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 04-MAR-2015, entry version 138. DE RecName: Full=Cyclin-dependent kinase 12; DE EC=2.7.11.22; DE EC=2.7.11.23; 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; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, RP SUBCELLULAR LOCATION, AND FUNCTION. RX PubMed=11683387; RA Ko T.K., Kelly E., Pines J.; RT "CrkRS: a novel conserved Cdc2-related protein kinase that colocalises RT with 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., RA Miyajima N., Tanaka A., Kotani H., Nomura N., Ohara O.; RT "Prediction of the coding sequences of unidentified human genes. XII. RT The complete sequences of 100 new cDNA clones from brain which code RT for large 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., RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [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., RA Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N., RA Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B., RA Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J., RA Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E., RA Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J., RA Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C., RA 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 RT the 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., RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R., RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., RA Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [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 RT project: 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., RA Mann M.; RT "Global, in vivo, and site-specific phosphorylation dynamics in RT signaling 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 RT phosphorylation 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; RP SER-423; THR-514; SER-681; SER-685 AND THR-692, AND IDENTIFICATION BY RP MASS 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 RT the 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; RP SER-383; SER-385; SER-400; SER-681; SER-685 AND THR-692, AND RP IDENTIFICATION BY MASS 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., RA Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in RT a 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 RT endocrine 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., RA Price D.H., Adelman K., Lis J.T., Greenleaf A.L.; RT "CDK12 is a transcription elongation-associated CTD kinase, the RT metazoan 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., RA Mann M.; RT "Quantitative phosphoproteomics reveals widespread full RT phosphorylation 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., RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [19] RP CHROMOSOMAL REARRANGEMENT WITH ERBB2, AND POSSIBLE INVOLVEMENT IN RP GASTRIC 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., RA Ler L.D., Dykema K., Gan A., Tao J., Lim S., Liu Y., Futreal P.A., RA Grabsch H., Furge K.A., Goh L.K., Rozen S., Teh B.T., Tan P.; RT "Genetic and structural variation in the gastric cancer kinome RT revealed 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 RT of 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; RP