Q99J95 (CDK9_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified July 9, 2014. Version 114. History...
Names and origin
|Protein names||Recommended name:|
Cyclin-dependent kinase 9
Cell division protein kinase 9
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||372 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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.
ATP + a protein = ADP + a phosphoprotein.
ATP + [DNA-directed RNA polymerase] = ADP + [DNA-directed RNA polymerase] phosphate.
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.
Associates with CCNT1/cyclin-T1, CCNT2/cyclin-T2 (isoform Aand 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). Ref.6
Nucleus. Cytoplasm By similarity. Nucleus › PML 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. Ref.6
Expressed at high levels in brain and kidney. Ref.1
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.
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.
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.
Polyubiquitinated and thus activated by UBR5. This ubiquitination is promoted by TFIIS/TCEA1 and favors 'Ser-2' phosphorylation of RPB1/POLR2A CTD By similarity.
Contains 1 protein kinase domain.
|This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]|
|Isoform 1 (identifier: Q99J95-1) |
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.
|Isoform 2 (identifier: Q99J95-2) |
The sequence of this isoform differs from the canonical sequence as follows:
|Note: No experimental confirmation available.|
|Isoform 3 (identifier: Q99J95-3) |
The sequence of this isoform differs from the canonical sequence as follows:
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 372||372||Cyclin-dependent kinase 9||PRO_0000085801|
|Domain||19 – 315||297||Protein kinase|
|Nucleotide binding||25 – 33||9||ATP By similarity|
|Nucleotide binding||104 – 106||3||ATP By similarity|
|Region||166 – 191||26||T-loop By similarity|
|Active site||149||1||Proton acceptor By similarity|
|Binding site||48||1||ATP By similarity|
|Binding site||167||1||ATP By similarity|
Amino acid modifications
|Modified residue||29||1||Phosphothreonine By similarity|
|Modified residue||44||1||N6-acetyllysine; by P300/CBP, PCAF/KAT2B and GCN5/KAT2A By similarity|
|Modified residue||48||1||N6-acetyllysine; by PCAF/KAT2B and GCN5/KAT2A By similarity|
|Modified residue||175||1||Phosphoserine By similarity|
|Modified residue||186||1||Phosphothreonine; by CaMK1D By similarity|
|Modified residue||347||1||Phosphoserine; by CDK9 and PKA By similarity|
|Modified residue||350||1||Phosphothreonine; by CDK9 By similarity|
|Modified residue||353||1||Phosphoserine; by CDK9 By similarity|
|Modified residue||354||1||Phosphothreonine; by CDK9 By similarity|
|Modified residue||357||1||Phosphoserine; by CDK9 By similarity|
|Modified residue||362||1||Phosphothreonine; by CDK9 By similarity|
|Modified residue||363||1||Phosphothreonine; by CDK9 By similarity|
|Alternative sequence||1 – 129||129||Missing in isoform 3.||VSP_016290|
|Alternative sequence||1 – 51||51||Missing in isoform 2.||VSP_016289|
|Sequence conflict||122||1||T → R in BAE34054. Ref.3|
|Sequence conflict||154||1||N → S in BAE25055. Ref.3|
|||"Cloning of murine CDK9/PITALRE and its tissue-specific expression in development."|
Bagella L., MacLachlan T.K., Buono R.J., Pisano M.M., Giordano A., De Luca A.
J. Cell. Physiol. 177:206-213(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY.
|||"Genomic organization, promoter analysis, and chromosomal mapping of the mouse gene encoding Cdk9."|
Bagella L., Stiegler P., De Luca A., Siracusa L.D., Giordano A.
J. Cell. Biochem. 78:170-178(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
|||"The transcriptional landscape of the mammalian genome."|
Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. Hayashizaki Y.
Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 3).
Strain: C57BL/6J and NOD.
Tissue: Eye, Lung and Spleen.
|||"Lineage-specific biology revealed by a finished genome assembly of the mouse."|
Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. Ponting C.P.
PLoS Biol. 7:E1000112-E1000112(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
|||"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] (ISOFORM 1).
Tissue: Mammary tumor.
|||"Feedback regulation of transcriptional termination by the mammalian circadian clock PERIOD complex."|
Padmanabhan K., Robles M.S., Westerling T., Weitz C.J.
Science 337:599-602(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION IN A LARGE PER COMPLEX, SUBCELLULAR LOCATION.
|+||Additional computationally mapped references.|
|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.
|RefSeq||NP_570930.1. NM_130860.3. [Q99J95-1]|
3D structure databases
|SMR||Q99J95. Positions 6-327. |
Protein-protein interaction databases
|BioGrid||223714. 6 interactions.|
|IntAct||Q99J95. 103 interactions.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSMUST00000009699; ENSMUSP00000009699; ENSMUSG00000009555. [Q99J95-1]|
ENSMUST00000120105; ENSMUSP00000113327; ENSMUSG00000009555. [Q99J95-2]
|UCSC||uc008jgn.2. mouse. [Q99J95-1]|
|MGI||MGI:1328368. Cdk9. |
Gene expression databases
Family and domain databases
|InterPro||IPR011009. Kinase-like_dom. |
|Pfam||PF00069. Pkinase. 1 hit. |
|SMART||SM00220. S_TKc. 1 hit. |
|SUPFAM||SSF56112. SSF56112. 1 hit. |
|PROSITE||PS00107. PROTEIN_KINASE_ATP. 1 hit. |
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
|ChiTaRS||CDK9. mouse. |
|Accession||Primary (citable) accession number: Q99J95|
Secondary accession number(s): B0R020 Q8BTN0
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|