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Cyclin-dependent kinase 9 (EC 2.7.11.22) (EC 2.7.11.23) (C-2K) (Cell division cycle 2-like protein kinase 4) (Cell division protein kinase 9) (Serine/threonine-protein kinase PITALRE) (Tat-associated kinase complex catalytic subunit)

 CDK9_HUMAN              Reviewed;         372 AA.
P50750; Q5JU24; Q5JU25; Q5U006; Q96TF1;
01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
21-JUN-2005, sequence version 3.
02-JUN-2021, entry version 231.
RecName: Full=Cyclin-dependent kinase 9;
EC=2.7.11.22 {ECO:0000269|PubMed:12037670, ECO:0000269|PubMed:20980437};
EC=2.7.11.23 {ECO:0000269|PubMed:21127351, ECO:0000269|PubMed:28426094};
AltName: Full=C-2K;
AltName: Full=Cell division cycle 2-like protein kinase 4;
AltName: Full=Cell division protein kinase 9;
AltName: Full=Serine/threonine-protein kinase PITALRE;
AltName: Full=Tat-associated kinase complex catalytic subunit;
Name=CDK9; Synonyms=CDC2L4, TAK;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
PubMed=8170997; DOI=10.1073/pnas.91.9.3834;
Grana X., de Luca A., Sang N., Fu Y., Claudio P.P., Rosenblatt J.,
Morgan D.O., Giordano A.;
"PITALRE, a nuclear CDC2-related protein kinase that phosphorylates the
retinoblastoma protein in vitro.";
Proc. Natl. Acad. Sci. U.S.A. 91:3834-3838(1994).
[2]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT ALA-231.
PubMed=7695608; DOI=10.1006/bbrc.1995.1375;
Best J.L., Presky D.H., Swerlick R.A., Burns D.K., Chu W.;
"Cloning of a full-length cDNA sequence encoding a cdc2-related protein
kinase from human endothelial cells.";
Biochem. Biophys. Res. Commun. 208:562-568(1995).
[3]
NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ALA-231.
PubMed=10903437; DOI=10.1016/s0378-1119(00)00215-8;
Liu H., Rice A.P.;
"Genomic organization and characterization of promoter function of the
human CDK9 gene.";
Gene 252:51-59(2000).
[4]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
Phelan M., Farmer A.;
"Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
[5]
NUCLEOTIDE SEQUENCE [GENOMIC DNA].
NIEHS SNPs program;
Submitted (JUN-2002) to the EMBL/GenBank/DDBJ databases.
[6]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
PubMed=15164053; DOI=10.1038/nature02465;
Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L.,
Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R.,
Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S.,
Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K.,
Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y.,
Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C.,
Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E.,
Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M.,
Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J.,
Frankish A., Frankland J.A., French L., Fricker D.G., Garner P.,
Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S.,
Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J.,
Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E.,
McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V.,
Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S.,
Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K.,
Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J.,
Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M.,
West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L.,
Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J.,
Dunham I.;
"DNA sequence and analysis of human chromosome 9.";
Nature 429:369-374(2004).
[7]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
TISSUE=Cervix;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA project:
the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[8]
INTERACTION WITH HIV TAT.
PubMed=9491887; DOI=10.1016/s0092-8674(00)80939-3;
Wei P., Garber M.E., Fang S.-M., Fischer W.H., Jones K.A.;
"A novel CDK9-associated C-type cyclin interacts directly with HIV-1 Tat
and mediates its high-affinity, loop-specific binding to TAR RNA.";
Cell 92:451-462(1998).
[9]
FUNCTION.
PubMed=9857195; DOI=10.1093/emboj/17.24.7395;
Wada T., Takagi T., Yamaguchi Y., Watanabe D., Handa H.;
"Evidence that P-TEFb alleviates the negative effect of DSIF on RNA
polymerase II-dependent transcription in vitro.";
EMBO J. 17:7395-7403(1998).
[10]
IDENTIFICATION IN A COMPLEX WITH CCNT1 AND CCNT2.
PubMed=9499409; DOI=10.1101/gad.12.5.755;
Peng J.-M., Zhu Y., Milton J.T., Price D.H.;
"Identification of multiple cyclin subunits of human P-TEFb.";
Genes Dev. 12:755-762(1998).
[11]
FUNCTION, AND IDENTIFICATION IN A COMPLEX WITH HTATSF1; CCNT1; RNA POL II;
SUPT5H AND NCL.
PubMed=10393184; DOI=10.1093/emboj/18.13.3688;
Parada C.A., Roeder R.G.;
"A novel RNA polymerase II-containing complex potentiates Tat-enhanced HIV-
1 transcription.";
EMBO J. 18:3688-3701(1999).
[12]
FUNCTION, AND INTERACTION WITH CCNK.
PubMed=10574912; DOI=10.1074/jbc.274.49.34527;
Fu T.J., Peng J., Lee G., Price D.H., Flores O.;
"Cyclin K functions as a CDK9 regulatory subunit and participates in RNA
polymerase II transcription.";
J. Biol. Chem. 274:34527-34530(1999).
[13]
FUNCTION.
PubMed=10912001; DOI=10.1016/s1097-2765(00)80272-5;
Wada T., Orphanides G., Hasegawa J., Kim D.-K., Shima D., Yamaguchi Y.,
Fukuda A., Hisatake K., Oh S., Reinberg D., Handa H.;
"FACT relieves DSIF/NELF-mediated inhibition of transcriptional elongation
and reveals functional differences between P-TEFb and TFIIH.";
Mol. Cell 5:1067-1072(2000).
[14]
FUNCTION.
PubMed=10757782; DOI=10.1128/mcb.20.9.2970-2983.2000;
Ivanov D., Kwak Y.T., Guo J., Gaynor R.B.;
"Domains in the SPT5 protein that modulate its transcriptional regulatory
properties.";
Mol. Cell. Biol. 20:2970-2983(2000).
[15]
PHOSPHORYLATION BY PKA, AUTOPHOSPHORYLATION, PHOSPHORYLATION AT SER-347;
THR-350; SER-353; THR-354 AND SER-357, INTERACTION WITH HIV TAT, AND
MUTAGENESIS OF 347-SER--SER-357 AND ASP-167.
PubMed=10958691; DOI=10.1128/mcb.20.18.6958-6969.2000;
Garber M.E., Mayall T.P., Suess E.M., Meisenhelder J., Thompson N.E.,
Jones K.A.;
"CDK9 autophosphorylation regulates high-affinity binding of the human
immunodeficiency virus type 1 tat-P-TEFb complex to TAR RNA.";
Mol. Cell. Biol. 20:6958-6969(2000).
[16]
FUNCTION, AND MUTAGENESIS OF ASP-167 AND THR-186.
PubMed=11145967; DOI=10.1074/jbc.m010908200;
Kim J.B., Sharp P.A.;
"Positive transcription elongation factor B phosphorylates hSPT5 and RNA
polymerase II carboxyl-terminal domain independently of cyclin-dependent
kinase-activating kinase.";
J. Biol. Chem. 276:12317-12323(2001).
[17]
FUNCTION.
PubMed=11112772; DOI=10.1074/jbc.m006130200;
Ping Y.-H., Rana T.M.;
"DSIF and NELF interact with RNA polymerase II elongation complex and HIV-1
Tat stimulates P-TEFb-mediated phosphorylation of RNA polymerase II and
DSIF during transcription elongation.";
J. Biol. Chem. 276:12951-12958(2001).
[18]
FUNCTION.
PubMed=11575923; DOI=10.1006/jmbi.2001.4991;
Lavoie S.B., Albert A.L., Handa H., Vincent M., Bensaude O.;
"The peptidyl-prolyl isomerase Pin1 interacts with hSpt5 phosphorylated by
Cdk9.";
J. Mol. Biol. 312:675-685(2001).
[19]
FUNCTION, AND INTERACTION WITH CCNK/CYCLIN K.
PubMed=11884399; DOI=10.1074/jbc.m200117200;
Lin X., Taube R., Fujinaga K., Peterlin B.M.;
"P-TEFb containing cyclin K and Cdk9 can activate transcription via RNA.";
J. Biol. Chem. 277:16873-16878(2002).
[20]
INTERACTION WITH AFF4.
PubMed=12065898; DOI=10.1159/000059424;
Estable M.C., Naghavi M.H., Kato H., Xiao H., Qin J., Vahlne A.,
Roeder R.G.;
"MCEF, the newest member of the AF4 family of transcription factors
involved in leukemia, is a positive transcription elongation factor-b-
associated protein.";
J. Biomed. Sci. 9:234-245(2002).
[21]
SUBCELLULAR LOCATION.
PubMed=12115727; DOI=10.1002/jcp.10130;
Napolitano G., Licciardo P., Carbone R., Majello B., Lania L.;
"CDK9 has the intrinsic property to shuttle between nucleus and cytoplasm,
and enhanced expression of cyclin T1 promotes its nuclear localization.";
J. Cell. Physiol. 192:209-215(2002).
[22]
FUNCTION.
PubMed=11809800; DOI=10.1128/mcb.22.4.1079-1093.2002;
Bourgeois C.F., Kim Y.K., Churcher M.J., West M.J., Karn J.;
"Spt5 cooperates with human immunodeficiency virus type 1 Tat by preventing
premature RNA release at terminator sequences.";
Mol. Cell. Biol. 22:1079-1093(2002).
[23]
FUNCTION AS MYOD1 KINASE, CATALYTIC ACTIVITY, AND INTERACTION WITH MYOD1
AND CCNT2.
PubMed=12037670; DOI=10.1038/sj.onc.1205493;
Simone C., Stiegler P., Bagella L., Pucci B., Bellan C., De Falco G.,
De Luca A., Guanti G., Puri P.L., Giordano A.;
"Activation of MyoD-dependent transcription by cdk9/cyclin T2.";
Oncogene 21:4137-4148(2002).
[24]
INTERACTION WITH SUPT5H.
PubMed=12718890; DOI=10.1016/s1097-2765(03)00101-1;
Kwak Y.T., Guo J., Prajapati S., Park K.-J., Surabhi R.M., Miller B.,
Gehrig P., Gaynor R.B.;
"Methylation of SPT5 regulates its interaction with RNA polymerase II and
transcriptional elongation properties.";
Mol. Cell 11:1055-1066(2003).
[25]
FUNCTION.
