Human Gene CDK9 (ENST00000373264.5) from GENCODE V44
Description: Homo sapiens cyclin dependent kinase 9 (CDK9), mRNA. (from RefSeq NM_001261) RefSeq Summary (NM_001261): The protein encoded by this gene is a member of the cyclin-dependent protein kinase (CDK) family. CDK family members are highly similar to the gene products of S. cerevisiae cdc28, and S. pombe cdc2, and known as important cell cycle regulators. This kinase was found to be a component of the multiprotein complex TAK/P-TEFb, which is an elongation factor for RNA polymerase II-directed transcription and functions by phosphorylating the C-terminal domain of the largest subunit of RNA polymerase II. This protein forms a complex with and is regulated by its regulatory subunit cyclin T or cyclin K. HIV-1 Tat protein was found to interact with this protein and cyclin T, which suggested a possible involvement of this protein in AIDS. [provided by RefSeq, Jul 2008]. Gencode Transcript: ENST00000373264.5 Gencode Gene: ENSG00000136807.14 Transcript (Including UTRs) Position: hg38 chr9:127,786,034-127,790,792 Size: 4,759 Total Exon Count: 7 Strand: + Coding Region Position: hg38 chr9:127,786,149-127,789,543 Size: 3,395 Coding Exon Count: 7
ID:CDK9_HUMAN DESCRIPTION: RecName: Full=Cyclin-dependent kinase 9; EC=2.7.11.22; EC=2.7.11.23; AltName: Full=C-2K; AltName: Full=Cell division cycle 2-like protein kinase 4; AltName: Full=Cell division protein kinase 9; AltName: Full=Serine/threonine-protein kinase PITALRE; AltName: Full=Tat-associated kinase complex catalytic subunit; FUNCTION: 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. CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. CATALYTIC ACTIVITY: ATP + [DNA-directed RNA polymerase] = ADP + [DNA-directed RNA polymerase] phosphate. ENZYME 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. SUBUNIT: 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. 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 preinitiation complex with BRD4 until new Thr-186 phosphorylation occurs after the synthesis of a short RNA. Binds to BRD4, probably to target chromatin binding. 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. Interacts with activated nuclear STAT3 and RELA/p65. Binds to AR and MYOD1. Forms a complex composed of CDK9, CCNT1/cyclin-T1, EP300 and GATA4 that stimulates hypertrophy in cardiomyocytes. Isoform 3 binds to KU70/XRCC6. INTERACTION: P04608:tat (xeno); NbExp=5; IntAct=EBI-1383449, EBI-6164389; 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). 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 by CBP/p300 promotes kinase activity, whereas acetylation of both Lys-44 and Lys-48 mediated by PCAF/KAT2B and GCN5/KAT2A reduces kinase activity. The acetylated form associates with PML bodies in the nuclear matrix and with the transcriptionally silent HIV-1 genome; deacetylated upon transcription stimulation. PTM: Polyubiquitinated and thus activated by UBR5. This ubiquitination is promoted by TFIIS/TCEA1 and favors 'Ser-2' phosphorylation of RPB1/POLR2A CTD. 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). SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily. SIMILARITY: Contains 1 protein kinase domain. SEQUENCE CAUTION: Sequence=CAI39767.1; Type=Erroneous gene model prediction; WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/cdk9/";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on P50750
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Gene Ontology (GO) Annotations with Structured Vocabulary
Molecular Function: GO:0000166 nucleotide binding GO:0000978 RNA polymerase II core promoter proximal region sequence-specific DNA binding GO:0001223 transcription coactivator binding GO:0003677 DNA binding GO:0003682 chromatin binding GO:0004672 protein kinase activity GO:0004674 protein serine/threonine kinase activity GO:0004693 cyclin-dependent protein serine/threonine kinase activity GO:0005515 protein binding GO:0005524 ATP binding GO:0008134 transcription factor binding GO:0008353 RNA polymerase II carboxy-terminal domain kinase activity GO:0016301 kinase activity GO:0016740 transferase activity GO:0017069 snRNA binding GO:0019901 protein kinase binding GO:0030332 cyclin binding GO:0044212 transcription regulatory region DNA binding GO:0097322 7SK snRNA binding
