Basic Information | Overview of PTM Sites | Experimental PTM Sites | Protein-Protein Interactions | Drug and Disease Associations | Related Literatures
Basic Information
Protein Name :  Cyclin-dependent kinase 9  

UniProtKB / Swiss-Prot ID :  CDK9_HUMAN

Gene Name (Synonyms) : 
CDK9, CDC2L4, TAK  

Species :  Homo sapiens (Human). 

Subcellular Localization :  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. A 

Protein 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 co-transcriptional 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. 

Protein Sequence MAKQYDSVECPFCDEVSKYEKLAKIGQGTFGEVFKARHRKTGQKVALKKVLMENEKEGFPITALREIKIL...
Predicted Secondary Structure CCCCCCCEEECCCCCCCCEEEEEEEECCCCEEEEEEEECCCCCEEEEEEECCHHCCCCHHHHHHHHHHHH...
Protein Variant
LocationDescription
59F -> L (in dbSNP:rs55640715). VAR_041982
231G -> A. VAR_013456
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Overview of Protein Modification Sites with Functional and Structural Information
Accessible Surface Area (ASA)
Pred. Secondary
Real Secondary
Disorder Prediction
Protein Domain
&
Experimental PTM Sites
Predicted PTM Sites
Protein Variant
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Experimental Post-Translational Modification Sites Download
Locations
Modification
Substrate Sites
&
Secondary Structure
Accessible Surface Area (%)
Resource
Reference
Structural Characterization
Orthologous
Protein Cluster
24Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)EKLAKIGQG
EEEEEEECC
58.78Phosphositeplus
Link
29Phosphothreonine.IGQGTFGEV
EECCCCEEE
22.15UniProtKB
Link
35Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)GEVFKARHR
EEEEEEEEC
50.08Phosphositeplus
Link
44N6-acetyllysineKTGQKVALK
CCCCEEEEE
30.71Phosphositeplus
Link
44N6-acetyllysine; by P300/CBP, PCAF/KAT2Band GCN5/KAT2A.KTGQKVALK
CCCCEEEEE
30.71UniProtKB
Link
48N6-acetyllysine; by PCAF/KAT2B andGCN5/KAT2A.KVALKKVLM
EEEEEEECC
30.97UniProtKB
Link
49N6-acetyllysineVALKKVLME
EEEEEECCH
41.26Phosphositeplus
Link
56Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)MENEKEGFP
CHHCCCCHH
74.78Phosphositeplus
Link
68Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)LREIKILQL
HHHHHHHHH
32.39Phosphositeplus
Link
88Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)ICRTKASPY
EEECCCCCC
27.75Phosphositeplus
Link
151Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)HRDMKAANV
EEECCCCCE
48.95Phosphositeplus
Link
164Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)DGVLKLADF
CCCEEEEEC
38.94Phosphositeplus
Link
175PhosphoserineARAFSLAKN
HHHHCCCCC
26.82PhosphoELM
Link
175PhosphoserineARAFSLAKN
HHHHCCCCC
26.82Phosphositeplus
Link
175Phosphoserine.ARAFSLAKN
HHHHCCCCC
26.82UniProtKB
Link
178Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)FSLAKNSQP
HCCCCCCCC
63.53Phosphositeplus
Link
180PhosphoserineLAKNSQPNR
CCCCCCCCE
46.43HPRD
Link
185PhosphotyrosineQPNRYTNRV
CCCEEEEEE
18.27Phosphositeplus
Link
185Phosphotyrosine.QPNRYTNRV
CCCEEEEEE
18.27UniProtKB
Link
186PhosphothreoninePNRYTNRVV
CCEEEEEEE
17.20HPRD
Link
186PhosphothreoninePNRYTNRVV
CCEEEEEEE
17.20PhosphoELM
Link
186PhosphothreoninePNRYTNRVV
CCEEEEEEE
17.20Phosphositeplus
Link
186Phosphothreonine; by CaMK1D.PNRYTNRVV
CCEEEEEEE
17.20UniProtKB
Link
194PhosphotyrosineVTLWYRPPE
EECCCCCHH
19.16Phosphositeplus
Link
269Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)LELVKGQKR
HHCCCCCCC
69.15Phosphositeplus
Link
330PhosphothreonineGMLSTHLTS
CCCCCCCCC
19.55HPRD
Link
330PhosphothreonineGMLSTHLTS
CCCCCCCCC
19.55SysPTM
Link
333PhosphothreonineSTHLTSMFE
CCCCCCHHH
15.56HPRD
Link
333PhosphothreonineSTHLTSMFE
CCCCCCHHH
15.56SysPTM
Link
334PhosphoserineTHLTSMFEY
CCCCCHHHH
28.03HPRD
Link
334PhosphoserineTHLTSMFEY
CCCCCHHHH
28.03SysPTM
Link
345Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)PPRRKGSQI
HHHCCCHHH
65.28Phosphositeplus
Link
347PhosphoserineRRKGSQITQ
HCCCHHHHH
22.80HPRD
Link
347PhosphoserineRRKGSQITQ
HCCCHHHHH
22.80Phosphositeplus
Link
347Phosphoserine; by CDK9 and PKA.RRKGSQITQ
HCCCHHHHH
22.80UniProtKB
Link
350PhosphothreonineGSQITQQST
CHHHHHCCC
16.96Phosphositeplus
Link
350Phosphothreonine; by CDK9.GSQITQQST
CHHHHHCCC
16.96UniProtKB
Link