PubMed=15564463; DOI=10.1128/jvi.78.24.13522-13533.2004;
Zhou M., Deng L., Lacoste V., Park H.U., Pumfery A., Kashanchi F.,
Brady J.N., Kumar A.;
"Coordination of transcription factor phosphorylation and histone
methylation by the P-TEFb kinase during human immunodeficiency virus type 1
transcription.";
J. Virol. 78:13522-13533(2004).
[26]
FUNCTION.
PubMed=14701750; DOI=10.1128/mcb.24.2.787-795.2004;
Fujinaga K., Irwin D., Huang Y., Taube R., Kurosu T., Peterlin B.M.;
"Dynamics of human immunodeficiency virus transcription: P-TEFb
phosphorylates RD and dissociates negative effectors from the
transactivation response element.";
Mol. Cell. Biol. 24:787-795(2004).
[27]
IDENTIFICATION IN INACTIVE 7SK SNRNP COMPLEX, AND PHOSPHORYLATION AT
THR-186.
PubMed=15965233; DOI=10.1074/jbc.m502712200;
Li Q., Price J.P., Byers S.A., Cheng D., Peng J., Price D.H.;
"Analysis of the large inactive P-TEFb complex indicates that it contains
one 7SK molecule, a dimer of HEXIM1 or HEXIM2, and two P-TEFb molecules
containing Cdk9 phosphorylated at threonine 186.";
J. Biol. Chem. 280:28819-28826(2005).
[28]
FUNCTION, AND INTERACTION WITH BRD4.
PubMed=16109376; DOI=10.1016/j.molcel.2005.06.027;
Jang M.K., Mochizuki K., Zhou M., Jeong H.S., Brady J.N., Ozato K.;
"The bromodomain protein Brd4 is a positive regulatory component of P-TEFb
and stimulates RNA polymerase II-dependent transcription.";
Mol. Cell 19:523-534(2005).
[29]
FUNCTION, AND INTERACTION WITH BRD4.
PubMed=16109377; DOI=10.1016/j.molcel.2005.06.029;
Yang Z., Yik J.H., Chen R., He N., Jang M.K., Ozato K., Zhou Q.;
"Recruitment of P-TEFb for stimulation of transcriptional elongation by the
bromodomain protein Brd4.";
Mol. Cell 19:535-545(2005).
[30]
FUNCTION IN CYTOKINE SIGNALING, AND INTERACTION WITH STAT3.
PubMed=17956865; DOI=10.1074/jbc.m706458200;
Hou T., Ray S., Brasier A.R.;
"The functional role of an interleukin 6-inducible CDK9.STAT3 complex in
human gamma-fibrinogen gene expression.";
J. Biol. Chem. 282:37091-37102(2007).
[31]
IDENTIFICATION IN THE 7SK SNRNP COMPLEX.
PubMed=17643375; DOI=10.1016/j.molcel.2007.06.027;
Jeronimo C., Forget D., Bouchard A., Li Q., Chua G., Poitras C.,
Therien C., Bergeron D., Bourassa S., Greenblatt J., Chabot B.,
Poirier G.G., Hughes T.R., Blanchette M., Price D.H., Coulombe B.;
"Systematic analysis of the protein interaction network for the human
transcription machinery reveals the identity of the 7SK capping enzyme.";
Mol. Cell 27:262-274(2007).
[32]
ACETYLATION AT LYS-44, IDENTIFICATION IN COMPLEX WITH NCOR1; HEXIM1 AND
HDAC3, AND MUTAGENESIS OF LYS-44.
PubMed=17452463; DOI=10.1128/mcb.00857-06;
Fu J., Yoon H.-G., Qin J., Wong J.;
"Regulation of P-TEFb elongation complex activity by CDK9 acetylation.";
Mol. Cell. Biol. 27:4641-4651(2007).
[33]
PHOSPHORYLATION AT THR-186, DEPHOSPHORYLATION BY PPP1CA, P-TEFB/7SK SNRNP
COMPLEX, SUBUNIT, INTERACTION WITH BRD4, AND ACTIVITY REGULATION.
PubMed=18483222; DOI=10.1101/gad.1636008;
Chen R., Liu M., Li H., Xue Y., Ramey W.N., He N., Ai N., Luo H., Zhu Y.,
Zhou N., Zhou Q.;
"PP2B and PP1alpha cooperatively disrupt 7SK snRNP to release P-TEFb for
transcription in response to Ca2+ signaling.";
Genes Dev. 22:1356-1368(2008).
[34]
PHOSPHORYLATION AT THR-186, AND DEPHOSPHORYLATION BY PPM1A AND PPM1B.
PubMed=18829461; DOI=10.1074/jbc.m807495200;
Wang Y., Dow E.C., Liang Y.Y., Ramakrishnan R., Liu H., Sung T.L., Lin X.,
Rice A.P.;
"Phosphatase PPM1A regulates phosphorylation of Thr-186 in the Cdk9 T-
loop.";
J. Biol. Chem. 283:33578-33584(2008).
[35]
IDENTIFICATION IN COMPLEX WITH LARP7 IN 7SK SNRNP COMPLEX.
PubMed=18249148; DOI=10.1016/j.molcel.2008.01.003;
He N., Jahchan N.S., Hong E., Li Q., Bayfield M.A., Maraia R.J., Luo K.,
Zhou Q.;
"A La-related protein modulates 7SK snRNP integrity to suppress P-TEFb-
dependent transcriptional elongation and tumorigenesis.";
Mol. Cell 29:588-599(2008).
[36]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-347, PHOSPHORYLATION [LARGE
SCALE ANALYSIS] AT SER-35 (ISOFORM 2), AND IDENTIFICATION BY MASS
SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Cervix carcinoma;
PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
Greff Z., Keri G., Stemmann O., Mann M.;
"Kinase-selective enrichment enables quantitative phosphoproteomics of the
kinome across the cell cycle.";
Mol. Cell 31:438-448(2008).
[37]
ACETYLATION AT LYS-44 AND LYS-48 BY PCAF/KAT2B AND GCN5/KAT2A, ACTIVITY
REGULATION BY ACETYLATION, AND SUBCELLULAR LOCATION.
PubMed=18250157; DOI=10.1128/mcb.01557-07;
Sabo A., Lusic M., Cereseto A., Giacca M.;
"Acetylation of conserved lysines in the catalytic core of cyclin-dependent
kinase 9 inhibits kinase activity and regulates transcription.";
Mol. Cell. Biol. 28:2201-2212(2008).
[38]
FUNCTION IN CYTOKINE SIGNALING, AND INTERACTION WITH RELA/P65.
PubMed=18362169; DOI=10.1128/mcb.01152-07;
Nowak D.E., Tian B., Jamaluddin M., Boldogh I., Vergara L.A., Choudhary S.,
Brasier A.R.;
"RelA Ser276 phosphorylation is required for activation of a subset of NF-
kappaB-dependent genes by recruiting cyclin-dependent kinase 9/cyclin T1
complexes.";
Mol. Cell. Biol. 28:3623-3638(2008).
[39]
FUNCTION IN HISTONE REGULATION.
PubMed=19844166; DOI=10.4161/cc.8.22.9890;
Pirngruber J., Shchebet A., Johnsen S.A.;
"Insights into the function of the human P-TEFb component CDK9 in the
regulation of chromatin modifications and co-transcriptional mRNA
processing.";
Cell Cycle 8:3636-3642(2009).
[40]
FUNCTION IN HISTONE H2B UBIQUITINATION.
PubMed=19575011; DOI=10.1038/embor.2009.108;
Pirngruber J., Shchebet A., Schreiber L., Shema E., Minsky N.,
Chapman R.D., Eick D., Aylon Y., Oren M., Johnsen S.A.;
"CDK9 directs H2B monoubiquitination and controls replication-dependent
histone mRNA 3'-end processing.";
EMBO Rep. 10:894-900(2009).
[41]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-347 AND THR-350,
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-35 (ISOFORM 2), AND
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
Mann M., Daub H.;
"Large-scale proteomics analysis of the human kinome.";
Mol. Cell. Proteomics 8:1751-1764(2009).
[42]
FUNCTION IN DNA REPAIR, AND INTERACTION WITH KU70/XRCC6.
PubMed=20493174; DOI=10.1016/j.bbrc.2010.05.092;
Liu H., Herrmann C.H., Chiang K., Sung T.L., Moon S.H., Donehower L.A.,
Rice A.P.;
"55K isoform of CDK9 associates with Ku70 and is involved in DNA repair.";
Biochem. Biophys. Res. Commun. 397:245-250(2010).
[43]
FUNCTION IN CDK9/CYCLIN K COMPLEX DURING REPLICATION STRESS.
PubMed=20930849; DOI=10.1038/embor.2010.153;
Yu D.S., Zhao R., Hsu E.L., Cayer J., Ye F., Guo Y., Shyr Y., Cortez D.;
"Cyclin-dependent kinase 9-cyclin K functions in the replication stress
response.";
EMBO Rep. 11:876-882(2010).
[44]
FUNCTION IN CARDIAC HYPERTROPHY, AND IDENTIFICATION IN COMPLEX WITH
CCNT1/CYCLIN-T1; EP300 AND GATA4.
PubMed=20081228; DOI=10.1074/jbc.m109.070458;
Sunagawa Y., Morimoto T., Takaya T., Kaichi S., Wada H., Kawamura T.,
Fujita M., Shimatsu A., Kita T., Hasegawa K.;
"Cyclin-dependent kinase-9 is a component of the p300/GATA4 complex
required for phenylephrine-induced hypertrophy in cardiomyocytes.";
J. Biol. Chem. 285:9556-9568(2010).
[45]
IDENTIFICATION IN THE SEC COMPLEX.
PubMed=20471948; DOI=10.1016/j.molcel.2010.04.013;
He N., Liu M., Hsu J., Xue Y., Chou S., Burlingame A., Krogan N.J.,
Alber T., Zhou Q.;
"HIV-1 Tat and host AFF4 recruit two transcription elongation factors into
a bifunctional complex for coordinated activation of HIV-1 transcription.";
Mol. Cell 38:428-438(2010).
[46]
IDENTIFICATION IN THE SEC COMPLEX.
PubMed=20159561; DOI=10.1016/j.molcel.2010.01.026;
Lin C., Smith E.R., Takahashi H., Lai K.C., Martin-Brown S., Florens L.,
Washburn M.P., Conaway J.W., Conaway R.C., Shilatifard A.;
"AFF4, a component of the ELL/P-TEFb elongation complex and a shared
subunit of MLL chimeras, can link transcription elongation to leukemia.";
Mol. Cell 37:429-437(2010).
