDB:4NST"
FT TURN 957..959
FT /evidence="ECO:0007829|PDB:4NST"
FT HELIX 961..965
FT /evidence="ECO:0007829|PDB:4NST"
FT TURN 967..971
FT /evidence="ECO:0007829|PDB:4NST"
FT HELIX 982..985
FT /evidence="ECO:0007829|PDB:4NST"
FT TURN 986..988
FT /evidence="ECO:0007829|PDB:4NST"
FT HELIX 991..1000
FT /evidence="ECO:0007829|PDB:4NST"
FT TURN 1005..1007
FT /evidence="ECO:0007829|PDB:4NST"
FT HELIX 1011..1014
FT /evidence="ECO:0007829|PDB:4NST"
FT HELIX 1018..1021
FT /evidence="ECO:0007829|PDB:4NST"
FT HELIX 1025..1027
FT /evidence="ECO:0007829|PDB:4NST"
FT STRAND 1035..1037
FT /evidence="ECO:0007829|PDB:4NST"
FT HELIX 1041..1045
FT /evidence="ECO:0007829|PDB:4NST"
SQ SEQUENCE 1490 AA; 164155 MW; D6B04B998ECDE58E CRC64;
MPNSERHGGK KDGSGGASGT LQPSSGGGSS NSRERHRLVS KHKRHKSKHS KDMGLVTPEA
ASLGTVIKPL VEYDDISSDS DTFSDDMAFK LDRRENDERR GSDRSDRLHK HRHHQHRRSR
DLLKAKQTEK EKSQEVSSKS GSMKDRISGS SKRSNEETDD YGKAQVAKSS SKESRSSKLH
KEKTRKEREL KSGHKDRSKS HRKRETPKSY KTVDSPKRRS RSPHRKWSDS SKQDDSPSGA
SYGQDYDLSP SRSHTSSNYD SYKKSPGSTS RRQSVSPPYK EPSAYQSSTR SPSPYSRRQR
SVSPYSRRRS SSYERSGSYS GRSPSPYGRR RSSSPFLSKR SLSRSPLPSR KSMKSRSRSP
AYSRHSSSHS KKKRSSSRSR HSSISPVRLP LNSSLGAELS RKKKERAAAA AAAKMDGKES
KGSPVFLPRK ENSSVEAKDS GLESKKLPRS VKLEKSAPDT ELVNVTHLNT EVKNSSDTGK
VKLDENSEKH LVKDLKAQGT RDSKPIALKE EIVTPKETET SEKETPPPLP TIASPPPPLP
TTTPPPQTPP LPPLPPIPAL PQQPPLPPSQ PAFSQVPASS TSTLPPSTHS KTSAVSSQAN
SQPPVQVSVK TQVSVTAAIP HLKTSTLPPL PLPPLLPGDD DMDSPKETLP SKPVKKEKEQ
RTRHLLTDLP LPPELPGGDL SPPDSPEPKA ITPPQQPYKK RPKICCPRYG ERRQTESDWG
KRCVDKFDII GIIGEGTYGQ VYKAKDKDTG ELVALKKVRL DNEKEGFPIT AIREIKILRQ
LIHRSVVNMK EIVTDKQDAL DFKKDKGAFY LVFEYMDHDL MGLLESGLVH FSEDHIKSFM
KQLMEGLEYC HKKNFLHRDI KCSNILLNNS GQIKLADFGL ARLYNSEESR PYTNKVITLW
YRPPELLLGE ERYTPAIDVW SCGCILGELF TKKPIFQANL ELAQLELISR LCGSPCPAVW
PDVIKLPYFN TMKPKKQYRR RLREEFSFIP SAALDLLDHM LTLDPSKRCT AEQTLQSDFL
KDVELSKMAP PDLPHWQDCH ELWSKKRRRQ RQSGVVVEEP PPSKTSRKET TSGTSTEPVK
NSSPAPPQPA PGKVESGAGD AIGLADITQQ LNQSELAVLL NLLQSQTDLS IPQMAQLLNI
HSNPEMQQQL EALNQSISAL TEATSQQQDS ETMAPEESLK EAPSAPVILP SAEQTTLEAS
STPADMQNIL AVLLSQLMKT QEPAGSLEEN NSDKNSGPQG PRRTPTMPQE EAAACPPHIL
PPEKRPPEPP GPPPPPPPPP LVEGDLSSAP QELNPAVTAA LLQLLSQPEA EPPGHLPHEH
QALRPMEYST RPRPNRTYGN TDGPETGFSA IDTDERNSGP ALTESLVQTL VKNRTFSGSL
SHLGESSSYQ GTGSVQFPGD QDLRFARVPL ALHPVVGQPF LKAEGSSNSV VHAETKLQNY
GELGPGTTGA SSSGAGLHWG GPTQSSAYGK LYRGPTRVPP RGGRGRGVPY