SER-334; 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., RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., RA Blagoev B.; RT "System-wide temporal characterization of the proteome and RT phosphoproteome of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [22] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-423; SER-681 AND RP SER-685, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP 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., RA Wang L., Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human RT liver phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [23] RP X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF 714-1063 IN COMPLEX WITH THE RP ATP ANALOG ADP; TRANSITION STATE ANALOG AND CCNK, FUNCTION, CATALYTIC RP ACTIVITY, SUBUNIT, INTERACTION WITH CCNK, PHOSPHORYLATION AT THR-893, RP IDENTIFICATION BY MASS SPECTROMETRY, MUTAGENESIS OF ASP-877, AND RP ENZYME 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., RA Geyer M.; RT "The structure and substrate specificity of human Cdk12/Cyclin K."; RL Nat. Commun. 5:3505-3505(2014). RN [24] RP VARIANTS [LARGE SCALE ANALYSIS] ALA-530; HIS-912; GLN-1189 AND RP LEU-1275. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E., RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., RA Yuen S.T., Leung S.Y., Wooster R., 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- CC terminal domain (CTD) of the large subunit of RNA polymerase II CC (POLR2A), thereby acting as a key regulator of transcription CC elongation. Regulates the expression of genes involved in DNA CC repair and is required for the maintenance of genomic stability. CC Preferentially phosphorylates 'Ser-5' in CTD repeats that are CC already phosphorylated at 'Ser-7', but can also phosphorylate CC 'Ser-2'. Required for RNA splicing, possibly by phosphorylating CC SRSF1/SF2. Involved in regulation of MAP kinase activity, possibly CC leading to affect the response to estrogen inhibitors. CC {ECO:0000269|PubMed:11683387, ECO:0000269|PubMed:19651820, CC ECO:0000269|PubMed:20952539, ECO:0000269|PubMed:22012619, CC ECO:0000269|PubMed:24662513}. CC -!- CATALYTIC ACTIVITY: ATP + [DNA-directed RNA polymerase] = ADP + CC [DNA-directed RNA polymerase] phosphate. CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. CC -!- ENZYME 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 CC with CCNK. {ECO:0000250, ECO:0000269|PubMed:22012619, CC ECO:0000269|PubMed:24662513}. CC -!- SUBCELLULAR LOCATION: Nucleus. Nucleus speckle. Note=Colocalized CC with nuclear speckles throughout interphase. 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 Note=No experimental confirmation available.; CC -!- TISSUE SPECIFICITY: Ubiquitously expressed. CC {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 CC cause gastric cancer. Deletions within 17q12 region producing CC fusion transcripts with ERBB2, leading to CDK12-ERBB2 fusion CC leading to trunctated CDK12 protein not in-frame with ERBB2. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC CC Ser/Thr protein kinase family. CDC2/CDKX subfamily. {ECO:0000305}. CC -!- SIMILARITY: Contains 1 protein kinase domain. CC {ECO:0000255|PROSITE-ProRule:PRU00159}. CC -!