[47]
FUNCTION IN AR KINASE, CATALYTIC ACTIVITY, AND INTERACTION WITH AR.
PubMed=20980437; DOI=10.1210/me.2010-0238;
Gordon V., Bhadel S., Wunderlich W., Zhang J., Ficarro S.B., Mollah S.A.,
Shabanowitz J., Hunt D.F., Xenarios I., Hahn W.C., Conaway M., Carey M.F.,
Gioeli D.;
"CDK9 regulates AR promoter selectivity and cell growth through serine 81
phosphorylation.";
Mol. Endocrinol. 24:2267-2280(2010).
[48]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=21269460; DOI=10.1186/1752-0509-5-17;
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
Bennett K.L., Superti-Furga G., Colinge J.;
"Initial characterization of the human central proteome.";
BMC Syst. Biol. 5:17-17(2011).
[49]
IDENTIFICATION IN THE SEC COMPLEX.
PubMed=22195968; DOI=10.1016/j.molcel.2011.12.008;
Smith E.R., Lin C., Garrett A.S., Thornton J., Mohaghegh N., Hu D.,
Jackson J., Saraf A., Swanson S.K., Seidel C., Florens L., Washburn M.P.,
Eissenberg J.C., Shilatifard A.;
"The little elongation complex regulates small nuclear RNA transcription.";
Mol. Cell 44:954-965(2011).
[50]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-186, AND IDENTIFICATION BY
MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=21406692; DOI=10.1126/scisignal.2001570;
Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
"System-wide temporal characterization of the proteome and phosphoproteome
of human embryonic stem cell differentiation.";
Sci. Signal. 4:RS3-RS3(2011).
[51]
ACTIVITY REGULATION BY CDKI-71.
PubMed=21484792; DOI=10.1002/ijc.26127;
Liu X., Shi S., Lam F., Pepper C., Fischer P.M., Wang S.;
"CDKI-71, a novel CDK9 inhibitor, is preferentially cytotoxic to cancer
cells compared to flavopiridol.";
Int. J. Cancer 130:1216-1226(2012).
[52]
FUNCTION AS RPB1/POLR2A CTD KINASE, CATALYTIC ACTIVITY, POLYUBIQUITINATION
BY UBR5, AND INTERACTION WITH UBR5 AND TFIIS/TCEA1.
PubMed=21127351; DOI=10.1074/jbc.m110.176628;
Cojocaru M., Bouchard A., Cloutier P., Cooper J.J., Varzavand K.,
Price D.H., Coulombe B.;
"Transcription factor IIS cooperates with the E3 ligase UBR5 to
ubiquitinate the CDK9 subunit of the positive transcription elongation
factor B.";
J. Biol. Chem. 286:5012-5022(2011).
[53]
PHOSPHORYLATION AT THR-186, ACTIVITY REGULATION, DEGRADATION BY THE
PROTEASOME, AND MUTAGENESIS OF THR-186.
PubMed=21448926; DOI=10.1002/jcp.22760;
Ramakrishnan R., Rice A.P.;
"Cdk9 T-loop phosphorylation is regulated by the calcium signaling
pathway.";
J. Cell. Physiol. 227:609-617(2012).
[54]
PHOSPHORYLATION AT SER-175, DEPHOSPHORYLATION AT SER-175 BY PP1, AND
MUTAGENESIS OF SER-175.
PubMed=21533037; DOI=10.1371/journal.pone.0018985;
Ammosova T., Obukhov Y., Kotelkin A., Breuer D., Beullens M., Gordeuk V.R.,
Bollen M., Nekhai S.;
"Protein phosphatase-1 activates CDK9 by dephosphorylating Ser175.";
PLoS ONE 6:E18985-E18985(2011).
[55]
REVIEW ON NELF AND DSIF KINASE ACTIVITY.
PubMed=16885020; DOI=10.1016/j.molcel.2006.06.014;
Peterlin B.M., Price D.H.;
"Controlling the elongation phase of transcription with P-TEFb.";
Mol. Cell 23:297-305(2006).
[56]
REVIEW ON CYTOKINE SIGNALING.
PubMed=18728388; DOI=10.4161/cc.7.17.6594;
Brasier A.R.;
"Expanding role of cyclin dependent kinases in cytokine inducible gene
expression.";
Cell Cycle 7:2661-2666(2008).
[57]
REVIEW ON TRANSCRIPTION REGULATION, AND INHIBITORS.
PubMed=19029809; DOI=10.4161/cc.7.23.7122;
Romano G., Giordano A.;
"Role of the cyclin-dependent kinase 9-related pathway in mammalian gene
expression and human diseases.";
Cell Cycle 7:3664-3668(2008).
[58]
REVIEW ON TRANSCRIPTION REGULATION, AND INHIBITORS.
PubMed=18423896; DOI=10.1016/j.tips.2008.03.003;
Wang S., Fischer P.M.;
"Cyclin-dependent kinase 9: a key transcriptional regulator and potential
drug target in oncology, virology and cardiology.";
Trends Pharmacol. Sci. 29:302-313(2008).
[59]
ACTIVITY REGULATION, AND GENE FAMILY.
PubMed=19238148; DOI=10.1038/nrc2602;
Malumbres M., Barbacid M.;
"Cell cycle, CDKs and cancer: a changing paradigm.";
Nat. Rev. Cancer 9:153-166(2009).
[60]
REVIEW ON CARDIAC HYPERTROPHY, AND INHIBITORS.
PubMed=19757441; DOI=10.1002/med.20172;
Krystof V., Chamrad I., Jorda R., Kohoutek J.;
"Pharmacological targeting of CDK9 in cardiac hypertrophy.";
Med. Res. Rev. 30:646-666(2010).
[61]
REVIEW ON GENOME INTEGRITY MAINTENANCE.
PubMed=21200140; DOI=10.4161/cc.10.1.14364;
Yu D.S., Cortez D.;
"A role for cdk9-cyclin k in maintaining genome integrity.";
Cell Cycle 10:28-32(2011).
[62]
INTERACTION WITH HERPES SIMPLEX VIRUS 1 PROTEIN ICP22.
PubMed=23029222; DOI=10.1371/journal.pone.0045749;
Guo L., Wu W.J., Liu L.D., Wang L.C., Zhang Y., Wu L.Q., Guan Y., Li Q.H.;
"Herpes simplex virus 1 ICP22 inhibits the transcription of viral gene
promoters by binding to and blocking the recruitment of P-TEFb.";
PLoS ONE 7:E45749-E45749(2012).
[63]
INTERACTION WITH BRD4 AND JMJD6.
PubMed=24360279; DOI=10.1016/j.cell.2013.10.056;
Liu W., Ma Q., Wong K., Li W., Ohgi K., Zhang J., Aggarwal A.,
Rosenfeld M.G.;
"Brd4 and JMJD6-associated anti-pause enhancers in regulation of
transcriptional pause release.";
Cell 155:1581-1595(2013).
[64]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-347, PHOSPHORYLATION [LARGE
SCALE ANALYSIS] AT THR-54 (ISOFORM 2), AND IDENTIFICATION BY MASS
SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Liver;
PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
Ye M., Zou H.;
"An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
phosphoproteome.";
J. Proteomics 96:253-262(2014).
[65]
INTERACTION WITH HSF1.
PubMed=27189267; DOI=10.1038/srep26294;
Pan X.Y., Zhao W., Zeng X.Y., Lin J., Li M.M., Shen X.T., Liu S.W.;
"Heat shock factor 1 mediates latent HIV reactivation.";
Sci. Rep. 6:26294-26294(2016).
[66]
FUNCTION, CATALYTIC ACTIVITY, ACETYLATION AT LYS-48, DEACETYLATION BY
SIRT7, AND MUTAGENESIS OF LYS-48.
PubMed=28426094; DOI=10.1093/nar/gkx053;
Blank M.F., Chen S., Poetz F., Schnoelzer M., Voit R., Grummt I.;
"SIRT7-dependent deacetylation of CDK9 activates RNA polymerase II
transcription.";
Nucleic Acids Res. 45:2675-2686(2017).
[67]
X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 1-345 IN COMPLEX WITH HIV-1 TAT
AND CCNT1, AND PHOSPHORYLATION AT THR-186.
PubMed=20535204; DOI=10.1038/nature09131;
Tahirov T.H., Babayeva N.D., Varzavand K., Cooper J.J., Sedore S.C.,
Price D.H.;
"Crystal structure of HIV-1 Tat complexed with human P-TEFb.";
Nature 465:747-751(2010).
[68]
X-RAY CRYSTALLOGRAPHY (2.48 ANGSTROMS) OF 2-330 IN COMPLEX WITH INHIBITOR
FLAVOPIRIDOL; ATP AND CCNT1, PHOSPHORYLATION AT THR-186 SER-347; THR-362
AND THR-363, AUTOPHOSPHORYLATION, AND MUTAGENESIS OF THR-186.
PubMed=18566585; DOI=10.1038/emboj.2008.121;
Baumli S., Lolli G., Lowe E.D., Troiani S., Rusconi L., Bullock A.N.,
Debreczeni J.E., Knapp S., Johnson L.N.;
"The structure of P-TEFb (CDK9/cyclin T1), its complex with flavopiridol
and regulation by phosphorylation.";
EMBO J. 27:1907-1918(2008).
[69]
X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) OF 2-330 IN COMPLEX WITH INHIBITOR
DRB, AND PHOSPHORYLATION AT THR-186.
PubMed=20851342; DOI=10.1016/j.chembiol.2010.07.012;
Baumli S., Endicott J.A., Johnson L.N.;
"Halogen bonds form the basis for selective P-TEFb inhibition by DRB.";
Chem. Biol. 17:931-936(2010).
[70]
X-RAY CRYSTALLOGRAPHY (3.00 ANGSTROMS) OF 2-330 IN COMPLEX WITH CCNT1;
INHIBITORS ROSCOVITINE AND CR8, PHOSPHORYLATION AT THR-186, AND ACTIVITY
REGULATION.
PubMed=21779453; DOI=10.1177/1947601910369817;
Bettayeb K., Baunbaek D., Delehouze C., Loaec N., Hole A.J., Baumli S.,
Endicott J.A., Douc-Rasy S., Benard J., Oumata N., Galons H., Meijer L.;
"CDK inhibitors roscovitine and CR8 trigger Mcl-1 down-regulation and
apoptotic cell death in neuroblastoma cells.";
Genes Cancer 1:369-380(2010).
