CDK9 - Cyclin-dependent kinase 9 - human protein (Function)
 
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CDK9 »  Cyclin-dependent kinase 9
 
Gene name:  CDK9
Entry whose protein(s) existence is based on evidence at protein level
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GENE REF ISO

Function

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Overview 
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.  
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  • CuratedUniProtKB
GO molecular function 
ATP bindingdefinition[GO:0005524]  
  • IEAUniProtKB KW
Chromatin bindingdefinition[GO:0003682] silver  
  • IEAOrtholog Compara
Cyclin-dependent protein serine/threonine kinase activitydefinition[GO:0004693]  
  • IEAEC 2 GO
DNA bindingdefinition[GO:0003677]  
1
  • IDAMGI
Protein bindingdefinition[GO:0005515]  
16
  • IPIIntAct
  • IPIHGNC
  • IPIUniProtKB
Protein kinase activitydefinition[GO:0004672]  
1
  • TASPINC
RNA polymerase II carboxy-terminal domain kinase activitydefinition[GO:0008353]  
1
  • IDAUniProtKB
snRNA bindingdefinition[GO:0017069] silver  
  • IEAOrtholog Compara
Transcription regulatory region DNA bindingdefinition[GO:0044212] silver  
  • IEAOrtholog Compara
GO biological process 
Cell proliferationdefinition[GO:0008283]  
1
  • TASPINC
Cellular response to cytokine stimulusdefinition[GO:0071345]  
1
  • IDAUniProtKB
DNA repairdefinition[GO:0006281]  
  • IEAUniProtKB KW
Negative regulation of cell cycle arrestdefinition[GO:0071157]  
1
  • IDAUniProtKB
Protein phosphorylationdefinition[GO:0006468]  
1
  • IDAMGI
Regulation of DNA repairdefinition[GO:0006282]  
1
  • IDAUniProtKB
Regulation of histone modificationdefinition[GO:0031056]  
1
  • IDAUniProtKB
Replication fork arrestdefinition[GO:0043111]  
1
  • IDAUniProtKB
Enzymatic activity 
This protein acts as an enzyme. It is known to catalyze the following reactions
EC 2.7.11.22: ATP + a protein ADP + a phosphoprotein.  
  • CuratedUniProtKB
EC 2.7.11.23: ATP + [DNA-directed RNA polymerase] ADP + [DNA-directed RNA polymerase] phosphate.  
  • CuratedUniProtKB
It is regulated in the following manner
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.  
6
  • CuratedUniProtKB
 
More information is available from:
Pathways 
According to Reactome, this protein belongs to the following pathways:
Formation of HIV elongation complex in the absence of HIV Tat  REACT_22201  
Formation of HIV-1 elongation complex containing HIV-1 Tat  REACT_6346  
HIV elongation arrest and recovery  REACT_6259  
Interactions of Tat with host cellular proteins  REACT_6905  
Pausing and recovery of HIV elongation  REACT_6244  
Pausing and recovery of Tat-mediated HIV elongation  REACT_6143  
RNA Polymerase II Pre-transcription Events  REACT_22107  
RNA Polymerase II Transcription Elongation  REACT_833  
SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription  REACT_120734  
Tat-mediated elongation of the HIV-1 transcript  REACT_6162  
Tat-mediated HIV elongation arrest and recovery  REACT_6344  
Note 
CDK9 inhibition contributes to the anticancer activity of most CDK inhibitors under clinical investigation (PubMed18423896 and PubMed21779453). As a retroviruses target during the hijack of host transcription (e.g. HIV), CDK9 inhibitors might become specific antiretroviral agents (PubMed18423896). May be a target for cardiac hypertrophy future treatments (PubMed19757441 and PubMed18423896). May also be a target in anti-inflammatory therapy in innate immunity and systemic inflammation (PubMed18728388).  
4
  • CuratedUniProtKB
 

Keywords

Biological process 
DNA damage  definition   [KW-0227]
DNA repair  definition   [KW-0234]
Transcription  definition   [KW-0804]
Transcription regulation  definition   [KW-0805]
Molecular function 
Kinase  definition   [KW-0418]
Serine/threonine-protein kinase  definition   [KW-0723]
Transferase  definition   [KW-0808]
Technical term 
Reference proteome  definition   [KW-1185]
 

Further external links

Other
GeneWiki: CDK9
GeneWiki: Cyclin-dependent_kinase_9
GenomeRNAi: 1025
PRO: PR:P50750
Chemistry
GuidetoPHARMACOLOGY: 1981