- SEQUENCE CAUTION: CC Sequence=BAA74927.2; Type=Erroneous initiation; Note=Translation N-terminally shortened.; Evidence={ECO:0000305}; 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; 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 UniGene; Hs.416108; -. 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 PDBsum; 4CXA; -. DR PDBsum; 4NST; -. DR PDBsum; 4UN0; -. DR ProteinModelPortal; Q9NYV4; -. DR SMR; Q9NYV4; 680-1048. DR BioGrid; 119715; 24. DR IntAct; Q9NYV4; 6. DR MINT; MINT-1191969; -. DR STRING; 9606.ENSP00000398880; -. DR PhosphoSite; Q9NYV4; -. DR DMDM; 308153421; -. DR MaxQB; Q9NYV4; -. DR PaxDb; Q9NYV4; -. DR PRIDE; Q9NYV4; -. DR DNASU; 51755; -. DR Ensembl; ENST00000430627; ENSP00000407720; ENSG00000167258. [Q9NYV4-2] DR Ensembl; ENST00000447079; ENSP00000398880; ENSG00000167258. [Q9NYV4-1] DR GeneID; 51755; -. DR KEGG; hsa:51755; -. DR UCSC; uc002hrw.4; human. [Q9NYV4-2] DR UCSC; uc010cvv.3; human. [Q9NYV4-1] DR CTD; 51755; -. DR GeneCards; GC17P037618; -. DR H-InvDB; HIX0013777; -. DR HGNC; HGNC:24224; CDK12. DR HPA; HPA008038; -. DR MIM; 615514; gene. DR neXtProt; NX_Q9NYV4; -. DR PharmGKB; PA165431656; -. DR eggNOG; COG0515; -. DR GeneTree; ENSGT00770000120511; -. DR HOGENOM; HOG000049118; -. DR HOVERGEN; HBG050852; -. DR InParanoid; Q9NYV4; -. DR KO; K08819; -. DR OMA; YSTRSHP; -. DR PhylomeDB; Q9NYV4; -. DR TreeFam; TF101060; -. DR BRENDA; 2.7.11.22; 2681. DR SignaLink; Q9NYV4; -. DR ChiTaRS; CDK12; human. DR GeneWiki; CRKRS; -. DR GenomeRNAi; 51755; -. DR NextBio; 55858; -. DR PRO; PR:Q9NYV4; -. DR Proteomes; UP000005640; Chromosome 17. DR Bgee; Q9NYV4; -. DR CleanEx; HS_CRKRS; -. DR ExpressionAtlas; Q9NYV4; baseline and differential. DR Genevestigator; Q9NYV4; -. DR GO; GO:0002944; C:cyclin K-CDK12 complex; IPI:MGI. 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:0005730; C:nucleolus; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:HPA. 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; IEA:UniProtKB-EC. DR GO; GO:0004672; F:protein kinase activity; IDA:HGNC. DR GO; GO:0008353; F:RNA polymerase II carboxy-terminal domain kinase activity; IMP:UniProtKB. DR GO; GO:0006397; P:mRNA processing; IEA:UniProtKB-KW. DR GO; GO:0070816; P:phosphorylation of RNA polymerase II C-terminal domain; IMP:UniProtKB. DR GO; GO:0046777; P:protein autophosphorylation; IDA:HGNC. DR GO; GO:0043405; P:regulation of MAP kinase activity; IMP:UniProtKB. DR GO; GO:0008380; P:RNA splicing; ISS:UniProtKB. DR InterPro; IPR011009; Kinase-like_dom. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR002290; Ser/Thr_dual-sp_kinase. 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; KW Chromosomal rearrangement; Complete proteome; Kinase; mRNA processing; KW mRNA splicing; Nucleotide-binding; Nucleus; Phosphoprotein; KW Polymorphism; Reference proteome; Serine/threonine-protein kinase; KW Transferase. FT CHAIN 1 1490 Cyclin-dependent kinase 12. FT /FTId=PRO_0000085715. FT DOMAIN 727 1020 Protein kinase. {ECO:0000255|PROSITE- FT ProRule:PRU00159}. FT NP_BIND 733 741 ATP. FT NP_BIND 814 819 ATP. FT COMPBIAS 407 413 Poly-Ala. FT COMPBIAS 535 540 Poly-Pro. FT COMPBIAS 1266 1280 Poly-Pro. FT ACT_SITE 859 859 Proton acceptor. {ECO:0000255|PROSITE- FT