[71]
VARIANT [LARGE SCALE ANALYSIS] LEU-59.
PubMed=17344846; DOI=10.1038/nature05610;
Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
Futreal P.A., Stratton M.R.;
"Patterns of somatic mutation in human cancer genomes.";
Nature 446:153-158(2007).
[72]
VARIANT CYS-225.
PubMed=30237576; DOI=10.1038/s41436-018-0138-x;
Maddirevula S., Alzahrani F., Al-Owain M., Al Muhaizea M.A., Kayyali H.R.,
AlHashem A., Rahbeeni Z., Al-Otaibi M., Alzaidan H.I., Balobaid A.,
El Khashab H.Y., Bubshait D.K., Faden M., Yamani S.A., Dabbagh O.,
Al-Mureikhi M., Jasser A.A., Alsaif H.S., Alluhaydan I., Seidahmed M.Z.,
Alabbasi B.H., Almogarri I., Kurdi W., Akleh H., Qari A., Al Tala S.M.,
Alhomaidi S., Kentab A.Y., Salih M.A., Chedrawi A., Alameer S., Tabarki B.,
Shamseldin H.E., Patel N., Ibrahim N., Abdulwahab F., Samira M., Goljan E.,
Abouelhoda M., Meyer B.F., Hashem M., Shaheen R., AlShahwan S.,
Alfadhel M., Ben-Omran T., Al-Qattan M.M., Monies D., Alkuraya F.S.;
"Autozygome and high throughput confirmation of disease genes candidacy.";
Genet. Med. 21:736-742(2019).
-!- FUNCTION: Protein kinase involved in the regulation of transcription
(PubMed:10574912, PubMed:10757782, PubMed:11145967, PubMed:11575923,
PubMed:11809800, PubMed:11884399, PubMed:14701750, PubMed:16109376,
PubMed:16109377, PubMed:20930849, PubMed:28426094). Member of the
cyclin-dependent kinase pair (CDK9/cyclin-T) complex, also called
positive transcription elongation factor b (P-TEFb), which facilitates
the transition from abortive to productive elongation by
phosphorylating the CTD (C-terminal domain) of the large subunit of RNA
polymerase II (RNAP II) POLR2A, SUPT5H and RDBP (PubMed:10574912,
PubMed:10757782, PubMed:11145967, PubMed:11575923, PubMed:11809800,
PubMed:11884399, PubMed:14701750, PubMed:16109376, PubMed:16109377,
PubMed:20930849, PubMed:28426094). This complex is inactive when in the
7SK snRNP complex form (PubMed:10574912, PubMed:10757782,
PubMed:11145967, PubMed:11575923, PubMed:11809800, PubMed:11884399,
PubMed:14701750, PubMed:16109376, PubMed:16109377, PubMed:20930849,
PubMed:28426094). Phosphorylates EP300, MYOD1, RPB1/POLR2A and AR and
the negative elongation factors DSIF and NELF (PubMed:9857195,
PubMed:10912001, PubMed:11112772, PubMed:12037670, PubMed:20081228,
PubMed:20980437, PubMed:21127351). Regulates cytokine inducible
transcription networks by facilitating promoter recognition of target
transcription factors (e.g. TNF-inducible RELA/p65 activation and IL-6-
inducible STAT3 signaling) (PubMed:17956865, PubMed:18362169). Promotes
RNA synthesis in genetic programs for cell growth, differentiation and
viral pathogenesis (PubMed:10393184, PubMed:11112772). P-TEFb is also
involved in cotranscriptional histone modification, mRNA processing and
mRNA export (PubMed:15564463, PubMed:19575011, PubMed:19844166).
Modulates a complex network of chromatin modifications including
histone H2B monoubiquitination (H2Bub1), H3 lysine 4 trimethylation
(H3K4me3) and H3K36me3; integrates phosphorylation during transcription
with chromatin modifications to control co-transcriptional histone mRNA
processing (PubMed:15564463, PubMed:19575011, PubMed:19844166). The
CDK9/cyclin-K complex has also a kinase activity towards CTD of RNAP II
and can substitute for CDK9/cyclin-T P-TEFb in vitro (PubMed:21127351).
Replication stress response protein; the CDK9/cyclin-K complex is
required for genome integrity maintenance, by promoting cell cycle
recovery from replication arrest and limiting single-stranded DNA
amount in response to replication stress, thus reducing the breakdown
of stalled replication forks and avoiding DNA damage (PubMed:20493174).
In addition, probable function in DNA repair of isoform 2 via
interaction with KU70/XRCC6 (PubMed:20493174). Promotes cardiac myocyte
enlargement (PubMed:20081228). RPB1/POLR2A phosphorylation on 'Ser-2'
in CTD activates transcription (PubMed:21127351). AR phosphorylation
modulates AR transcription factor promoter selectivity and cell growth.
DSIF and NELF phosphorylation promotes transcription by inhibiting
their negative effect (PubMed:9857195, PubMed:10912001,
PubMed:11112772). The phosphorylation of MYOD1 enhances its
transcriptional activity and thus promotes muscle differentiation
(PubMed:12037670). {ECO:0000269|PubMed:10393184,
ECO:0000269|PubMed:10574912, ECO:0000269|PubMed:10757782,
ECO:0000269|PubMed:10912001, ECO:0000269|PubMed:11112772,
ECO:0000269|PubMed:11145967, ECO:0000269|PubMed:11575923,
ECO:0000269|PubMed:11809800, ECO:0000269|PubMed:11884399,
ECO:0000269|PubMed:12037670, ECO:0000269|PubMed:14701750,
ECO:0000269|PubMed:15564463, ECO:0000269|PubMed:16109376,
ECO:0000269|PubMed:16109377, ECO:0000269|PubMed:17956865,
ECO:0000269|PubMed:18362169, ECO:0000269|PubMed:19575011,
ECO:0000269|PubMed:19844166, ECO:0000269|PubMed:20081228,
ECO:0000269|PubMed:20493174, ECO:0000269|PubMed:20930849,
ECO:0000269|PubMed:20980437, ECO:0000269|PubMed:21127351,
ECO:0000269|PubMed:28426094, ECO:0000269|PubMed:9857195}.
-!- CATALYTIC ACTIVITY:
Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
[protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.22;
Evidence={ECO:0000269|PubMed:12037670, ECO:0000269|PubMed:20980437};
PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17990;
Evidence={ECO:0000269|PubMed:12037670, ECO:0000269|PubMed:20980437};
-!- CATALYTIC ACTIVITY:
Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
EC=2.7.11.22; Evidence={ECO:0000269|PubMed:12037670,
ECO:0000269|PubMed:20980437};
PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46609;
Evidence={ECO:0000269|PubMed:12037670, ECO:0000269|PubMed:20980437};
-!- CATALYTIC ACTIVITY:
Reaction=[DNA-directed RNA polymerase] + ATP = ADP + H(+) + phospho-
[DNA-directed RNA polymerase]; Xref=Rhea:RHEA:10216, Rhea:RHEA-
COMP:11321, Rhea:RHEA-COMP:11322, ChEBI:CHEBI:15378,
ChEBI:CHEBI:30616, ChEBI:CHEBI:43176, ChEBI:CHEBI:68546,
ChEBI:CHEBI:456216; EC=2.7.11.23;
Evidence={ECO:0000269|PubMed:21127351, ECO:0000269|PubMed:28426094};
PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:10217;
Evidence={ECO:0000269|PubMed:21127351, ECO:0000269|PubMed:28426094};
-!- ACTIVITY REGULATION: Inhibited by CDKI-71, CR8, GPC-286199, AG-024322,
flavopiridol (alvocidib), RBG-286147, anilinopyrimidine 32,
arylazopyrazole 31b, indirubin 3'-monoxime, meriolin 3,P276-00,
olomoucine II, pyrazolotriazine, meriolin, variolin, thiazolyl-
pyrimidine, thiazolyl-pyrimidine, indirubin-30-monoxime, ZK 304709, AG-
012986, AT7519, R547, RGB-286638, imidazole pyrimidine, EXEL-3700,
EXEL-8647, 5,6-dichloro-1-b-ribofur-anosyl-benzimidazole (DRB), P276-
00, roscovitine (seliciclib, CYC202) and SNS-032 (BMS-387032).
Activation by Thr-186 phosphorylation is calcium Ca(2+) signaling
pathway-dependent; actively inactivated by dephosphorylation mediated
by PPP1CA, PPM1A and PPM1B. Reversibly repressed by acetylation at Lys-
44 and Lys-48. {ECO:0000269|PubMed:18250157,
ECO:0000269|PubMed:18483222, ECO:0000269|PubMed:19238148,
ECO:0000269|PubMed:21448926, ECO:0000269|PubMed:21484792,
ECO:0000269|PubMed:21779453}.
-!- SUBUNIT: Component of the super elongation complex (SEC), at least
composed of EAF1, EAF2, CDK9, MLLT3/AF9, AFF (AFF1 or AFF4), the P-TEFb
complex and ELL (ELL, ELL2 or ELL3). Associates with CCNT1/cyclin-T1,
CCNT2/cyclin-T2 (isoform A and isoform B) or CCNK/cyclin-K to form
active P-TEFb. P-TEFb forms a complex with AFF4/AF5Q31 and is part of
the super elongation complex (SEC). Component of a complex which is
composed of at least 5 members: HTATSF1/Tat-SF1, P-TEFb complex, RNA
pol II, SUPT5H and NCL/nucleolin. Associates with UBR5 and forms a
transcription regulatory complex composed of CDK9, RNAP II, UBR5 and
TFIIS/TCEA1 that can stimulate target gene transcription (e.g. gamma
fibrinogen/FGG) by recruiting their promoters. Component of the 7SK
snRNP inactive complex which is composed of at least 8 members: P-TEFb
(composed of CDK9 and CCNT1/cyclin-T1), HEXIM1, HEXIM2, LARP7, BCDIN3,
SART3 proteins and 7SK and U6 snRNAs. This inactive 7SK snRNP complex
can also interact with NCOR1 and HDAC3, probably to regulate CDK9
acetylation. Release of P-TEFb from P-TEFb/7SK snRNP complex requires
both PP2B to transduce calcium Ca(2+) signaling in response to stimuli
(e.g. UV or hexamethylene bisacetamide (HMBA)) and PPP1CA to
dephosphorylate Thr-186. This released P-TEFb remains inactive in the
pre-initiation complex with BRD4 until new Thr-186 phosphorylation
occurs after the synthesis of a short RNA (PubMed:10393184,
PubMed:10574912, PubMed:12037670, PubMed:11884399, PubMed:12065898,
PubMed:12718890, PubMed:15965233, PubMed:16109376, PubMed:17452463,
PubMed:17643375, PubMed:18249148, PubMed:18483222, PubMed:18566585,
PubMed:20159561, PubMed:20471948, PubMed:21127351, PubMed:21779453,
PubMed:22195968, PubMed:9491887). Interacts with BRD4; to target
chromatin binding (PubMed:16109376, PubMed:16109377, PubMed:18483222).