Biological Process: GO:0006281 DNA repair GO:0006282 regulation of DNA repair GO:0006351 transcription, DNA-templated GO:0006355 regulation of transcription, DNA-templated GO:0006366 transcription from RNA polymerase II promoter GO:0006367 transcription initiation from RNA polymerase II promoter GO:0006368 transcription elongation from RNA polymerase II promoter GO:0006468 protein phosphorylation GO:0006974 cellular response to DNA damage stimulus GO:0008283 cell proliferation GO:0010613 positive regulation of cardiac muscle hypertrophy GO:0016310 phosphorylation GO:0031056 regulation of histone modification GO:0031297 replication fork processing GO:0033129 positive regulation of histone phosphorylation GO:0042493 response to drug GO:0042795 snRNA transcription from RNA polymerase II promoter GO:0045944 positive regulation of transcription from RNA polymerase II promoter GO:0050434 positive regulation of viral transcription GO:0051147 regulation of muscle cell differentiation GO:0070816 phosphorylation of RNA polymerase II C-terminal domain GO:0071157 negative regulation of cell cycle arrest GO:0071345 cellular response to cytokine stimulus GO:1900364 negative regulation of mRNA polyadenylation GO:1903839 positive regulation of mRNA 3'-UTR binding GO:2001168 positive regulation of histone H2B ubiquitination GO:0007346 regulation of mitotic cell cycle
JD406159 - Sequence 387183 from Patent EP1572962. JD141747 - Sequence 122771 from Patent EP1572962. X80230 - H.sapiens mRNA (clone C-2k) mRNA for serine/threonine protein kinase. JD211276 - Sequence 192300 from Patent EP1572962. L25676 - Homo sapiens CDC2-related kinase (PITALRE) mRNA, complete cds. BC001968 - Homo sapiens cyclin-dependent kinase 9, mRNA (cDNA clone MGC:5166 IMAGE:3460767), complete cds. JD177112 - Sequence 158136 from Patent EP1572962. JD452757 - Sequence 433781 from Patent EP1572962. JD373077 - Sequence 354101 from Patent EP1572962. JD373078 - Sequence 354102 from Patent EP1572962. AK313828 - Homo sapiens cDNA, FLJ94450, highly similar to Homo sapiens cyclin-dependent kinase 9 (CDC2-related kinase) (CDK9), mRNA. JD456148 - Sequence 437172 from Patent EP1572962. AB590139 - Synthetic construct DNA, clone: pFN21AB0443, Homo sapiens CDK9 gene for cyclin-dependent kinase 9, without stop codon, in Flexi system. DQ891182 - Synthetic construct clone IMAGE:100003812; FLH169922.01X; RZPDo839H0896D cyclin-dependent kinase 9 (CDC2-related kinase) (CDK9) gene, encodes complete protein. DQ894364 - Synthetic construct Homo sapiens clone IMAGE:100008824; FLH169918.01L; RZPDo839H0895D cyclin-dependent kinase 9 (CDC2-related kinase) (CDK9) gene, encodes complete protein. DQ894365 - Synthetic construct Homo sapiens clone IMAGE:100008825; FLH263695.01L; RZPDo839H0995D cyclin-dependent kinase 9 (CDC2-related kinase) (CDK9) gene, encodes complete protein. KJ896585 - Synthetic construct Homo sapiens clone ccsbBroadEn_05979 CDK9 gene, encodes complete protein. KJ905169 - Synthetic construct Homo sapiens clone ccsbBroadEn_14579 CDK9 gene, encodes complete protein. AB451421 - Homo sapiens CDK9 mRNA for cyclin-dependent kinase 9, partial cds, clone: FLJ08130AAAF. AB451289 - Homo sapiens CDK9 mRNA for cyclin-dependent kinase 9, complete cds, clone: FLJ08130AAAN. BT019903 - Homo sapiens cyclin-dependent kinase 9 (CDC2-related kinase) mRNA, complete cds. DQ570855 - Homo sapiens piRNA piR-30967, complete sequence. JD566744 - Sequence 547768 from Patent EP1572962. JD238511 - Sequence 219535 from Patent EP1572962. JD483088 - Sequence 464112 from Patent EP1572962. JD072641 - Sequence 53665 from Patent EP1572962. JD298621 - Sequence 279645 from Patent EP1572962. JD252310 - Sequence 233334 from Patent EP1572962. JD078211 - Sequence 59235 from Patent EP1572962. JD340162 - Sequence 321186 from Patent EP1572962.
