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Protein

Cyclin-dependent kinase 9

Gene

Cdk9

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at transcript leveli

Functioni

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 (By similarity).By similarity

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.
ATP + [DNA-directed RNA polymerase] = ADP + [DNA-directed RNA polymerase] phosphate.

Enzyme regulationi

Activation by Thr-186 phosphorylation is calcium Ca2+ signaling pathway-dependent; actively inactivated by dephosphorylation mediated by PPP1CA, PPM1A and PPM1B. Reversibly repressed by acetylation at Lys-44 and Lys-48 (By similarity).By similarity

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei48 – 481ATPPROSITE-ProRule annotation
Active sitei149 – 1491Proton acceptorPROSITE-ProRule annotation
Binding sitei167 – 1671ATPPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi25 – 339ATPPROSITE-ProRule annotation
Nucleotide bindingi104 – 1063ATPPROSITE-ProRule annotation

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

DNA damage, DNA repair, Transcription, Transcription regulation

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

ReactomeiREACT_273293. RNA Polymerase II Pre-transcription Events.
REACT_283793. Formation of RNA Pol II elongation complex.
REACT_336382. SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription.
REACT_343091. RNA Polymerase II Transcription Elongation.

Names & Taxonomyi

Protein namesi
Recommended name:
Cyclin-dependent kinase 9 (EC:2.7.11.22, EC:2.7.11.23)
Alternative name(s):
Cell division protein kinase 9
Gene namesi
Name:Cdk9
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
ProteomesiUP000002494 Componenti: Chromosome 3

Organism-specific databases

RGDi1359638. Cdk9.

Subcellular locationi

  • Nucleus By similarity
  • Cytoplasm By similarity
  • NucleusPML body By similarity

  • 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 (By similarity).By similarity

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 372372Cyclin-dependent kinase 9PRO_0000085802Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei29 – 291PhosphothreonineBy similarity
Modified residuei44 – 441N6-acetyllysine; by P300/CBP, PCAF/KAT2B and GCN5/KAT2ABy similarity
Modified residuei48 – 481N6-acetyllysine; by PCAF/KAT2B and GCN5/KAT2ABy similarity
Modified residuei175 – 1751PhosphoserineBy similarity
Modified residuei186 – 1861Phosphothreonine; by CaMK1DBy similarity
Modified residuei347 – 3471Phosphoserine; by CDK9 and PKABy similarity
Modified residuei350 – 3501Phosphothreonine; by CDK9By similarity
Modified residuei353 – 3531Phosphoserine; by CDK9By similarity
Modified residuei354 – 3541Phosphothreonine; by CDK9By similarity
Modified residuei357 – 3571Phosphoserine; by CDK9By similarity
Modified residuei362 – 3621Phosphothreonine; by CDK9By similarity
Modified residuei363 – 3631Phosphothreonine; by CDK9By similarity

Post-translational modificationi

Autophosphorylation at Thr-186, Ser-347, Thr-350, Ser-353, Thr-354 and Ser-357 triggers kinase activity by promoting cyclin and substrate binding upon conformational changes. Thr-186 phosphorylation requires the calcium Ca2+ signaling pathway, including CaMK1D and calmodulin. This inhibition is relieved by Thr-29 dephosphorylation. Phosphorylation at Ser-175 inhibits kinase activity. Can be phosphorylated on either Thr-362 or Thr-363 but not on both simultaneously (By similarity).By similarity
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 (By similarity).By similarity
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; deacetylated upon transcription stimulation (By similarity).By similarity
Polyubiquitinated and thus activated by UBR5. This ubiquitination is promoted by TFIIS/TCEA1 and favors 'Ser-2' phosphorylation of RPB1/POLR2A CTD (By similarity).By similarity

Keywords - PTMi

Acetylation, Phosphoprotein, Ubl conjugation

Proteomic databases

PRIDEiQ641Z4.

PTM databases

PhosphoSiteiQ641Z4.

Expressioni

Gene expression databases

GenevisibleiQ641Z4. RN.

Interactioni

Subunit structurei

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 Ca2+ 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. Interacts with BRD4, probably to target chromatin binding. 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. 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).By similarity

Protein-protein interaction databases

BioGridi263196. 1 interaction.
IntActiQ641Z4. 1 interaction.
STRINGi10116.ENSRNOP00000037778.

