ID CDK9_RAT Reviewed; 372 AA.
AC Q641Z4;
DT 01-FEB-2005, integrated into UniProtKB/Swiss-Prot.
DT 25-OCT-2004, sequence version 1.
DT 27-MAR-2024, entry version 162.
DE RecName: Full=Cyclin-dependent kinase 9;
DE EC=2.7.11.22;
DE EC=2.7.11.23;
DE AltName: Full=Cell division protein kinase 9;
GN Name=Cdk9;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
CC -!- FUNCTION: Protein kinase involved in the regulation of transcription.
CC Member of the cyclin-dependent kinase pair (CDK9/cyclin-T) complex,
CC also called positive transcription elongation factor b (P-TEFb), which
CC facilitates the transition from abortive to productive elongation by
CC phosphorylating the CTD (C-terminal domain) of the large subunit of RNA
CC polymerase II (RNAP II) POLR2A, SUPT5H and RDBP. This complex is
CC inactive when in the 7SK snRNP complex form. Phosphorylates EP300,
CC MYOD1, RPB1/POLR2A and AR and the negative elongation factors DSIF and
CC NELFE. Regulates cytokine inducible transcription networks by
CC facilitating promoter recognition of target transcription factors (e.g.
CC TNF-inducible RELA/p65 activation and IL-6-inducible STAT3 signaling).
CC Promotes RNA synthesis in genetic programs for cell growth,
CC differentiation and viral pathogenesis. P-TEFb is also involved in
CC cotranscriptional histone modification, mRNA processing and mRNA
CC export. Modulates a complex network of chromatin modifications
CC including histone H2B monoubiquitination (H2Bub1), H3 lysine 4
CC trimethylation (H3K4me3) and H3K36me3; integrates phosphorylation
CC during transcription with chromatin modifications to control co-
CC transcriptional histone mRNA processing. The CDK9/cyclin-K complex has
CC also a kinase activity towards CTD of RNAP II and can substitute for
CC CDK9/cyclin-T P-TEFb in vitro. Replication stress response protein; the
CC CDK9/cyclin-K complex is required for genome integrity maintenance, by
CC promoting cell cycle recovery from replication arrest and limiting
CC single-stranded DNA amount in response to replication stress, thus
CC reducing the breakdown of stalled replication forks and avoiding DNA
CC damage. In addition, probable function in DNA repair of isoform 2 via
CC interaction with KU70/XRCC6. Promotes cardiac myocyte enlargement.
CC RPB1/POLR2A phosphorylation on 'Ser-2' in CTD activates transcription.
CC AR phosphorylation modulates AR transcription factor promoter
CC selectivity and cell growth. DSIF and NELF phosphorylation promotes
CC transcription by inhibiting their negative effect. The phosphorylation
CC of MYOD1 enhances its transcriptional activity and thus promotes muscle
CC differentiation. Catalyzes phosphorylation of KAT5, promoting KAT5
CC recruitment to chromatin and histone acetyltransferase activity.
CC {ECO:0000250|UniProtKB:P50750}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.22;
CC Evidence={ECO:0000250|UniProtKB:P50750};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17990;
CC Evidence={ECO:0000250|UniProtKB:P50750};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.22; Evidence={ECO:0000250|UniProtKB:P50750};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46609;
CC Evidence={ECO:0000250|UniProtKB:P50750};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=[DNA-directed RNA polymerase] + ATP = ADP + H(+) + phospho-
CC [DNA-directed RNA polymerase]; Xref=Rhea:RHEA:10216, Rhea:RHEA-
CC COMP:11321, Rhea:RHEA-COMP:11322, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:43176, ChEBI:CHEBI:68546,
CC ChEBI:CHEBI:456216; EC=2.7.11.23;
CC Evidence={ECO:0000250|UniProtKB:P50750};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:10217;
CC Evidence={ECO:0000250|UniProtKB:P50750};
CC -!- ACTIVITY REGULATION: Activation by Thr-186 phosphorylation is calcium
CC Ca(2+) signaling pathway-dependent; actively inactivated by
CC dephosphorylation mediated by PPP1CA, PPM1A and PPM1B. Reversibly
CC repressed by acetylation at Lys-44 and Lys-48 (By similarity).
CC {ECO:0000250|UniProtKB:P50750}.