Interacts with JMJD6 (PubMed:24360279). Interacts with activated
nuclear STAT3 and RELA/p65 (PubMed:17956865, PubMed:18362169). Binds to
AR and MYOD1 (PubMed:12037670, PubMed:20980437). Forms a complex
composed of CDK9, CCNT1/cyclin-T1, EP300 and GATA4 that stimulates
hypertrophy in cardiomyocytes (PubMed:20081228). The large PER complex
involved in the repression of transcriptional termination is composed
of at least PER2, CDK9, DDX5, DHX9, NCBP1 and POLR2A (By similarity).
Interacts with HSF1 (PubMed:27189267). Interacts with TBX21 (By
similarity). Isoform 3: binds to KU70/XRCC6 (PubMed:20535204).
Interacts with WDR43 (By similarity). {ECO:0000250|UniProtKB:Q99J95,
ECO:0000269|PubMed:10393184, ECO:0000269|PubMed:10574912,
ECO:0000269|PubMed:11884399, ECO:0000269|PubMed:12037670,
ECO:0000269|PubMed:12065898, ECO:0000269|PubMed:12718890,
ECO:0000269|PubMed:15965233, ECO:0000269|PubMed:16109376,
ECO:0000269|PubMed:16109377, ECO:0000269|PubMed:17452463,
ECO:0000269|PubMed:17643375, ECO:0000269|PubMed:17956865,
ECO:0000269|PubMed:18249148, ECO:0000269|PubMed:18362169,
ECO:0000269|PubMed:18483222, ECO:0000269|PubMed:18566585,
ECO:0000269|PubMed:20081228, ECO:0000269|PubMed:20159561,
ECO:0000269|PubMed:20471948, ECO:0000269|PubMed:20535204,
ECO:0000269|PubMed:20980437, ECO:0000269|PubMed:21127351,
ECO:0000269|PubMed:21779453, ECO:0000269|PubMed:22195968,
ECO:0000269|PubMed:24360279, ECO:0000269|PubMed:27189267,
ECO:0000269|PubMed:9491887}.
-!- SUBUNIT: (Microbial infection) Interacts with the acidic/proline-rich
region of HIV-1 and HIV-2 Tat via T-loop region and is thus required
for HIV to hijack host transcription machinery during its replication
through cooperative binding to viral TAR RNA (PubMed:10958691,
PubMed:9491887). Interacts with herpes simplex virus 1 protein ICP22;
this interaction inhibits the positive transcription elongation factor
b (P-TEFb) (PubMed:23029222). {ECO:0000269|PubMed:10958691,
ECO:0000269|PubMed:23029222, ECO:0000269|PubMed:9491887}.
-!- INTERACTION:
P50750; Q13535: ATR; NbExp=3; IntAct=EBI-1383449, EBI-968983;
P50750; Q8WXE1: ATRIP; NbExp=3; IntAct=EBI-1383449, EBI-747353;
P50750; O60885-1: BRD4; NbExp=9; IntAct=EBI-1383449, EBI-9345088;
P50750; O60563: CCNT1; NbExp=25; IntAct=EBI-1383449, EBI-2479671;
P50750; O60583: CCNT2; NbExp=5; IntAct=EBI-1383449, EBI-2836757;
P50750; O60583-1: CCNT2; NbExp=2; IntAct=EBI-1383449, EBI-9077118;
P50750; O60583-2: CCNT2; NbExp=3; IntAct=EBI-1383449, EBI-9077112;
P50750; Q16543: CDC37; NbExp=4; IntAct=EBI-1383449, EBI-295634;
P50750; Q9HAW4: CLSPN; NbExp=3; IntAct=EBI-1383449, EBI-1369377;
P50750; Q13451: FKBP5; NbExp=5; IntAct=EBI-1383449, EBI-306914;
P50750; O94992: HEXIM1; NbExp=11; IntAct=EBI-1383449, EBI-2832510;
P50750; P07900: HSP90AA1; NbExp=2; IntAct=EBI-1383449, EBI-296047;
P50750; P08238: HSP90AB1; NbExp=2; IntAct=EBI-1383449, EBI-352572;
P50750; Q6NYC1: JMJD6; NbExp=5; IntAct=EBI-1383449, EBI-8464037;
P50750; Q4G0J3: LARP7; NbExp=11; IntAct=EBI-1383449, EBI-2371923;
P50750; P53041: PPP5C; NbExp=3; IntAct=EBI-1383449, EBI-716663;
P50750; P40763: STAT3; NbExp=2; IntAct=EBI-1383449, EBI-518675;
P50750; P04608: tat; Xeno; NbExp=8; IntAct=EBI-1383449, EBI-6164389;
P50750-2; P28799: GRN; NbExp=3; IntAct=EBI-12029902, EBI-747754;
P50750-2; P28799-2: GRN; NbExp=3; IntAct=EBI-12029902, EBI-25860013;
P50750-2; Q6XYB7-2: LBX2; NbExp=3; IntAct=EBI-12029902, EBI-12029900;
-!- SUBCELLULAR LOCATION: Nucleus. Cytoplasm. Nucleus, PML body.
Note=Accumulates on chromatin in response to replication stress.
Complexed with CCNT1 in nuclear speckles, but uncomplexed form in the
cytoplasm. The translocation from nucleus to cytoplasm is XPO1/CRM1-
dependent. Associates with PML body when acetylated.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=2;
Name=1;
IsoId=P50750-1; Sequence=Displayed;
Name=2;
IsoId=P50750-2; Sequence=VSP_016288;
-!- TISSUE SPECIFICITY: Ubiquitous.
-!- INDUCTION: By replication stress, in chromatin. Probably degraded by
the proteasome upon Thr-186 dephosphorylation.
-!- PTM: Autophosphorylation at Thr-186, Ser-347, Thr-350, Ser-353, Thr-354
and Ser-357 triggers kinase activity by promoting cyclin and substrate
binding (e.g. HIV TAT) upon conformational changes. Thr-186
phosphorylation requires the calcium Ca(2+) signaling pathway,
including CaMK1D and calmodulin. This inhibition is relieved by Thr-29
dephosphorylation. However, phosphorylation at Thr-29 is inhibitory
within the HIV transcription initiation complex. Phosphorylation at
Ser-175 inhibits kinase activity. Can be phosphorylated on either Thr-
362 or Thr-363 but not on both simultaneously (PubMed:18566585).
{ECO:0000269|PubMed:10958691, ECO:0000269|PubMed:15965233,
ECO:0000269|PubMed:18483222, ECO:0000269|PubMed:18566585,
ECO:0000269|PubMed:18829461, ECO:0000269|PubMed:20535204,
ECO:0000269|PubMed:20851342, ECO:0000269|PubMed:21448926,
ECO:0000269|PubMed:21533037, ECO:0000269|PubMed:21779453}.
-!- PTM: Dephosphorylation of Thr-186 by PPM1A and PPM1B blocks CDK9
activity and may lead to CDK9 proteasomal degradation. However, PPP1CA-
mediated Thr-186 dephosphorylation is required to release P-TEFb from
its inactive P-TEFb/7SK snRNP complex. Dephosphorylation of C-terminus
Thr and Ser residues by protein phosphatase-1 (PP1) triggers CDK9
activity, contributing to the activation of HIV-1 transcription.
-!- PTM: N6-acetylation of Lys-44 promotes kinase activity, whereas
acetylation of both Lys-44 and Lys-48 mediated by PCAF/KAT2B and
GCN5/KAT2A reduces kinase activity (PubMed:17452463, PubMed:18250157).
The acetylated form associates with PML bodies in the nuclear matrix
and with the transcriptionally silent HIV-1 genome; deacetylated upon
transcription stimulation (PubMed:17452463, PubMed:18250157).
Deacetylated by SIRT7, promoting the kinase activity and subsequent
'Ser-2' phosphorylation of the C-terminal domain (CTD) of RNA
polymerase II (PubMed:28426094). {ECO:0000269|PubMed:17452463,
ECO:0000269|PubMed:18250157, ECO:0000269|PubMed:28426094}.
-!- PTM: Polyubiquitinated and thus activated by UBR5. This ubiquitination
is promoted by TFIIS/TCEA1 and favors 'Ser-2' phosphorylation of
RPB1/POLR2A CTD. {ECO:0000269|PubMed:21127351}.
-!- DISEASE: Note=Chronic activation of CDK9 causes cardiac myocyte
enlargement leading to cardiac hypertrophy and confers predisposition
to heart failure.
-!- MISCELLANEOUS: CDK9 inhibition contributes to the anticancer activity
of most CDK inhibitors under clinical investigation (PubMed:18423896
and PubMed:21779453). As a retroviruses target during the hijack of
host transcription (e.g. HIV), CDK9 inhibitors might become specific
antiretroviral agents (PubMed:18423896). May be a target for cardiac
hypertrophy future treatments (PubMed:19757441 and PubMed:18423896).
May also be a target in anti-inflammatory therapy in innate immunity
and systemic inflammation (PubMed:18728388).
{ECO:0000305|PubMed:18423896, ECO:0000305|PubMed:18728388}.
-!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr
protein kinase family. CDC2/CDKX subfamily. {ECO:0000305}.
-!- WEB RESOURCE: Name=NIEHS-SNPs;
URL="http://egp.gs.washington.edu/data/cdk9/";
---------------------------------------------------------------------------
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EMBL; L25676; AAA35668.1; -; mRNA.
EMBL; X80230; CAA56516.1; -; mRNA.
EMBL; AF255306; AAF72183.1; -; Genomic_DNA.
EMBL; BT019903; AAV38706.1; -; mRNA.
EMBL; AF517840; AAM54039.1; -; Genomic_DNA.
EMBL; AL162586; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; BC001968; AAH01968.1; -; mRNA.
CCDS; CCDS6879.1; -. [P50750-1]
PIR; A55262; A55262.
