UniProt Accession

 CDK9_HUMAN; P50750; Q5JU24; Q5JU25; Q5U006; Q96TF1 

Genbank Protein ID

 L25676; X80230; AF255306; BT019903; AF517840; AL162586; AL162586; BC001968 

Genbank Nucleotide ID

 AAA35668.1; CAA56516.1; AAF72183.1; AAV38706.1; AAM54039.1; CAI39767.1; CAI39768.1; AAH01968.1 

Protein Name

 Cyclin-dependent kinase 9 

Protein Synonyms/Alias

 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 

Gene Name

 CDK9 

Gene Synonyms/Alias

 CDC2L4; TAK 

Created Date

 July 27, 2013 

Organism

 Homo sapiens (Human) 

NCBI Taxa ID

 9606 

Lysine Modification

Position	Peptide	Type	References
3	*****MAKQYDSVEC	acetylation	[1]
3	*****MAKQYDSVEC	ubiquitination	[2, 3]
18	PFCDEVSKYEKLAKI	ubiquitination	[3, 4]
24	SKYEKLAKIGQGTFG	ubiquitination	[3, 4, 5, 6, 7]
35	GTFGEVFKARHRKTG	ubiquitination	[1, 2, 3, 4, 5, 6, 7]
44	RHRKTGQKVALKKVL	acetylation	[8, 9]
48	TGQKVALKKVLMENE	acetylation	[8, 9]
56	KVLMENEKEGFPITA	ubiquitination	[3, 5, 7]
68	ITALREIKILQLLKH	ubiquitination	[3, 5, 6, 10]
74	IKILQLLKHENVVNL	ubiquitination	[6]
88	LIEICRTKASPYNRC	ubiquitination	[5]
151	KILHRDMKAANVLIT	ubiquitination	[3, 5, 6]
164	ITRDGVLKLADFGLA	ubiquitination	[2, 3, 4, 5, 6, 7, 10, 11]
178	ARAFSLAKNSQPNRY	ubiquitination	[1, 2, 3, 4, 5, 6, 7, 11]
269	YEKLELVKGQKRKVK	ubiquitination	[1, 3, 5]
280	RKVKDRLKAYVRDPY	ubiquitination	[3]
294	YALDLIDKLLVLDPA	ubiquitination	[3, 7]
345	YLAPPRRKGSQITQQ	ubiquitination	[1, 3, 5]

Reference

 [1] Integrated proteomic analysis of post-translational modifications by serial enrichment.
 Mertins P, Qiao JW, Patel J, Udeshi ND, Clauser KR, Mani DR, Burgess MW, Gillette MA, Jaffe JD, Carr SA.
 Nat Methods. 2013 Jul;10(7):634-7. [PMID: 23749302]
 [2] Methods for quantification of in vivo changes in protein ubiquitination following proteasome and deubiquitinase inhibition.
 Udeshi ND, Mani DR, Eisenhaure T, Mertins P, Jaffe JD, Clauser KR, Hacohen N, Carr SA.
 Mol Cell Proteomics. 2012 May;11(5):148-59. [PMID: 22505724]
 [3] Refined preparation and use of anti-diglycine remnant (K-ε-GG) antibody enables routine quantification of 10,000s of ubiquitination sites in single proteomics experiments.
 Udeshi ND, Svinkina T, Mertins P, Kuhn E, Mani DR, Qiao JW, Carr SA.
 Mol Cell Proteomics. 2013 Mar;12(3):825-31. [PMID: 23266961]
 [4] Global identification of modular cullin-RING ligase substrates.
 Emanuele MJ, Elia AE, Xu Q, Thoma CR, Izhar L, Leng Y, Guo A, Chen YN, Rush J, Hsu PW, Yen HC, Elledge SJ.
 Cell. 2011 Oct 14;147(2):459-74. [PMID: 21963094]
 [5] Systematic and quantitative assessment of the ubiquitin-modified proteome.
 Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, Sowa ME, Rad R, Rush J, Comb MJ, Harper JW, Gygi SP.
 Mol Cell. 2011 Oct 21;44(2):325-40. [PMID: 21906983]
 [6] Ubiquitin ligase substrate identification through quantitative proteomics at both the protein and peptide levels.
 Lee KA, Hammerle LP, Andrews PS, Stokes MP, Mustelin T, Silva JC, Black RA, Doedens JR.
 J Biol Chem. 2011 Dec 2;286(48):41530-8. [PMID: 21987572]
 [7] Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization.
 Sarraf SA, Raman M, Guarani-Pereira V, Sowa ME, Huttlin EL, Gygi SP, Harper JW.
 Nature. 2013 Apr 18;496(7445):372-6. [PMID: 23503661]
 [8] Regulation of P-TEFb elongation complex activity by CDK9 acetylation.
 Fu J, Yoon HG, Qin J, Wong J.
 Mol Cell Biol. 2007 Jul;27(13):4641-51. [PMID: 17452463]
 [9] Acetylation of conserved lysines in the catalytic core of cyclin-dependent kinase 9 inhibits kinase activity and regulates transcription.
 Sabò A, Lusic M, Cereseto A, Giacca M.
 Mol Cell Biol. 2008 Apr;28(7):2201-12. [PMID: 18250157]
 [10] A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.
 Wagner SA, Beli P, Weinert BT, Nielsen ML, Cox J, Mann M, Choudhary C.
 Mol Cell Proteomics. 2011 Oct;10(10):M111.013284. [PMID: 21890473]
 [11] Proteomic analyses reveal divergent ubiquitylation site patterns in murine tissues.
 Wagner SA, Beli P, Weinert BT, Schölz C, Kelstrup CD, Young C, Nielsen ML, Olsen JV, Brakebusch C, Choudhary C.
 Mol Cell Proteomics. 2012 Dec;11(12):1578-85. [PMID: 22790023] 

