CDK9

CDK9 (Cyclin Dependent Kinase 9) is a Protein Coding gene. Diseases associated with CDK9 include Central Nervous System Vasculitis and Laryngeal Tuberculosis. Among its related pathways are Formation of HIV elongation complex in the absence of HIV Tat and Gene Expression. Gene Ontology (GO) annotations related to this gene include transferase activity, transferring phosphorus-containing groups and protein tyrosine kinase activity. An important paralog of this gene is CDK12.

Cyclin Dependent Kinase 9

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).

Cell population proliferation Source: ProtInc
Cellular response to cytokine stimulus Source: UniProtKB
DNA repair Source: UniProtKB-KW
Negative regulation of cell cycle arrest Source: UniProtKB
Negative regulation of mRNA polyadenylation Source: UniProtKB
Phosphorylation of RNA polymerase II C-terminal domain Source: UniProtKB
Positive regulation of cardiac muscle hypertrophy Source: Ensembl
Positive regulation of histone H2B ubiquitination Source: UniProtKB
Positive regulation of histone phosphorylation Source: UniProtKB
Positive regulation of mRNA 3'-UTR binding Source: UniProtKB
Positive regulation of transcription by RNA polymerase II Source: UniProtKB
Positive regulation of viral transcription Source: Reactome
Protein phosphorylation Source: MGI
Regulation of DNA repair Source: UniProtKB
Regulation of histone modification Source: UniProtKB
Regulation of muscle cell differentiation Source: UniProtKB
Replication fork processing Source: UniProtKB
Response to drug Source: Ensembl
snRNA transcription by RNA polymerase II Source: Reactome
Transcription by RNA polymerase II Source: Reactome
Transcription elongation from RNA polymerase II promoter Source: Reactome
Transcription initiation from RNA polymerase II promoter Source: ProtInc

Cytoplasm; Nucleus; PML body. 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.

Chronic activation of CDK9 causes cardiac myocyte enlargement leading to cardiac hypertrophy and confers predisposition to heart failure.

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 Ca2+ 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).
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.
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).
Polyubiquitinated and thus activated by UBR5. This ubiquitination is promoted by TFIIS/TCEA1 and favors 'Ser-2' phosphorylation of RPB1/POLR2A CTD.