RefSeq; NP_001252.1; NM_001261.3. [P50750-1]
PDB; 1PF6; Model; -; A=1-372.
PDB; 3BLH; X-ray; 2.48 A; A=2-330.
PDB; 3BLQ; X-ray; 2.90 A; A=2-330.
PDB; 3BLR; X-ray; 2.80 A; A=2-330.
PDB; 3LQ5; X-ray; 3.00 A; A=2-330.
PDB; 3MI9; X-ray; 2.10 A; A=1-345.
PDB; 3MIA; X-ray; 3.00 A; A=1-345.
PDB; 3MY1; X-ray; 2.80 A; A=2-330.
PDB; 3TN8; X-ray; 2.95 A; A=2-330.
PDB; 3TNH; X-ray; 3.20 A; A=2-330.
PDB; 3TNI; X-ray; 3.23 A; A=2-330.
PDB; 4BCF; X-ray; 3.01 A; A=2-330.
PDB; 4BCG; X-ray; 3.08 A; A=2-330.
PDB; 4BCH; X-ray; 2.96 A; A=2-330.
PDB; 4BCI; X-ray; 3.10 A; A=2-330.
PDB; 4BCJ; X-ray; 3.16 A; A=2-330.
PDB; 4EC8; X-ray; 3.60 A; A=2-372.
PDB; 4EC9; X-ray; 3.21 A; A=2-372.
PDB; 4IMY; X-ray; 2.94 A; A/C/E=1-330.
PDB; 4OGR; X-ray; 3.00 A; A/E/I=1-330.
PDB; 4OR5; X-ray; 2.90 A; A/F=7-332.
PDB; 5L1Z; X-ray; 5.90 A; A=1-330.
PDB; 6CYT; X-ray; 3.50 A; A=1-330.
PDB; 6GZH; X-ray; 3.17 A; A=1-326.
PDB; 6Z45; X-ray; 3.37 A; A=1-330.
PDBsum; 1PF6; -.
PDBsum; 3BLH; -.
PDBsum; 3BLQ; -.
PDBsum; 3BLR; -.
PDBsum; 3LQ5; -.
PDBsum; 3MI9; -.
PDBsum; 3MIA; -.
PDBsum; 3MY1; -.
PDBsum; 3TN8; -.
PDBsum; 3TNH; -.
PDBsum; 3TNI; -.
PDBsum; 4BCF; -.
PDBsum; 4BCG; -.
PDBsum; 4BCH; -.
PDBsum; 4BCI; -.
PDBsum; 4BCJ; -.
PDBsum; 4EC8; -.
PDBsum; 4EC9; -.
PDBsum; 4IMY; -.
PDBsum; 4OGR; -.
PDBsum; 4OR5; -.
PDBsum; 5L1Z; -.
PDBsum; 6CYT; -.
PDBsum; 6GZH; -.
PDBsum; 6Z45; -.
SMR; P50750; -.
BioGRID; 107459; 578.
ComplexPortal; CPX-222; Positive transcription elongation factor B, CDK9-cyclinT1 complex.
ComplexPortal; CPX-321; Positive transcription elongation factor B, CDK9-cyclinT2a complex.
ComplexPortal; CPX-322; Positive transcription elongation factor B, CDK9-cyclinT2b complex.
CORUM; P50750; -.
DIP; DIP-29016N; -.
ELM; P50750; -.
IntAct; P50750; 90.
MINT; P50750; -.
STRING; 9606.ENSP00000362361; -.
BindingDB; P50750; -.
ChEMBL; CHEMBL3116; -.
DrugBank; DB03496; Alvocidib.
DrugBank; DB06195; Seliciclib.
DrugCentral; P50750; -.
GuidetoPHARMACOLOGY; 1981; -.
iPTMnet; P50750; -.
PhosphoSitePlus; P50750; -.
SwissPalm; P50750; -.
BioMuta; CDK9; -.
DMDM; 68067660; -.
CPTAC; CPTAC-1602; -.
EPD; P50750; -.
jPOST; P50750; -.
MassIVE; P50750; -.
MaxQB; P50750; -.
PaxDb; P50750; -.
PeptideAtlas; P50750; -.
PRIDE; P50750; -.
ProteomicsDB; 56263; -. [P50750-1]
ProteomicsDB; 56264; -. [P50750-2]
Antibodypedia; 1447; 553 antibodies.
DNASU; 1025; -.
Ensembl; ENST00000373264; ENSP00000362361; ENSG00000136807. [P50750-1]
GeneID; 1025; -.
KEGG; hsa:1025; -.
UCSC; uc004bse.3; human. [P50750-1]
CTD; 1025; -.
DisGeNET; 1025; -.
GeneCards; CDK9; -.
HGNC; HGNC:1780; CDK9.
HPA; ENSG00000136807; Low tissue specificity.
MIM; 603251; gene.
neXtProt; NX_P50750; -.
OpenTargets; ENSG00000136807; -.
PharmGKB; PA26316; -.
VEuPathDB; HostDB:ENSG00000136807.11; -.
eggNOG; KOG0669; Eukaryota.
GeneTree; ENSGT00940000155373; -.
HOGENOM; CLU_000288_181_1_1; -.
InParanoid; P50750; -.
OMA; KDPTGCD; -.
PhylomeDB; P50750; -.
TreeFam; TF101039; -.
BRENDA; 2.7.11.22; 2681.
BRENDA; 2.7.11.23; 2681.
PathwayCommons; P50750; -.
Reactome; R-HSA-112382; Formation of RNA Pol II elongation complex.
Reactome; R-HSA-167152; Formation of HIV elongation complex in the absence of HIV Tat.
Reactome; R-HSA-167200; Formation of HIV-1 elongation complex containing HIV-1 Tat.
Reactome; R-HSA-167238; Pausing and recovery of Tat-mediated HIV elongation.
Reactome; R-HSA-167243; Tat-mediated HIV elongation arrest and recovery.
Reactome; R-HSA-167246; Tat-mediated elongation of the HIV-1 transcript.
Reactome; R-HSA-167287; HIV elongation arrest and recovery.
Reactome; R-HSA-167290; Pausing and recovery of HIV elongation.
Reactome; R-HSA-176034; Interactions of Tat with host cellular proteins.
Reactome; R-HSA-2173796; SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription.
Reactome; R-HSA-674695; RNA Polymerase II Pre-transcription Events.
Reactome; R-HSA-6796648; TP53 Regulates Transcription of DNA Repair Genes.
Reactome; R-HSA-6807505; RNA polymerase II transcribes snRNA genes.
Reactome; R-HSA-75955; RNA Polymerase II Transcription Elongation.
Reactome; R-HSA-9018519; Estrogen-dependent gene expression.
SignaLink; P50750; -.
SIGNOR; P50750; -.
BioGRID-ORCS; 1025; 806 hits in 997 CRISPR screens.
ChiTaRS; CDK9; human.
EvolutionaryTrace; P50750; -.
GeneWiki; CDK9; -.
GeneWiki; Cyclin-dependent_kinase_9; -.
GenomeRNAi; 1025; -.
Pharos; P50750; Tchem.
PRO; PR:P50750; -.
Proteomes; UP000005640; Chromosome 9.
RNAct; P50750; protein.
Bgee; ENSG00000136807; Expressed in right ovary and 198 other tissues.
ExpressionAtlas; P50750; baseline and differential.
Genevisible; P50750; HS.
GO; GO:0008024; C:cyclin/CDK positive transcription elongation factor complex; IDA:UniProtKB.
GO; GO:0036464; C:cytoplasmic ribonucleoprotein granule; IDA:HPA.
GO; GO:0016592; C:mediator complex; IBA:GO_Central.
GO; GO:0016020; C:membrane; HDA:UniProtKB.
GO; GO:0005654; C:nucleoplasm; IDA:HPA.
GO; GO:0005634; C:nucleus; IBA:GO_Central.
GO; GO:0070691; C:P-TEFb complex; IDA:FlyBase.
GO; GO:0016605; C:PML body; IDA:UniProtKB.
GO; GO:0008023; C:transcription elongation factor complex; IDA:UniProtKB.
GO; GO:0097322; F:7SK snRNA binding; IDA:UniProtKB.
GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
GO; GO:0003682; F:chromatin binding; ISS:UniProtKB.
GO; GO:0004693; F:cyclin-dependent protein serine/threonine kinase activity; IDA:UniProtKB.
GO; GO:0003677; F:DNA binding; IDA:MGI.
GO; GO:0004672; F:protein kinase activity; TAS:ProtInc.
GO; GO:0019901; F:protein kinase binding; IEA:Ensembl.
GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:FlyBase.
GO; GO:0106311; F:protein threonine kinase activity; IEA:RHEA.
GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IEA:Ensembl.
GO; GO:0008353; F:RNA polymerase II CTD heptapeptide repeat kinase activity; IDA:UniProtKB.
GO; GO:0001223; F:transcription coactivator binding; IPI:UniProtKB.
GO; GO:0008283; P:cell population proliferation; TAS:ProtInc.
GO; GO:0071345; P:cellular response to cytokine stimulus; IDA:UniProtKB.
GO; GO:0006281; P:DNA repair; IEA:UniProtKB-KW.
GO; GO:0071157; P:negative regulation of cell cycle arrest; IDA:UniProtKB.
GO; GO:1900364; P:negative regulation of mRNA polyadenylation; IMP:UniProtKB.
GO; GO:0070816; P:phosphorylation of RNA polymerase II C-terminal domain; IDA:UniProtKB.
GO; GO:0010613; P:positive regulation of cardiac muscle hypertrophy; IEA:Ensembl.
GO; GO:2001168; P:positive regulation of histone H2B ubiquitination; IMP:UniProtKB.
GO; GO:0033129; P:positive regulation of histone phosphorylation; IMP:UniProtKB.
GO; GO:1903839; P:positive regulation of mRNA 3'-UTR binding; IDA:UniProtKB.
GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:UniProtKB.
GO; GO:0050434; P:positive regulation of viral transcription; TAS:Reactome.
GO; GO:0006468; P:protein phosphorylation; IDA:MGI.
GO; GO:0006282; P:regulation of DNA repair; IDA:UniProtKB.
GO; GO:0031056; P:regulation of histone modification; IDA:UniProtKB.
GO; GO:0051147; P:regulation of muscle cell differentiation; IMP:UniProtKB.
GO; GO:0031297; P:replication fork processing; IDA:UniProtKB.
GO; GO:0042493; P:response to drug; IEA:Ensembl.
