CDK9
entrez
1025
canonical
uniprot
P50750
canonical
ensembl
ENSG00000136807
resolver
ensp
ENSP00000362361
resolver
genesymbol
CDK9
resolver
genesymbol_syn
CDC2L4
resolver
genesymbol_syn
TAK
resolver
hgnc
HGNC:1780
resolver
uniprot
Q5JU24
resolver
uniprot
Q5JU25
resolver
uniprot
Q5U006
resolver
uniprot
Q96TF1
resolver
uniprot_entry
CDK9_HUMAN
resolver
uniprot_sec
Q5JU24
resolver
uniprot_sec
Q5JU25
resolver
uniprot_sec
Q5U006
resolver
uniprot_sec
Q96TF1
resolver
activity_regulation
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}.
uniprot
proteins
amino_acid_sequence
MAKQYDSVECPFCDEVSKYEKLAKIGQGTFGEVFKARHRKTGQKVALKKVLMENEKEGFPITALREIKILQLLKHENVVNLIEICRTKASPYNRCKGSIYLVFDFCEHDLAGLLSNVLVKFTLSEIKRVMQMLLNGLYYIHRNKILHRDMKAANVLITRDGVLKLADFGLARAFSLAKNSQPNRYTNRVVTLWYRPPELLLGERDYGPPIDLWGAGCIMAEMWTRSPIMQGNTEQHQLALISQLCGSITPEVWPNVDNYELYEKLELVKGQKRKVKDRLKAYVRDPYALDLIDKLLVLDPAQRIDSDDALNHDFFWSDPMPSDLKGMLSTHLTSMFEYLAPPRRKGSQITQQSTNQSRNPATTNQTEFERVF
uniprot
proteins
disease_involvement
DISEASE: Note=Chronic activation of CDK9 causes cardiac myocyte enlargement leading to cardiac hypertrophy and confers predisposition to heart failure.
uniprot
proteins
ec_number
2.7.11.22
uniprot
proteins
ec_number
2.7.11.23
uniprot
proteins
function
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, PubMed:29335245). 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:16427012, PubMed:20930849, PubMed:28426094, PubMed:30134174). 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 NELFE (PubMed:10912001, PubMed:11112772, PubMed:12037670, PubMed:16427012, PubMed:20081228, PubMed:20980437, PubMed:21127351, PubMed:9857195). 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, PubMed:28539972). 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). Also catalyzes phosphorylation of histone H1.4 (H1-4) at 'Ser-187' (H1.4S187Ph), a modification associated with transcription activation (PubMed:28539972). 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:10912001, PubMed:11112772, PubMed:9857195). The phosphorylation of MYOD1 enhances its transcriptional activity and thus promotes muscle differentiation (PubMed:12037670). Catalyzes phosphorylation of KAT5, promoting KAT5 recruitment to chromatin and histone acetyltransferase activity (PubMed:29335245). {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:16427012, 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:28539972, ECO:0000269|PubMed:29335245, ECO:0000269|PubMed:30134174, ECO:0000269|PubMed:9857195}.
uniprot
proteins
mass_dalton
42778
uniprot
proteins
mutagenesis
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 HIVTAT."; /evidence="ECO:0000269|PubMed:10958691"; MUTAGEN 347..357; /note="SQITQQSTNQS->EQIEQQEENQE: Mimics autophosphorylation and promotes interaction with HIVTAT."; /evidence="ECO:0000269|PubMed:10958691
uniprot
proteins
post_translational_modification
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 (PubMed:18483222, PubMed:18829461). However, PPP1CA-mediated Thr-186 dephosphorylation is required to release P-TEFb from its inactive P-TEFb/7SK snRNP complex (PubMed:18483222, PubMed:18829461). Dephosphorylated at Ser-347 by the PNUTS-PP1 complex during RNA polymerase II transcription pause-release (PubMed:39603239). Dephosphorylation of C-terminus Thr and Ser residues by protein phosphatase-1 (PP1) triggers CDK9 activity, contributing to the activation of HIV-1 transcription. {ECO:0000269|PubMed:18483222, ECO:0000269|PubMed:18829461, ECO:0000269|PubMed:39603239}.; 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}.
