UniProt functional annotation for P50750



	UniProt functional annotation for P50750

UniProt code: P50750.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

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}.

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.

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}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



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}.
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.
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}.