Structurei

3D structure databases

ProteinModelPortaliQ641Z4.
SMRiQ641Z4. Positions 8-332.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini19 – 315297Protein kinasePROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni166 – 19126T-loopBy similarityAdd
BLAST

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiCOG0515.
GeneTreeiENSGT00800000124088.
HOGENOMiHOG000233024.
HOVERGENiHBG014652.
InParanoidiQ641Z4.
KOiK02211.
OMAiERMLSTH.
OrthoDBiEOG76DTSM.
PhylomeDBiQ641Z4.
TreeFamiTF101039.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q641Z4-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MAKQYDSVEC PFCDEVTKYE KLAKIGQGTF GEVFKAKHRQ TGQKVALKKV
60 70 80 90 100
LMENEKEGFP ITALREIKIL QLLKHENVVN LIEICRTKAS PYNRCKGSIY
110 120 130 140 150
LVFDFCEHDL AGLLSNVLVK FTLSEIKRVM QMLLNGLYYI HRNKILHRDM
160 170 180 190 200
KAANVLITRD GVLKLADFGL ARAFSLAKNS QPNRYTNRVV TLWYRPPELL
210 220 230 240 250
LGERDYGPPI DLWGAGCIMA EMWTRSPIMQ GNTEQHQLAL ISQLCGSITP
260 270 280 290 300
EVWPNVDKYE LFEKLELVKG QKRKVKDRLK AYVRDPYALD LIDKLLVLDP
310 320 330 340 350
AQRIDSDDAL NHDFFWSDPM PSDLKGMLST HLTSMFEYLA PPRRKGSQIT
360 370
QQSTNQSRNP ATTNQTEFER VF
Length:372
Mass (Da):42,762
Last modified:October 25, 2004 - v1
Checksum:i973B18869F9963E3
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
BC082037 mRNA. Translation: AAH82037.1.
RefSeqiNP_001007744.1. NM_001007743.1.
UniGeneiRn.98228.

Genome annotation databases

EnsembliENSRNOT00000032893; ENSRNOP00000037778; ENSRNOG00000022586.
GeneIDi362110.
KEGGirno:362110.
UCSCiRGD:1359638. rat.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
BC082037 mRNA. Translation: AAH82037.1.
RefSeqiNP_001007744.1. NM_001007743.1.
UniGeneiRn.98228.

3D structure databases

ProteinModelPortaliQ641Z4.
SMRiQ641Z4. Positions 8-332.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi263196. 1 interaction.
IntActiQ641Z4. 1 interaction.
STRINGi10116.ENSRNOP00000037778.

PTM databases

PhosphoSiteiQ641Z4.

Proteomic databases

PRIDEiQ641Z4.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSRNOT00000032893; ENSRNOP00000037778; ENSRNOG00000022586.
GeneIDi362110.
KEGGirno:362110.
UCSCiRGD:1359638. rat.

Organism-specific databases

CTDi1025.
RGDi1359638. Cdk9.

Phylogenomic databases

eggNOGiCOG0515.
GeneTreeiENSGT00800000124088.
HOGENOMiHOG000233024.
HOVERGENiHBG014652.
InParanoidiQ641Z4.
KOiK02211.
OMAiERMLSTH.
OrthoDBiEOG76DTSM.
PhylomeDBiQ641Z4.
TreeFamiTF101039.

Enzyme and pathway databases

ReactomeiREACT_273293. RNA Polymerase II Pre-transcription Events.
REACT_283793. Formation of RNA Pol II elongation complex.
REACT_336382. SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription.
REACT_343091. RNA Polymerase II Transcription Elongation.

Miscellaneous databases

NextBioi678687.
PROiQ641Z4.

Gene expression databases

GenevisibleiQ641Z4. RN.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

  1. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Tissue: Testis.

Entry informationi

Entry nameiCDK9_RAT
AccessioniPrimary (citable) accession number: Q641Z4
Entry historyi
Integrated into UniProtKB/Swiss-Prot: February 1, 2005
Last sequence update: October 25, 2004
Last modified: July 22, 2015
This is version 106 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.