CC -!- SUBUNIT: Component of the super elongation complex (SEC), at least
CC composed of EAF1, EAF2, CDK9, MLLT3/AF9, AFF (AFF1 or AFF4), the P-TEFb
CC complex and ELL (ELL, ELL2 or ELL3). Associates with CCNT1/cyclin-T1,
CC CCNT2/cyclin-T2 (isoform A and isoform B) or CCNK/cyclin-K to form
CC active P-TEFb. P-TEFb forms a complex with AFF4/AF5Q31 and is part of
CC the super elongation complex (SEC). Component of a complex which is
CC composed of at least 5 members: HTATSF1/Tat-SF1, P-TEFb complex, RNA
CC pol II, SUPT5H, and NCL/nucleolin. Associates with UBR5 and forms a
CC transcription regulatory complex composed of CDK9, RNAP II, UBR5 and
CC TFIIS/TCEA1 that can stimulate target gene transcription (e.g. gamma
CC fibrinogen/FGG) by recruiting their promoters. Component of the 7SK
CC snRNP inactive complex which is composed of at least 8 members: P-TEFb
CC (composed of CDK9 and CCNT1/cyclin-T1), HEXIM1, HEXIM2, LARP7, BCDIN3,
CC SART3 proteins and 7SK and U6 snRNAs. This inactive 7SK snRNP complex
CC can also interact with NCOR1 and HDAC3, probably to regulate CDK9
CC acetylation. Release of P-TEFb from P-TEFb/7SK snRNP complex requires
CC both PP2B to transduce calcium Ca(2+) signaling in response to stimuli
CC (e.g. UV or hexamethylene bisacetamide (HMBA)), and PPP1CA to
CC dephosphorylate Thr-186. This released P-TEFb remains inactive in the
CC pre-initiation complex with BRD4 until new Thr-186 phosphorylation
CC occurs after the synthesis of a short RNA. Interacts with BRD4; to
CC target chromatin binding. Interacts with JMJD6. Interacts with
CC activated nuclear STAT3 and RELA/p65. Binds to AR and MYOD1. Forms a
CC complex composed of CDK9, CCNT1/cyclin-T1, EP300 and GATA4 that
CC stimulates hypertrophy in cardiomyocytes (By similarity). The large PER
CC complex involved in the repression of transcriptional termination is
CC composed of at least PER2, CDK9, DDX5, DHX9, NCBP1 and POLR2A (By
CC similarity). Interacts with HSF1 (By similarity). Interacts with TBX21
CC (By similarity). Interacts with WDR43 (By similarity). Interacts with
CC ZMYND8; the association appears to occur between homodimeric ZMYND8 and
CC the activated form of the P-TEFb complex (By similarity).
CC {ECO:0000250|UniProtKB:P50750, ECO:0000250|UniProtKB:Q99J95}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250}. Cytoplasm {ECO:0000250}.
CC Nucleus, PML body {ECO:0000250}. Note=Accumulates on chromatin in
CC response to replication stress. Complexed with CCNT1 in nuclear
CC speckles, but uncomplexed form in the cytoplasm. The translocation from
CC nucleus to cytoplasm is XPO1/CRM1-dependent. Associates with PML body
CC when acetylated (By similarity). {ECO:0000250}.
CC -!- PTM: Autophosphorylation at Thr-186, Ser-347, Thr-350, Ser-353, Thr-354
CC and Ser-357 triggers kinase activity by promoting cyclin and substrate
CC binding upon conformational changes. Thr-186 phosphorylation requires
CC the calcium Ca(2+) signaling pathway, including CaMK1D and calmodulin.
CC This inhibition is relieved by Thr-29 dephosphorylation.
CC Phosphorylation at Ser-175 inhibits kinase activity. Can be
CC phosphorylated on either Thr-362 or Thr-363 but not on both
CC simultaneously (By similarity). {ECO:0000250|UniProtKB:P50750}.
CC -!- PTM: Dephosphorylation of Thr-186 by PPM1A and PPM1B blocks CDK9
CC activity and may lead to CDK9 proteasomal degradation. However, PPP1CA-
CC mediated Thr-186 dephosphorylation is required to release P-TEFb from
CC its inactive P-TEFb/7SK snRNP complex. Dephosphorylation of C-terminus
CC Thr and Ser residues by protein phosphatase-1 (PP1) triggers CDK9
CC activity (By similarity). {ECO:0000250}.