GO; GO:0042795; P:snRNA transcription by RNA polymerase II; TAS:Reactome.
GO; GO:0006366; P:transcription by RNA polymerase II; TAS:Reactome.
GO; GO:0006368; P:transcription elongation from RNA polymerase II promoter; TAS:Reactome.
GO; GO:0006367; P:transcription initiation from RNA polymerase II promoter; TAS:ProtInc.
DisProt; DP01309; -.
InterPro; IPR011009; Kinase-like_dom_sf.
InterPro; IPR000719; Prot_kinase_dom.
InterPro; IPR017441; Protein_kinase_ATP_BS.
InterPro; IPR008271; Ser/Thr_kinase_AS.
Pfam; PF00069; Pkinase; 1.
SMART; SM00220; S_TKc; 1.
SUPFAM; SSF56112; SSF56112; 1.
PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
1: Evidence at protein level;
3D-structure; Acetylation; Alternative splicing; ATP-binding; Cytoplasm;
DNA damage; DNA repair; Kinase; Nucleotide-binding; Nucleus;
Phosphoprotein; Reference proteome; Serine/threonine-protein kinase;
Transcription; Transcription regulation; Transferase; Ubl conjugation.
CHAIN 1..372
/note="Cyclin-dependent kinase 9"
/id="PRO_0000085800"
DOMAIN 19..315
/note="Protein kinase"
/evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
NP_BIND 25..33
/note="ATP"
/evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
NP_BIND 104..106
/note="ATP"
/evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
ECO:0000269|PubMed:18566585"
REGION 166..191
/note="T-loop"
REGION 343..372
/note="Disordered"
/evidence="ECO:0000256|SAM:MobiDB-lite"
COMPBIAS 345..372
/note="Polar residues"
/evidence="ECO:0000256|SAM:MobiDB-lite"
ACT_SITE 149
/note="Proton acceptor"
/evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
ECO:0000255|PROSITE-ProRule:PRU10027"
BINDING 48
/note="ATP"
/evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
ECO:0000269|PubMed:18566585"
BINDING 167
/note="ATP"
/evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
ECO:0000269|PubMed:18566585"
MOD_RES 44
/note="N6-acetyllysine; by P300/CBP, PCAF/KAT2B and
GCN5/KAT2A"
/evidence="ECO:0000269|PubMed:17452463,
ECO:0000269|PubMed:18250157"
MOD_RES 48
/note="N6-acetyllysine; by PCAF/KAT2B and GCN5/KAT2A"
/evidence="ECO:0000269|PubMed:18250157,
ECO:0000269|PubMed:28426094"
MOD_RES 175
/note="Phosphoserine"
/evidence="ECO:0000269|PubMed:21533037"
MOD_RES 186
/note="Phosphothreonine; by CaMK1D"
/evidence="ECO:0000269|PubMed:15965233,
ECO:0000269|PubMed:18483222, ECO:0000269|PubMed:18566585,
ECO:0000269|PubMed:18829461, ECO:0000269|PubMed:20535204,
ECO:0000269|PubMed:20851342, ECO:0000269|PubMed:21448926,
ECO:0000269|PubMed:21779453, ECO:0007744|PubMed:21406692"
MOD_RES 347
/note="Phosphoserine; by CDK9 and PKA"
/evidence="ECO:0000269|PubMed:10958691,
ECO:0000269|PubMed:18566585, ECO:0007744|PubMed:18691976,
ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:24275569"
MOD_RES 350
/note="Phosphothreonine; by CDK9"
/evidence="ECO:0000269|PubMed:10958691,
ECO:0007744|PubMed:19369195"
MOD_RES 353
/note="Phosphoserine; by CDK9"
/evidence="ECO:0000269|PubMed:10958691"
MOD_RES 354
/note="Phosphothreonine; by CDK9"
/evidence="ECO:0000269|PubMed:10958691"
MOD_RES 357
/note="Phosphoserine; by CDK9"
/evidence="ECO:0000269|PubMed:10958691"
MOD_RES 362
/note="Phosphothreonine; by CDK9"
/evidence="ECO:0000269|PubMed:18566585"
MOD_RES 363
/note="Phosphothreonine; by CDK9"
/evidence="ECO:0000269|PubMed:18566585"
VAR_SEQ 1
/note="M -> MQRDAPPRAPAPAPRLPAPPIGAAASSGGGGGGGSGGGGGGASAAPA
PPGLSGTTSPRGPGGGRRAEEAGSAPRGRKWPWRRKWRGRGGAWSAAAAGPGAGAAAAA
TGGGGGALEAAM (in isoform 2)"
/evidence="ECO:0000305"
/id="VSP_016288"
VARIANT 59
/note="F -> L (in dbSNP:rs55640715)"
/evidence="ECO:0000269|PubMed:17344846"
/id="VAR_041982"
VARIANT 225
/note="R -> C (found in patients with global developmental
delay and epilepsy with history of choanal atresia; unknown
pathological significance; dbSNP:rs767418586)"
/evidence="ECO:0000269|PubMed:30237576"
/id="VAR_082140"
VARIANT 231
/note="G -> A"
/evidence="ECO:0000269|PubMed:10903437,
ECO:0000269|PubMed:7695608"
/id="VAR_013456"
MUTAGEN 44
/note="K->R: Impaired kinase and transcriptional elongation
activities, but normal cyclin T1 and HEXIM1 binding."
/evidence="ECO:0000269|PubMed:17452463"
MUTAGEN 48
/note="K->Q: Mimics acetylation; leading to impaired
protein kinase activity."
/evidence="ECO:0000269|PubMed:28426094"
MUTAGEN 48
/note="K->R: Decreased acetylation; leading to enhanced
protein kinase activity."
/evidence="ECO:0000269|PubMed:28426094"
MUTAGEN 167
/note="D->N: Abrogates kinase activity."
/evidence="ECO:0000269|PubMed:10958691,
ECO:0000269|PubMed:11145967"
MUTAGEN 175
/note="S->A: Constitutive kinase activity."
/evidence="ECO:0000269|PubMed:21533037"
MUTAGEN 175
/note="S->D: Mimics phosphorylation, constitutive loss of
kinase activity."
/evidence="ECO:0000269|PubMed:21533037"
MUTAGEN 186
/note="T->A: Abrogates autophosphorylation; no effect on
kinase activity, but impaired CTD phosphorylation."
/evidence="ECO:0000269|PubMed:11145967,
ECO:0000269|PubMed:18566585, ECO:0000269|PubMed:21448926"
MUTAGEN 186
/note="T->D: Mimics autophosphorylation; constitutive
kinase activity, independently of calcium signaling."
/evidence="ECO:0000269|PubMed:11145967,
ECO:0000269|PubMed:18566585, ECO:0000269|PubMed:21448926"
MUTAGEN 347..357
/note="SQITQQSTNQS->AQIAQQAANQA: Loss of
autophosphorylation and impaired interaction with HIV TAT."
/evidence="ECO:0000269|PubMed:10958691"
MUTAGEN 347..357
/note="SQITQQSTNQS->EQIEQQEENQE: Mimics autophosphorylation
and promotes interaction with HIV TAT."
/evidence="ECO:0000269|PubMed:10958691"
CONFLICT 163
/note="L -> P (in Ref. 4; AAV38706)"
/evidence="ECO:0000305"
STRAND 11..13
/evidence="ECO:0007829|PDB:6GZH"
HELIX 16..18
/evidence="ECO:0007829|PDB:3MI9"
STRAND 19..24
/evidence="ECO:0007829|PDB:3MI9"
STRAND 28..30
/evidence="ECO:0007829|PDB:3BLR"
STRAND 32..38
/evidence="ECO:0007829|PDB:3MI9"
TURN 39..41
/evidence="ECO:0007829|PDB:3MI9"
STRAND 44..49
/evidence="ECO:0007829|PDB:3MI9"
STRAND 56..59
/evidence="ECO:0007829|PDB:3MI9"
HELIX 61..72
/evidence="ECO:0007829|PDB:3MI9"
STRAND 81..87
/evidence="ECO:0007829|PDB:3MI9"
STRAND 98..104
/evidence="ECO:0007829|PDB:3MI9"
STRAND 107..109
/evidence="ECO:0007829|PDB:3MI9"
HELIX 110..115
/evidence="ECO:0007829|PDB:3MI9"
STRAND 116..118
/evidence="ECO:0007829|PDB:3LQ5"
HELIX 123..142
/evidence="ECO:0007829|PDB:3MI9"
HELIX 152..154
/evidence="ECO:0007829|PDB:3MI9"
STRAND 155..157
/evidence="ECO:0007829|PDB:3MI9"
STRAND 159..161
/evidence="ECO:0007829|PDB:6GZH"
STRAND 163..165
/evidence="ECO:0007829|PDB:3MI9"
HELIX 168..170
/evidence="ECO:0007829|PDB:4OGR"
STRAND 178..181
/evidence="ECO:0007829|PDB:3MI9"
HELIX 192..194
/evidence="ECO:0007829|PDB:3MI9"
HELIX 197..200
/evidence="ECO:0007829|PDB:3MI9"
HELIX 209..224
/evidence="ECO:0007829|PDB:3MI9"
HELIX 234..245
/evidence="ECO:0007829|PDB:3MI9"
TURN 250..252
/evidence="ECO:0007829|PDB:3MI9"
HELIX 256..258
/evidence="ECO:0007829|PDB:3MI9"
HELIX 260..262
/evidence="ECO:0007829|PDB:3MI9"
HELIX 263..265
/evidence="ECO:0007829|PDB:3MY1"
HELIX 275..283
/evidence="ECO:0007829|PDB:3MI9"
HELIX 286..295
/evidence="ECO:0007829|PDB:3MI9"
HELIX 300..302
/evidence="ECO:0007829|PDB:3MI9"
HELIX 306..310
/evidence="ECO:0007829|PDB:3MI9"
HELIX 313..316
/evidence="ECO:0007829|PDB:3MI9"
STRAND 317..319
/evidence="ECO:0007829|PDB:3MI9"
HELIX 325..329
/evidence="ECO:0007829|PDB:3MI9"
HELIX 335..339
/evidence="ECO:0007829|PDB:3MI9"
MOD_RES P50750-2:35
/note="Phosphoserine"
/evidence="ECO:0007744|PubMed:18691976,
ECO:0007744|PubMed:19369195"
MOD_RES P50750-2:54
/note="Phosphothreonine"