ProRule:PRU00159, ECO:0000255|PROSITE- FT ProRule:PRU10027}. FT BINDING 756 756 ATP. FT BINDING 1040 1040 ATP. FT MOD_RES 57 57 Phosphothreonine. FT {ECO:0000269|PubMed:18691976}. FT MOD_RES 73 73 Phosphotyrosine. FT {ECO:0000269|PubMed:18691976}. FT MOD_RES 236 236 Phosphoserine. FT {ECO:0000269|PubMed:19690332, FT ECO:0000269|PubMed:20068231, FT ECO:0000269|PubMed:21406692}. FT MOD_RES 249 249 Phosphoserine. FT {ECO:0000269|PubMed:18669648, FT ECO:0000269|PubMed:20068231, FT ECO:0000269|PubMed:21406692}. FT MOD_RES 274 274 Phosphoserine. FT {ECO:0000269|PubMed:21406692}. FT MOD_RES 276 276 Phosphoserine. FT {ECO:0000269|PubMed:21406692}. FT MOD_RES 301 301 Phosphoserine. FT {ECO:0000269|PubMed:18669648, FT ECO:0000269|PubMed:21406692}. FT MOD_RES 303 303 Phosphoserine. FT {ECO:0000269|PubMed:18669648, FT ECO:0000269|PubMed:21406692}. FT MOD_RES 310 310 Phosphoserine. FT {ECO:0000269|PubMed:21406692}. FT MOD_RES 312 312 Phosphoserine. FT {ECO:0000269|PubMed:21406692}. FT MOD_RES 318 318 Phosphoserine. FT {ECO:0000269|PubMed:18669648}. FT MOD_RES 323 323 Phosphoserine. FT {ECO:0000269|PubMed:18669648}. FT MOD_RES 325 325 Phosphoserine. FT {ECO:0000269|PubMed:18669648}. FT MOD_RES 332 332 Phosphoserine. FT {ECO:0000269|PubMed:18669648, FT ECO:0000269|PubMed:21406692}. FT MOD_RES 333 333 Phosphoserine. FT {ECO:0000269|PubMed:18669648, FT ECO:0000269|PubMed:21406692}. FT MOD_RES 334 334 Phosphoserine. FT {ECO:0000269|PubMed:18669648, FT ECO:0000269|PubMed:21406692}. FT MOD_RES 338 338 Phosphoserine. FT {ECO:0000269|PubMed:21406692}. FT MOD_RES 345 345 Phosphoserine. FT {ECO:0000269|PubMed:18669648}. FT MOD_RES 383 383 Phosphoserine. FT {ECO:0000269|PubMed:18669648, FT ECO:0000269|PubMed:19690332}. FT MOD_RES 385 385 Phosphoserine. FT {ECO:0000269|PubMed:18669648, FT ECO:0000269|PubMed:19690332, FT ECO:0000269|PubMed:20068231}. FT MOD_RES 400 400 Phosphoserine. FT {ECO:0000269|PubMed:18669648, FT ECO:0000269|PubMed:18691976, FT ECO:0000269|PubMed:20068231}. FT MOD_RES 420 420 Phosphoserine. FT {ECO:0000269|PubMed:19369195}. FT MOD_RES 423 423 Phosphoserine. FT {ECO:0000269|PubMed:18691976, FT ECO:0000269|PubMed:19369195, FT ECO:0000269|PubMed:20068231, FT ECO:0000269|PubMed:21406692, FT ECO:0000269|PubMed:24275569}. FT MOD_RES 514 514 Phosphothreonine. FT {ECO:0000269|PubMed:18691976}. FT MOD_RES 681 681 Phosphoserine. FT {ECO:0000269|PubMed:17081983, FT ECO:0000269|PubMed:18669648, FT ECO:0000269|PubMed:18691976, FT ECO:0000269|PubMed:19369195, FT ECO:0000269|PubMed:19690332, FT ECO:0000269|PubMed:20068231, FT ECO:0000269|PubMed:21406692, FT ECO:0000269|PubMed:24275569}. FT MOD_RES 685 685 Phosphoserine. FT {ECO:0000269|PubMed:17081983, FT ECO:0000269|PubMed:18669648, FT ECO:0000269|PubMed:18691976, FT ECO:0000269|PubMed:19369195, FT ECO:0000269|PubMed:19690332, FT ECO:0000269|PubMed:20068231, FT ECO:0000269|PubMed:21406692, FT ECO:0000269|PubMed:24275569}. FT MOD_RES 692 692 Phosphothreonine. FT {ECO:0000269|PubMed:18669648, FT ECO:0000269|PubMed:18691976, FT ECO:0000269|PubMed:19369195}. FT MOD_RES 893 893 Phosphothreonine. FT {ECO:0000269|PubMed:20068231, FT ECO:0000269|PubMed:21406692, FT ECO:0000269|PubMed:24662513}. FT MOD_RES 1053 1053 Phosphoserine. FT {ECO:0000269|PubMed:19369195}. FT MOD_RES 