CC -!- PTM: N6-acetylation of Lys-44 promotes kinase activity, whereas
CC acetylation of both Lys-44 and Lys-48 mediated by PCAF/KAT2B and
CC GCN5/KAT2A reduces kinase activity. The acetylated form associates with
CC PML bodies in the nuclear matrix and with the transcriptionally silent
CC HIV-1 genome; deacetylated upon transcription stimulation. Deacetylated
CC by SIRT7, promoting the kinase activity and subsequent 'Ser-2'
CC phosphorylation of the C-terminal domain (CTD) of RNA polymerase II.
CC {ECO:0000250|UniProtKB:P50750}.
CC -!- PTM: Polyubiquitinated and thus activated by UBR5. This ubiquitination
CC is promoted by TFIIS/TCEA1 and favors 'Ser-2' phosphorylation of
CC RPB1/POLR2A CTD (By similarity). {ECO:0000250|UniProtKB:P50750}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr
CC protein kinase family. CDC2/CDKX subfamily. {ECO:0000305}.
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DR EMBL; BC082037; AAH82037.1; -; mRNA.
DR RefSeq; NP_001007744.1; NM_001007743.1.
DR AlphaFoldDB; Q641Z4; -.
DR SMR; Q641Z4; -.
DR BioGRID; 263196; 1.
DR IntAct; Q641Z4; 1.
DR MINT; Q641Z4; -.
DR STRING; 10116.ENSRNOP00000037778; -.
DR iPTMnet; Q641Z4; -.
DR PhosphoSitePlus; Q641Z4; -.
DR jPOST; Q641Z4; -.
DR PaxDb; 10116-ENSRNOP00000037778; -.
DR GeneID; 362110; -.
DR KEGG; rno:362110; -.
DR UCSC; RGD:1359638; rat.
DR AGR; RGD:1359638; -.
DR CTD; 1025; -.
DR RGD; 1359638; Cdk9.
DR VEuPathDB; HostDB:ENSRNOG00000022586; -.
DR eggNOG; KOG0669; Eukaryota.
DR HOGENOM; CLU_000288_181_1_1; -.
DR InParanoid; Q641Z4; -.
DR OrthoDB; 244018at2759; -.
DR PhylomeDB; Q641Z4; -.
DR TreeFam; TF101039; -.
DR Reactome; R-RNO-112382; Formation of RNA Pol II elongation complex.
DR Reactome; R-RNO-2173796; SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription.
DR Reactome; R-RNO-674695; RNA Polymerase II Pre-transcription Events.
DR Reactome; R-RNO-6796648; TP53 Regulates Transcription of DNA Repair Genes.
DR Reactome; R-RNO-6807505; RNA polymerase II transcribes snRNA genes.
DR Reactome; R-RNO-75955; RNA Polymerase II Transcription Elongation.
DR Reactome; R-RNO-9018519; Estrogen-dependent gene expression.
DR PRO; PR:Q641Z4; -.
DR Proteomes; UP000002494; Chromosome 3.
DR Bgee; ENSRNOG00000022586; Expressed in thymus and 20 other cell types or tissues.
DR Genevisible; Q641Z4; RN.
DR GO; GO:0008024; C:cyclin/CDK positive transcription elongation factor complex; ISS:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; ISO:RGD.
DR GO; GO:0070691; C:P-TEFb complex; ISS:UniProtKB.
DR GO; GO:0016605; C:PML body; ISO:RGD.
DR GO; GO:0008023; C:transcription elongation factor complex; ISS:UniProtKB.
DR GO; GO:0097322; F:7SK snRNA binding; ISS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0003682; F:chromatin binding; IDA:RGD.
DR GO; GO:0004693; F:cyclin-dependent protein serine/threonine kinase activity; ISO:RGD.
DR GO; GO:0003677; F:DNA binding; ISO:RGD.
DR GO; GO:0016301; F:kinase activity; ISO:RGD.
DR GO; GO:0019901; F:protein kinase binding; ISO:RGD.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; ISS:UniProtKB.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; ISO:RGD.
DR GO; GO:0008353; F:RNA polymerase II CTD heptapeptide repeat kinase activity; ISS:UniProtKB.
DR GO; GO:0017069; F:snRNA binding; ISO:RGD.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; ISO:RGD.
DR GO; GO:0001223; F:transcription coactivator binding; ISO:RGD.
DR GO; GO:0071345; P:cellular response to cytokine stimulus; ISO:RGD.
DR GO; GO:0006281; P:DNA repair; IEA:UniProtKB-KW.
DR GO; GO:0120186; P:negative regulation of protein localization to chromatin; ISO:RGD.
DR GO; GO:0051647; P:nucleus localization; ISO:RGD.