uniprot
proteins
protein_family
CDC2/CDKX subfamily
uniprot
proteins
protein_family
CMGC Ser/Thr protein kinase family
uniprot
proteins
protein_family
Protein kinase superfamily
uniprot
proteins
pubmed
10393184
uniprot
proteins
pubmed
10574912
uniprot
proteins
pubmed
10757782
uniprot
proteins
pubmed
10903437
uniprot
proteins
pubmed
10912001
uniprot
proteins
pubmed
10958691
uniprot
proteins
pubmed
11112772
uniprot
proteins
pubmed
11145967
uniprot
proteins
pubmed
11575923
uniprot
proteins
pubmed
11809800
uniprot
proteins
pubmed
11884399
uniprot
proteins
pubmed
12037670
uniprot
proteins
pubmed
12065898
uniprot
proteins
pubmed
12115727
uniprot
proteins
pubmed
12718890
uniprot
proteins
pubmed
14701750
uniprot
proteins
pubmed
15164053
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15564463
uniprot
proteins
pubmed
15965233
uniprot
proteins
pubmed
16109376
uniprot
proteins
pubmed
16109377
uniprot
proteins
pubmed
16427012
uniprot
proteins
pubmed
16885020
uniprot
proteins
pubmed
17344846
uniprot
proteins
pubmed
17452463
uniprot
proteins
pubmed
17643375
uniprot
proteins
pubmed
17956865
uniprot
proteins
pubmed
18249148
uniprot
proteins
pubmed
18250157
uniprot
proteins
pubmed
18362169
uniprot
proteins
pubmed
18423896
uniprot
proteins
pubmed
18483222
uniprot
proteins
pubmed
18566585
uniprot
proteins
pubmed
18691976
uniprot
proteins
pubmed
18728388
uniprot
proteins
pubmed
18829461
uniprot
proteins
pubmed
19029809
uniprot
proteins
pubmed
19238148
uniprot
proteins
pubmed
19369195
uniprot
proteins
pubmed
19575011
uniprot
proteins
pubmed
19757441
uniprot
proteins
pubmed
19844166
uniprot
proteins
pubmed
20081228
uniprot
proteins
pubmed
20159561
uniprot
proteins
pubmed
20471948
uniprot
proteins
pubmed
20493174
uniprot
proteins
pubmed
20535204
uniprot
proteins
pubmed
20851342
uniprot
proteins
pubmed
20930849
uniprot
proteins
pubmed
20980437
uniprot
proteins
pubmed
21127351
uniprot
proteins
pubmed
21200140
uniprot
proteins
pubmed
21269460
uniprot
proteins
pubmed
21406692
uniprot
proteins
pubmed
21448926
uniprot
proteins
pubmed
21484792
uniprot
proteins
pubmed
21533037
uniprot
proteins
pubmed
21779453
uniprot
proteins
pubmed
22195968
uniprot
proteins
pubmed
23029222
uniprot
proteins
pubmed
24275569
uniprot
proteins
pubmed
24360279
uniprot
proteins
pubmed
25233083
uniprot
proteins
pubmed
27189267
uniprot
proteins
pubmed
28426094
uniprot
proteins
pubmed
28539972
uniprot
proteins
pubmed
29335245
uniprot
proteins
pubmed
30134174
uniprot
proteins
pubmed
30237576
uniprot
proteins
pubmed
34696162
uniprot
proteins
pubmed
39603239
uniprot
proteins
pubmed
7695608
uniprot
proteins
pubmed
8170997
uniprot
proteins
pubmed
9491887
uniprot
proteins
pubmed
9499409
uniprot
proteins
pubmed
9857195
uniprot
proteins
sequence_length
372
uniprot
proteins
subcellular_location
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.
uniprot
proteins