1083 1083 Phosphoserine. FT {ECO:0000269|PubMed:20068231, FT ECO:0000269|PubMed:21406692}. FT MOD_RES 1244 1244 Phosphothreonine. FT {ECO:0000269|PubMed:19690332}. FT VAR_SEQ 349 349 Missing (in isoform 3). FT {ECO:0000303|PubMed:14702039}. FT /FTId=VSP_040908. FT VAR_SEQ 1205 1274 DMQNILAVLLSQLMKTQEPAGSLEENNSDKNSGPQGPRRTP FT TMPQEEAAACPPHILPPEKRPPEPPGPPP -> ILWYMQRP FT NCKTMGSWGQEPLGPAAQEQAFTGGAQLSLLLMENSIGGLQ FT ESHQEGEEGEEFLTNPETSVS (in isoform 3). FT {ECO:0000303|PubMed:14702039}. FT /FTId=VSP_040909. FT VAR_SEQ 1254 1262 Missing (in isoform 2). FT {ECO:0000303|PubMed:10048485, FT ECO:0000303|PubMed:15489334}. FT /FTId=VSP_030284. FT VAR_SEQ 1275 1490 Missing (in isoform 3). FT {ECO:0000303|PubMed:14702039}. FT /FTId=VSP_040910. FT VARIANT 530 530 P -> A (in dbSNP:rs56121596). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_041968. FT VARIANT 912 912 R -> H (in a colorectal adenocarcinoma FT sample; somatic mutation). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_041969. FT VARIANT 1189 1189 L -> Q (in dbSNP:rs56362165). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_041970. FT VARIANT 1275 1275 P -> L (in dbSNP:rs34070318). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_041971. FT MUTAGEN 877 877 D->N: Abolishes kinase activity. FT {ECO:0000269|PubMed:24662513}. FT CONFLICT 133 133 S -> G (in Ref. 4; BAG63886). FT {ECO:0000305}. FT CONFLICT 268 268 S -> G (in Ref. 4; BAG63886). FT {ECO:0000305}. FT CONFLICT 639 639 D -> G (in Ref. 1; AAF36401). FT {ECO:0000305}. FT CONFLICT 737 737 T -> I (in Ref. 4; BAG63886). FT {ECO:0000305}. FT CONFLICT 745 745 K -> R (in Ref. 1; AAF36401). FT {ECO:0000305}. FT CONFLICT 822 822 G -> V (in Ref. 4; BAG63886). FT {ECO:0000305}. FT CONFLICT 1195 1195 T -> M (in Ref. 1; AAF36401, 2; BAA74927 FT and 6; AAI50266). {ECO:0000305}. FT HELIX 724 726 {ECO:0000244|PDB:4NST}. FT STRAND 727 735 {ECO:0000244|PDB:4NST}. FT STRAND 737 746 {ECO:0000244|PDB:4NST}. FT TURN 747 749 {ECO:0000244|PDB:4NST}. FT STRAND 752 758 {ECO:0000244|PDB:4NST}. FT STRAND 762 764 {ECO:0000244|PDB:4CXA}. FT HELIX 769 778 {ECO:0000244|PDB:4NST}. FT STRAND 789 794 {ECO:0000244|PDB:4NST}. FT STRAND 802 804 {ECO:0000244|PDB:4CXA}. FT STRAND 809 814 {ECO:0000244|PDB:4NST}. FT STRAND 817 819 {ECO:0000244|PDB:4NST}. FT HELIX 820 826 {ECO:0000244|PDB:4NST}. FT HELIX 833 852 {ECO:0000244|PDB:4NST}. FT HELIX 862 864 {ECO:0000244|PDB:4NST}. FT STRAND 865 867 {ECO:0000244|PDB:4NST}. FT STRAND 873 875 {ECO:0000244|PDB:4NST}. FT STRAND 886 888 {ECO:0000244|PDB:4NST}. FT HELIX 899 901 {ECO:0000244|PDB:4NST}. FT HELIX 904 907 {ECO:0000244|PDB:4NST}. FT HELIX 916 931 {ECO:0000244|PDB:4NST}. FT HELIX 941 952 {ECO:0000244|PDB:4NST}. FT TURN 957 959 {ECO:0000244|PDB:4NST}. FT HELIX 961 965 {ECO:0000244|PDB:4NST}. FT TURN 967 971 {ECO:0000244|PDB:4NST}. FT HELIX 982 985 {ECO:0000244|PDB:4NST}. FT TURN 986 988 {ECO:0000244|PDB:4NST}. FT HELIX 991 1000 {ECO:0000244|PDB:4NST}. FT TURN 1005 1007 {ECO:0000244|PDB:4NST}. FT HELIX 1011 1014 {ECO:0000244|PDB:4NST}. FT HELIX 1018 1021 {ECO:0000244|PDB:4NST}. FT HELIX 1025 1027 {ECO:0000244|PDB:4NST}. FT STRAND 1035 1037 {ECO:0000244|PDB:4NST}. FT HELIX 1041 1045 {ECO:0000244|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 //