DR GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW.
DR GO; GO:0043923; P:positive regulation by host of viral transcription; ISO:RGD.
DR GO; GO:0010613; P:positive regulation of cardiac muscle hypertrophy; IMP:RGD.
DR GO; GO:0120187; P:positive regulation of protein localization to chromatin; ISS:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0032968; P:positive regulation of transcription elongation by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0051726; P:regulation of cell cycle; ISO:RGD.
DR GO; GO:0006282; P:regulation of DNA repair; ISO:RGD.
DR GO; GO:0031440; P:regulation of mRNA 3'-end processing; ISO:RGD.
DR GO; GO:0051147; P:regulation of muscle cell differentiation; ISO:RGD.
DR GO; GO:0031297; P:replication fork processing; ISO:RGD.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEP:RGD.
DR GO; GO:0006366; P:transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0140673; P:transcription elongation-coupled chromatin remodeling; ISO:RGD.
DR CDD; cd07865; STKc_CDK9; 1.
DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR PANTHER; PTHR24056; CELL DIVISION PROTEIN KINASE; 1.
DR PANTHER; PTHR24056:SF546; CYCLIN-DEPENDENT KINASE 9; 1.
DR Pfam; PF12330; Haspin_kinase; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 2: Evidence at transcript level;
KW Acetylation; ATP-binding; Cytoplasm; DNA damage; DNA repair; Kinase;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Transcription; Transcription regulation;
KW Transferase; Ubl conjugation.
FT CHAIN 1..372
FT /note="Cyclin-dependent kinase 9"
FT /id="PRO_0000085802"
FT DOMAIN 19..315
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 166..191
FT /note="T-loop"
FT /evidence="ECO:0000250"
FT REGION 343..372
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 345..372
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 149
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 25..33
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 48
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 104..106
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 167
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 44
FT /note="N6-acetyllysine; by EP300/CBP, PCAF/KAT2B and
FT GCN5/KAT2A"
FT /evidence="ECO:0000250|UniProtKB:P50750"
FT MOD_RES 48
FT /note="N6-acetyllysine; by PCAF/KAT2B and GCN5/KAT2A"
FT /evidence="ECO:0000250|UniProtKB:P50750"
FT MOD_RES 175
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P50750"
FT MOD_RES 186
FT /note="Phosphothreonine; by CaMK1D"
FT /evidence="ECO:0000250|UniProtKB:P50750"
FT MOD_RES 347
FT /note="Phosphoserine; by CDK9 and PKA"
FT /evidence="ECO:0000250|UniProtKB:P50750"
FT MOD_RES 350
FT /note="Phosphothreonine; by CDK9"
FT /evidence="ECO:0000250|UniProtKB:P50750"
FT MOD_RES 353
FT /note="Phosphoserine; by CDK9"
FT /evidence="ECO:0000250|UniProtKB:P50750"
FT MOD_RES 354
FT /note="Phosphothreonine; by CDK9"
FT /evidence="ECO:0000250|UniProtKB:P50750"
FT MOD_RES 357
FT /note="Phosphoserine; by CDK9"
FT /evidence="ECO:0000250|UniProtKB:P50750"
FT MOD_RES 362
FT /note="Phosphothreonine; by CDK9"
FT /evidence="ECO:0000250|UniProtKB:P50750"
FT MOD_RES 363
FT /note="Phosphothreonine; by CDK9"
FT /evidence="ECO:0000250|UniProtKB:P50750"
SQ SEQUENCE 372 AA; 42762 MW; 973B18869F9963E3 CRC64;
MAKQYDSVEC PFCDEVTKYE KLAKIGQGTF GEVFKAKHRQ TGQKVALKKV LMENEKEGFP
ITALREIKIL QLLKHENVVN LIEICRTKAS PYNRCKGSIY LVFDFCEHDL AGLLSNVLVK
FTLSEIKRVM QMLLNGLYYI HRNKILHRDM KAANVLITRD GVLKLADFGL ARAFSLAKNS
QPNRYTNRVV TLWYRPPELL LGERDYGPPI DLWGAGCIMA EMWTRSPIMQ GNTEQHQLAL
ISQLCGSITP EVWPNVDKYE LFEKLELVKG QKRKVKDRLK AYVRDPYALD LIDKLLVLDP
AQRIDSDDAL NHDFFWSDPM PSDLKGMLST HLTSMFEYLA PPRRKGSQIT QQSTNQSRNP
ATTNQTEFER VF
//