Biochemical and Signaling Pathways
Reactome (by CSHL, EBI, and GO)
Protein P50750 (Reactome details) participates in the following event(s):
R-HSA-112430 Formation of P-TEFb complex R-HSA-167235 Formation of the P-TEFb(Cyclin T1:Cdk9) complex R-HSA-112381 Hyperphosphorylation (Ser2) of RNA Pol II CTD by P-TEFb complex R-HSA-167084 Hyperphosphorylation (Ser2) of RNA Pol II CTD by P-TEFb complex R-HSA-6810234 General transcription factors bind SNAPc:POU2F1:ZNF143:snRNA gene R-HSA-113429 Elongating transcript encounters a lesion in the template R-HSA-167234 Association of Tat with P-TEFb(Cyclin T1:Cdk9) R-HSA-112379 Recruitment of elongation factors to form elongation complex R-HSA-113411 2-4 nt.backtracking of Pol II complex on the template leading to elongation pausing R-HSA-113412 Pol II elongation complex moves on the template as transcript elongates R-HSA-113414 7-14 nt. Backtracking of Pol II complex on the template leading to elongation arrest R-HSA-112385 Addition of nucleotides leads to transcript elongation R-HSA-112392 Resumption of elongation after recovery from pausing R-HSA-113413 TFIIS-mediated recovery of elongation from arrest R-HSA-112395 Abortive termination of elongation after arrest R-HSA-112396 Separation of elongating transcript from template R-HSA-167077 Recruitment of elongation factors to form HIV-1 elongation complex R-HSA-167282 2-4 nt.backtracking of Pol II complex on the HIV-1 template leading to elongation pausing R-HSA-167284 7-14 nt. Backtracking of Pol II complex on the HIV-1 template leading to elongation arrest R-HSA-167288 TFIIS-mediated recovery of HIV-1 elongation from arrest R-HSA-167292 Resumption of elongation of HIV-1 transcript after recovery from pausing R-HSA-167481 Abortive termination of HIV-1 elongation after arrest R-HSA-6810238 RNA polymerase II binds initiation factors at promoter of snRNA gene (U1, U2, U4, U4atac, U5, U11, U12) R-HSA-167191 Hyperphosphorylation (Ser2) of RNA Pol II CTD by the P-TEFb(Cyclin T1:Cdk9) complex R-HSA-9012315 ESR1:ESTG:P-TEFb recruited to paused RNA polymerase II on MYB gene R-HSA-6797616 CCNK:CDK12 binds RNA Pol II at DNA repair genes R-HSA-6810235 RPAP2 binds RNA polymerase II phosphorylated at serine-7 residues of heptad repeats in the C-terminal domain R-HSA-6810233 CDK7 phosphorylates serine-5 and serine-7 of heptad repeats in C-terminal domain of RNA polymerase II at snRNA promoter R-HSA-6814885 CBCAP complex binds 7-methylguanosine cap of snRNA R-HSA-2176475 Phosphorylation of SMAD2 and SMAD3 linker regions by CDK8 or CDK9 R-HSA-167150 Resumption of elongation of HIV-1 transcript after recovery from pausing R-HSA-167076 2-4 nt.backtracking of Pol II complex on the HIV-1 template leading to elongation pausing R-HSA-167148 TFIIS-mediated recovery of elongation from arrest R-HSA-167459 Abortive termination of HIV-1 elongation after arrest (Tat-containing elongation complex) R-HSA-167090 7-14 nt. Backtracking of Pol II complex on the HIV-1 template leading to elongation arrest R-HSA-170706 Phosphorylation of NEFL by the P-TEFb(Cyclin T1:Cdk9) complex R-HSA-167192 Pol II elongation complex moves on the HIV-1 template as transcript elongates R-HSA-167181 Addition of nucleotides leads to HIV-1 transcript elongation R-HSA-167197 Separation of elongating HIV-1 transcript from template R-HSA-170704 Phosphorylation of DSIF by the P-TEFb(Cyclin T1:Cdk9) complex R-HSA-167196 Recruitment of elongation factors to form HIV-1 elongation complex R-HSA-9012319 p-TEFb phosphorylates serine 2 in RNA polymerase II CTD R-HSA-6797606 CDK12 phosphorylates RNA Pol II CTD at DNA repair genes R-HSA-674695 RNA Polymerase II Pre-transcription Events R-HSA-176034 Interactions of Tat with host cellular proteins R-HSA-112382 Formation of RNA Pol II elongation complex R-HSA-167152 Formation of HIV elongation complex in the absence of HIV Tat R-HSA-6807505 RNA polymerase II transcribes snRNA genes R-HSA-167200 Formation of HIV-1 elongation complex containing HIV-1 Tat R-HSA-73857 RNA Polymerase II Transcription R-HSA-162909 Host Interactions of HIV factors R-HSA-75955 RNA Polymerase II Transcription Elongation R-HSA-167290 Pausing and recovery of HIV elongation R-HSA-167287 HIV elongation arrest and recovery R-HSA-167172 Transcription of the HIV genome R-HSA-9018519 Estrogen-dependent gene expression R-HSA-167246 Tat-mediated elongation of the HIV-1 transcript R-HSA-74160 Gene expression (Transcription) R-HSA-162906 HIV Infection R-HSA-6796648 TP53 Regulates Transcription of DNA Repair Genes R-HSA-2173796 SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription R-HSA-162599 Late Phase of HIV Life Cycle R-HSA-167238 Pausing and recovery of Tat-mediated HIV elongation R-HSA-167243 Tat-mediated HIV elongation arrest and recovery R-HSA-8939211 ESR-mediated signaling R-HSA-167169 HIV Transcription Elongation R-HSA-5663205 Infectious disease R-HSA-3700989 Transcriptional Regulation by TP53 R-HSA-2173793 Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer R-HSA-162587 HIV Life Cycle R-HSA-9006931 Signaling by Nuclear Receptors R-HSA-1643685 Disease R-HSA-212436 Generic Transcription Pathway R-HSA-170834 Signaling by TGF-beta Receptor Complex R-HSA-162582 Signal Transduction R-HSA-9006936 Signaling by TGF-beta family members
US Server
