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Protein

Cyclin-dependent kinase 9

Gene

Cdk9

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein 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)DescriptionActionsGraphical viewLength
Binding sitei48ATPPROSITE-ProRule annotation1
Active sitei149Proton acceptorPROSITE-ProRule annotation1
Binding sitei167ATPPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi25 – 33ATPPROSITE-ProRule annotation9
Nucleotide bindingi104 – 106ATPPROSITE-ProRule annotation3

GO - Molecular functioni

  • 7SK snRNA binding Source: UniProtKB
  • ATP binding Source: UniProtKB-KW
  • chromatin binding Source: UniProtKB
  • cyclin binding Source: GO_Central
  • cyclin-dependent protein serine/threonine kinase activity Source: MGI
  • DNA binding Source: MGI
  • protein kinase binding Source: MGI
  • RNA polymerase II carboxy-terminal domain kinase activity Source: MGI
  • RNA polymerase II proximal promoter sequence-specific DNA binding Source: MGI
  • snRNA binding Source: MGI
  • transcription coactivator binding Source: MGI
  • transcription factor binding Source: MGI
  • transcription regulatory region DNA binding Source: BHF-UCL

GO - Biological processi

Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase
Biological processDNA damage, DNA repair, Transcription, Transcription regulation
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

ReactomeiR-MMU-112382 Formation of RNA Pol II elongation complex
R-MMU-2173796 SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription
R-MMU-674695 RNA Polymerase II Pre-transcription Events
R-MMU-6796648 TP53 Regulates Transcription of DNA Repair Genes
R-MMU-6807505 RNA polymerase II transcribes snRNA genes
R-MMU-75955 RNA Polymerase II Transcription Elongation
R-MMU-9018519 Estrogen-dependent gene expression

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
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 2

Organism-specific databases

MGIiMGI:1328368 Cdk9

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000858011 – 372Cyclin-dependent kinase 9Add BLAST372

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei44N6-acetyllysine; by P300/CBP, PCAF/KAT2B and GCN5/KAT2ABy similarity1
Modified residuei48N6-acetyllysine; by PCAF/KAT2B and GCN5/KAT2ABy similarity1
Modified residuei175PhosphoserineBy similarity1
Modified residuei186Phosphothreonine; by CaMK1DBy similarity1
Modified residuei347Phosphoserine; by CDK9 and PKABy similarity1
Modified residuei350Phosphothreonine; by CDK9By similarity1
Modified residuei353Phosphoserine; by CDK9By similarity1
Modified residuei354Phosphothreonine; by CDK9By similarity1
Modified residuei357Phosphoserine; by CDK9By similarity1
Modified residuei362Phosphothreonine; by CDK9By similarity1
Modified residuei363Phosphothreonine; by CDK9By similarity1

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

EPDiQ99J95
PaxDbiQ99J95
PeptideAtlasiQ99J95
PRIDEiQ99J95

PTM databases

iPTMnetiQ99J95
PhosphoSitePlusiQ99J95

Expressioni

Tissue specificityi

Expressed at high levels in brain and kidney.1 Publication

Gene expression databases

BgeeiENSMUSG00000009555
CleanExiMM_CDK9
ExpressionAtlasiQ99J95 baseline and differential
GenevisibleiQ99J95 MM

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 (active). Interacts with HSF1 (By similarity). Interacts with TBX21 (PubMed:27292648).By similarity2 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

Protein-protein interaction databases

BioGridi223714, 7 interactors
ComplexPortaliCPX-230 Positive transcription elongation factor B, CDK9-cyclinT1 complex
CPX-323 Positive transcription elongation factor B, CDK9-cyclinT2a complex
CORUMiQ99J95
DIPiDIP-46368N
IntActiQ99J95, 104 interactors
MINTiQ99J95
STRINGi10090.ENSMUSP00000009699

Structurei

3D structure databases

ProteinModelPortaliQ99J95
SMRiQ99J95
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini19 – 315Protein kinasePROSITE-ProRule annotationAdd BLAST297

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni166 – 191T-loopBy similarityAdd BLAST26

Sequence similaritiesi

Phylogenomic databases

eggNOGiKOG0600 Eukaryota
ENOG410XPIR LUCA
GeneTreeiENSGT00890000139396
HOVERGENiHBG014652
InParanoidiQ99J95
KOiK02211
OMAiKDPTGCD
OrthoDBiEOG091G08Z8
PhylomeDBiQ99J95
TreeFamiTF101039

Family and domain databases

InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR008271 Ser/Thr_kinase_AS
PfamiView protein in Pfam
PF00069 Pkinase, 1 hit
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q99J95-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« 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:June 1, 2001 - v1
Checksum:i973B18869F9963E3
GO
Isoform 2 (identifier: Q99J95-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-51: Missing.

Note: No experimental confirmation available.
Show »
Length:321
Mass (Da):37,002
Checksum:i4E7C2E2B4DB2042A
GO
Isoform 3 (identifier: Q99J95-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-129: Missing.

Show »
Length:243
Mass (Da):28,026
Checksum:i99DBB3953EB6971A
GO

Sequence cautioni

The sequence BAE25966 differs from that shown. Reason: Frameshift at position 46.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti122T → R in BAE34054 (PubMed:16141072).Curated1
Sequence conflicti154N → S in BAE25055 (PubMed:16141072).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0162901 – 129Missing in isoform 3. 1 PublicationAdd BLAST129
Alternative sequenceiVSP_0162891 – 51Missing in isoform 2. 1 PublicationAdd BLAST51

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF327431 mRNA Translation: AAK15699.1
AF327569 Genomic DNA Translation: AAK15706.1
AK089276 mRNA Translation: BAC40824.1
AK142397 mRNA Translation: BAE25055.1
AK143217 mRNA Translation: BAE25312.1
AK144607 mRNA Translation: BAE25966.1 Frameshift.
AK157340 mRNA Translation: BAE34054.1
AL772271 Genomic DNA Translation: CAQ13017.1
BC003901 mRNA Translation: AAH03901.1
CCDSiCCDS15927.1 [Q99J95-1]
RefSeqiNP_570930.1, NM_130860.3 [Q99J95-1]
XP_011237303.1, XM_011239001.1 [Q99J95-3]
UniGeneiMm.27557

Genome annotation databases

EnsembliENSMUST00000009699; ENSMUSP00000009699; ENSMUSG00000009555 [Q99J95-1]
ENSMUST00000120105; ENSMUSP00000113327; ENSMUSG00000009555 [Q99J95-2]
GeneIDi107951
KEGGimmu:107951
UCSCiuc008jgn.2 mouse [Q99J95-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiCDK9_MOUSE
AccessioniPrimary (citable) accession number: Q99J95
Secondary accession number(s): B0R020
, Q3U002, Q3UMY2, Q3UPT3, Q3UQI6, Q8BTN0
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 2005
Last sequence update: June 1, 2001
Last modified: June 20, 2018
This is version 153 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

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