/evidence="ECO:0007744|PubMed:24275569"
SEQUENCE 372 AA; 42778 MW; 69E851CC6F7A0388 CRC64;
MAKQYDSVEC PFCDEVSKYE KLAKIGQGTF GEVFKARHRK TGQKVALKKV LMENEKEGFP
ITALREIKIL QLLKHENVVN LIEICRTKAS PYNRCKGSIY LVFDFCEHDL AGLLSNVLVK
FTLSEIKRVM QMLLNGLYYI HRNKILHRDM KAANVLITRD GVLKLADFGL ARAFSLAKNS
QPNRYTNRVV TLWYRPPELL LGERDYGPPI DLWGAGCIMA EMWTRSPIMQ GNTEQHQLAL
ISQLCGSITP EVWPNVDNYE LYEKLELVKG QKRKVKDRLK AYVRDPYALD LIDKLLVLDP
AQRIDSDDAL NHDFFWSDPM PSDLKGMLST HLTSMFEYLA PPRRKGSQIT QQSTNQSRNP
ATTNQTEFER VF


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Pathways :
WP1493: Carbon assimilation C4 pathway
WP1619: Amino sugar and nucleotide sugar metabolism
WP1946: Cori Cycle
WP253: Glycolysis
WP1653: Galactose metabolism
WP414: Cell Cycle and Cell Division
WP1672: Mismatch repair
WP1681: Pantothenate and CoA biosynthesis
WP1567: Glycolysis and Gluconeogenesis
WP2341: vitamin B1 (thiamin) biosynthesis and salvage pathway
WP1844: MAP kinase cascade
WP32: Translation Factors
WP1703: Streptomycin biosynthesis
WP1566: Citrate cycle (TCA cycle)
WP2340: Thiamine (vitamin B1) biosynthesis and salvage
WP1659: Glycine, serine and threonine metabolism
WP1701: Starch and sucrose metabolism
WP2272: Pathogenic Escherichia coli infection
WP1678: Nucleotide excision repair
WP1663: Homologous recombination
WP1676: Non-homologous end-joining
WP2292: Chemokine signaling pathway
WP1694: Pyrimidine metabolism
WP2199: Seed Development
WP1411: Cell Division: First embryonic mitosis

Related Genes :
[CDK9 CDC2L4 TAK] Cyclin-dependent kinase 9 (EC 2.7.11.22) (EC 2.7.11.23) (C-2K) (Cell division cycle 2-like protein kinase 4) (Cell division protein kinase 9) (Serine/threonine-protein kinase PITALRE) (Tat-associated kinase complex catalytic subunit)
[CDK7 CAK CAK1 CDKN7 MO15 STK1] Cyclin-dependent kinase 7 (EC 2.7.11.22) (EC 2.7.11.23) (39 kDa protein kinase) (p39 Mo15) (CDK-activating kinase 1) (Cell division protein kinase 7) (Serine/threonine-protein kinase 1) (TFIIH basal transcription factor complex kinase subunit)
[Cdk11b Cdc2l1 Cdk11] Cyclin-dependent kinase 11B (Cell division cycle 2-like protein kinase 1) (Cell division protein kinase 11) (Cyclin-dependent kinase 11) (EC 2.7.11.22) (Galactosyltransferase-associated protein kinase p58/GTA) (PITSLRE serine/threonine-protein kinase CDC2L1)
[CDK13 CDC2L CDC2L5 CHED KIAA1791] Cyclin-dependent kinase 13 (EC 2.7.11.22) (EC 2.7.11.23) (CDC2-related protein kinase 5) (Cell division cycle 2-like protein kinase 5) (Cell division protein kinase 13) (hCDK13) (Cholinesterase-related cell division controller)
[Cdk9] Cyclin-dependent kinase 9 (EC 2.7.11.22) (EC 2.7.11.23) (Cell division protein kinase 9)
[Cdk7 Cak Cdkn7 Crk4 Mo15 Mpk-7] Cyclin-dependent kinase 7 (EC 2.7.11.22) (EC 2.7.11.23) (39 kDa protein kinase) (P39 Mo15) (CDK-activating kinase) (CR4 protein kinase) (CRK4) (Cell division protein kinase 7) (Protein-tyrosine kinase MPK-7) (TFIIH basal transcription factor complex kinase subunit)
[CDK11B CDC2L1 CDK11 PITSLREA PK58] Cyclin-dependent kinase 11B (EC 2.7.11.22) (Cell division cycle 2-like protein kinase 1) (CLK-1) (Cell division protein kinase 11B) (Galactosyltransferase-associated protein kinase p58/GTA) (PITSLRE serine/threonine-protein kinase CDC2L1) (p58 CLK-1)
[Cdk5 Cdkn5 Crk6] Cyclin-dependent-like kinase 5 (EC 2.7.11.1) (CR6 protein kinase) (CRK6) (Cell division protein kinase 5) (Serine/threonine-protein kinase PSSALRE) (Tau protein kinase II catalytic subunit) (TPKII catalytic subunit)
[cdk-2 K03E5.3] Cyclin-dependent kinase 2 (EC 2.7.11.22) (Cell division protein kinase 2)
[CDK5 CDKN5] Cyclin-dependent-like kinase 5 (EC 2.7.11.1) (Cell division protein kinase 5) (Serine/threonine-protein kinase PSSALRE) (Tau protein kinase II catalytic subunit) (TPKII catalytic subunit)
[CDK11A CDC2L2 CDC2L3 PITSLREB] Cyclin-dependent kinase 11A (EC 2.7.11.22) (Cell division cycle 2-like protein kinase 2) (Cell division protein kinase 11A) (Galactosyltransferase-associated protein kinase p58/GTA) (PITSLRE serine/threonine-protein kinase CDC2L2)
[Cdk1 Cdc2 Cdc2a Cdkn1] Cyclin-dependent kinase 1 (CDK1) (EC 2.7.11.22) (EC 2.7.11.23) (Cell division control protein 2 homolog) (Cell division protein kinase 1) (p34 protein kinase)
[CDK5 CDKN5] Cyclin-dependent-like kinase 5 (EC 2.7.11.1) (Cell division protein kinase 5) (Proline-directed protein kinase 33 kDa subunit) (PDPK) (Serine/threonine-protein kinase PSSALRE) (Tau protein kinase II catalytic subunit) (TPKII catalytic subunit)
[Cdk5 Cdkn5] Cyclin-dependent-like kinase 5 (EC 2.7.11.1) (Cell division protein kinase 5) (Serine/threonine-protein kinase PSSALRE) (Tau protein kinase II catalytic subunit) (TPKII catalytic subunit)
[Cdk1 cdc2 CG5363] Cyclin-dependent kinase 1 (CDK1) (EC 2.7.11.22) (EC 2.7.11.23) (Cell division control protein 2 homolog) (Cell division protein kinase 1) (p34 protein kinase)
[CDK1 CDC2 CDC28A CDKN1 P34CDC2] Cyclin-dependent kinase 1 (CDK1) (EC 2.7.11.22) (EC 2.7.11.23) (Cell division control protein 2 homolog) (Cell division protein kinase 1) (p34 protein kinase)
[Cdk7 Cak Cak1 Mo15] Cyclin-dependent kinase 7 (EC 2.7.11.22) (EC 2.7.11.23) (39 protein kinase) (P39 Mo15) (CDK-activating kinase 1) (Cell division protein kinase 7) (TFIIH basal transcription factor complex kinase subunit) (Fragment)
[CDK9] Cyclin-dependent kinase 9 (EC 2.7.11.22) (EC 2.7.11.23) (Cell division protein kinase 9)
[Cdk1 Cdc2 Cdc2a Cdkn1] Cyclin-dependent kinase 1 (CDK1) (EC 2.7.11.22) (EC 2.7.11.23) (Cell division control protein 2 homolog) (Cell division protein kinase 1) (p34 protein kinase)
[Cdk9] Cyclin-dependent kinase 9 (EC 2.7.11.22) (EC 2.7.11.23) (Cell division protein kinase 9)
[Cdk8 CG10572] Cyclin-dependent kinase 8 (EC 2.7.11.22) (EC 2.7.11.23) (Cell division protein kinase 8) (DmCdk8) (Mediator complex subunit Cdk8) (Mediator of RNA polymerase II transcription subunit Cdk8)
[cdk1 cdcB DDB_G0272813] Cyclin-dependent kinase 1 (CDK1) (EC 2.7.11.22) (EC 2.7.11.23) (Cell division control protein 2 homolog) (Cell division protein kinase 1) (p34 protein kinase)
[cdk-9 H25P06.2] Probable cyclin-dependent kinase 9 (EC 2.7.11.22) (EC 2.7.11.23) (Cell division protein kinase 9)
[CDK8] Cyclin-dependent kinase 8 (EC 2.7.11.22) (EC 2.7.11.23) (Cell division protein kinase 8) (Mediator complex subunit CDK8) (Mediator of RNA polymerase II transcription subunit CDK8) (Protein kinase K35)
[cdk1-b cdc2 cdc2x1.2] Cyclin-dependent kinase 1-B (CDK1-B) (EC 2.7.11.22) (EC 2.7.11.23) (Cell division control protein 2 homolog 2) (Cell division control protein 2-B) (Cell division protein kinase 1) (p34 protein kinase 2)
[cdk1-a cdc2-a cdc2x1.1] Cyclin-dependent kinase 1-A (CDK1-A) (EC 2.7.11.22) (EC 2.7.11.23) (Cell division control protein 2 homolog 1) (Cell division control protein 2-A) (Cell division protein kinase 1-A) (p34 protein kinase 1)
[CDK1 CDC2 CDKN1] Cyclin-dependent kinase 1 (CDK1) (EC 2.7.11.22) (EC 2.7.11.23) (Cell division control protein 2 homolog) (Cell division protein kinase 1) (p34 protein kinase)
[Cdk8] Cyclin-dependent kinase 8 (EC 2.7.11.22) (EC 2.7.11.23) (Cell division protein kinase 8) (Mediator complex subunit CDK8) (Mediator of RNA polymerase II transcription subunit CDK8)
[cdk-5 T27E9.3] Cyclin-dependent-like kinase 5 (EC 2.7.11.1) (Cell division protein kinase 5)
[CDK1 CDC2 CDKN1] Cyclin-dependent kinase 1 (CDK1) (EC 2.7.11.22) (EC 2.7.11.23) (Cell division control protein 2 homolog) (Cell division protein kinase 1) (p34 protein kinase)

Bibliography :