Functional Description

 Protein kinase involved in the regulation of transcription. 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. This complex is inactive when in the 7SK snRNP complex form. Phosphorylates EP300, MYOD1, RPB1/POLR2A and AR, and the negative elongation factors DSIF and NELF. 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). Promotes RNA synthesis in genetic programs for cell growth, differentiation and viral pathogenesis. P-TEFb is also involved in cotranscriptional histone modification, mRNA processing and mRNA export. 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. 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. 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. In addition, probable function in DNA repair of isoform 2 via interaction with KU70/XRCC6. Promotes cardiac myocyte enlargement. RPB1/POLR2A phosphorylation on 'Ser-2' in CTD activates transcription. AR phosphorylation modulates AR transcription factor promoter selectivity and cell growth. DSIF and NELF phosphorylation promotes transcription by inhibiting their negative effect. The phosphorylation of MYOD1 enhances its transcriptional activity and thus promotes muscle differentiation. 

Sequence Annotation

 DOMAIN 19 315 Protein kinase.
 NP_BIND 25 33 ATP (By similarity).
 NP_BIND 104 106 ATP.
 REGION 166 191 T-loop.
 ACT_SITE 149 149 Proton acceptor (By similarity).
 BINDING 48 48 ATP.
 BINDING 167 167 ATP.
 MOD_RES 29 29 Phosphothreonine.
 MOD_RES 44 44 N6-acetyllysine; by P300/CBP, PCAF/KAT2B
 MOD_RES 48 48 N6-acetyllysine; by PCAF/KAT2B and
 MOD_RES 175 175 Phosphoserine.
 MOD_RES 186 186 Phosphothreonine; by CaMK1D.
 MOD_RES 347 347 Phosphoserine; by CDK9 and PKA.
 MOD_RES 350 350 Phosphothreonine; by CDK9.
 MOD_RES 353 353 Phosphoserine; by CDK9.
 MOD_RES 354 354 Phosphothreonine; by CDK9.
 MOD_RES 357 357 Phosphoserine; by CDK9.
 MOD_RES 362 362 Phosphothreonine; by CDK9.
 MOD_RES 363 363 Phosphothreonine; by CDK9.  

Keyword

 3D-structure; Acetylation; Alternative splicing; ATP-binding; Complete proteome; Cytoplasm; DNA damage; DNA repair; Kinase; Nucleotide-binding; Nucleus; Phosphoprotein; Polymorphism; Reference proteome; Serine/threonine-protein kinase; Transcription; Transcription regulation; Transferase; Ubl conjugation. 

Sequence Source

 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 

Protein Length

 372 AA 

Protein Sequence

Gene Ontology

 GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
 GO:0016605; C:PML body; IDA:UniProtKB.
 GO:0008024; C:positive transcription elongation factor complex b; IDA:UniProtKB.
 GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
 GO:0004693; F:cyclin-dependent protein serine/threonine kinase activity; TAS:ProtInc.
 GO:0003677; F:DNA binding; IDA:MGI.
 GO:0008353; F:RNA polymerase II carboxy-terminal domain kinase activity; IDA:UniProtKB.
 GO:0017069; F:snRNA binding; IEA:Compara.
 GO:0044212; F:transcription regulatory region DNA binding; IEA:Compara.
 GO:0008283; P:cell proliferation; TAS:ProtInc.
 GO:0071345; P:cellular response to cytokine stimulus; IDA:UniProtKB.
 GO:0006281; P:DNA repair; IEA:UniProtKB-KW.
 GO:0071157; P:negative regulation of cell cycle arrest; IDA:UniProtKB.
 GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; TAS:Reactome.
 GO:0050434; P:positive regulation of viral transcription; TAS:Reactome.
 GO:0006282; P:regulation of DNA repair; IDA:UniProtKB.
 GO:0031056; P:regulation of histone modification; IDA:UniProtKB.
 GO:0043111; P:replication fork arrest; IDA:UniProtKB.
 GO:0006368; P:transcription elongation from RNA polymerase II promoter; TAS:Reactome.
 GO:0006367; P:transcription initiation from RNA polymerase II promoter; TAS:Reactome.
 GO:0007179; P:transforming growth factor beta receptor signaling pathway; TAS:Reactome.
 GO:0022415; P:viral reproductive process; TAS:Reactome. 

Interpro

 IPR011009; Kinase-like_dom.
 IPR000719; Prot_kinase_cat_dom.
 IPR017441; Protein_kinase_ATP_BS.
 IPR002290; Ser/Thr_dual-sp_kinase_dom.
 IPR008271; Ser/Thr_kinase_AS. 

Pfam

 PF00069; Pkinase 

SMART

 SM00220; S_TKc 

PROSITE

 PS00107; PROTEIN_KINASE_ATP
 PS50011; PROTEIN_KINASE_DOM
 PS00108; PROTEIN_KINASE_ST 

PRINTS