353PhosphoserineITQQSTNQS
HHHCCCCCC
21.36HPRD
Link
353PhosphoserineITQQSTNQS
HHHCCCCCC
21.36Phosphositeplus
Link
353Phosphoserine; by CDK9.ITQQSTNQS
HHHCCCCCC
21.36UniProtKB
Link
354Phosphothreonine; by CDK9.TQQSTNQSR
HHCCCCCCC
32.70UniProtKB
Link
357Phosphoserine; by CDK9.STNQSRNPA
CCCCCCCCC
35.77UniProtKB
Link
362PhosphothreonineRNPATTNQT
CCCCCCCCC
27.77Phosphositeplus
Link
362Phosphothreonine; by CDK9.RNPATTNQT
CCCCCCCCC
27.77UniProtKB
Link
363PhosphothreonineNPATTNQTE
CCCCCCCCC
27.69Phosphositeplus
Link
363Phosphothreonine; by CDK9.NPATTNQTE
CCCCCCCCC
27.69UniProtKB
Link
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Protein-Protein Interactions
      Interacting Protein      
Interaction type
Source ID
      Resource      
      Pubmed ID      
Domain-Domain Interactions
RBBP7_HUMANphysical interactionMINT-4303684MINT17255935
DHX30_HUMANdirect interactionMINT-4303891MINT17255935
NR2E3_HUMANphysical interactionMINT-4303806MINT17255935
NR2E3_HUMANphysical interactionMINT-4303537MINT17255935
NR2E3_HUMANdirect interactionMINT-4303827MINT17255935
UB2R1_HUMANin vitroHPRD:16016HPRD11689688
GRN_HUMANin vivoHPRD:16016HPRD12588988
NFKB1_HUMANin vitro
in vivo
HPRD:16016HPRD12173051
TF65_HUMANin vitro
in vivo
HPRD:16016HPRD12173051
HTSF1_HUMANin vitro
in vivo
HPRD:16016HPRD9649438
ANDR_HUMANin vitro
in vivo
HPRD:16016HPRD11266437
SERPH_HUMANin vitroHPRD:16016HPRD11572868
MYBB_HUMANin vitro
in vivo
HPRD:16016HPRD10656684
SKP2_HUMANin vitro
in vivo
HPRD:16016HPRD12861003
11689688
PIN1_HUMANin vitro
in vivo
HPRD:16016HPRD11575923
IL6RB_HUMANin vitro
in vivo
HPRD:16016HPRD12386808
CD5R1_HUMANin vitroHPRD:16016HPRD12037672
TRAF2_HUMANin vivo
yeast 2-hybrid
HPRD:16016HPRD9827693
CCNT1_HUMANin vitro
in vivo
HPRD:16016HPRD15528190
11689688
14627702
9872325
10617616
11145967
11713533
11713532
12894230
12115727
10465067
94
CCNT2_HUMANin vitro
in vivo
HPRD:16016HPRD9499409
10465067
11282025
CUL1_HUMANin vivoHPRD:16016HPRD12861003
11689688
SPT5H_HUMANin vitroHPRD:16016HPRD11145967
11575923
NBN_HUMANin vitro
in vivo
HPRD:16016HPRD9258347
8170997
8870681
ZMYM6_HUMANyeast 2-hybridHPRD:16016HPRD11282025
11884399
CCNK_HUMANin vitro
in vivo
yeast 2-hybrid
HPRD:16016HPRD11884399
10574912
MED21_HUMANin vitro
in vivo
HPRD:16016HPRD9872325
11278802
CTDSL_HUMANin vitroHPRD:16016HPRD10617616
15009212
11278802
11145967
11572868
11884399
12052871
STK36_HUMANin vitroHPRD:16016HPRD9557739
RB_HUMANin vitroHPRD:16016HPRD9258347
8170997
8870681
RPB1_HUMANin vivoHPRD:16016HPRD11575923
P53_HUMANin vitroHPRD:16016HPRD16552184
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Disease Reference
Kegg disease
There are no disease associations of PTM sites.
Drug Reference
There are no disease associations of PTM sites.
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Related Literatures of Post-Translational Modification
Acetylation
ReferencePubMed
"Regulation of P-TEFb elongation complex activity by CDK9acetylation.";
Fu J., Yoon H.-G., Qin J., Wong J.;
Mol. Cell. Biol. 27:4641-4651(2007).
Cited for: ACETYLATION AT LYS-44 BY P300/CBP, IDENTIFICATION IN COMPLEX WITHNCOR1; HEXIM1 AND HDAC3, AND MUTAGENESIS OF LYS-44.
"Acetylation of conserved lysines in the catalytic core of cyclin-dependent kinase 9 inhibits kinase activity and regulatestranscription.";
Sabo A., Lusic M., Cereseto A., Giacca M.;
Mol. Cell. Biol. 28:2201-2212(2008).
Cited for: ACETYLATION AT LYS-44 AND LYS-48 BY PCAF/KAT2B AND GCN5/KAT2A, ENZYMEREGULATION BY ACETYLATION, AND SUBCELLULAR LOCATION.
Phosphorylation
ReferencePubMed
"CDK9 autophosphorylation regulates high-affinity binding of the humanimmunodeficiency virus type 1 tat-P-TEFb complex to TAR RNA.";
Garber M.E., Mayall T.P., Suess E.M., Meisenhelder J., Thompson N.E.,Jones K.A.;
Mol. Cell. Biol. 20:6958-6969(2000).
Cited for: PHOSPHORYLATION BY PKA, AUTOPHOSPHORYLATION, PHOSPHORYLATION ATSER-347; THR-350; SER-353; THR-354 AND SER-357, INTERACTION WITH HIVTAT, AND MUTAGENESIS OF 347-SER--SER-357 AND ASP-167.
"Analysis of the large inactive P-TEFb complex indicates that itcontains one 7SK molecule, a dimer of HEXIM1 or HEXIM2, and two P-TEFbmolecules containing Cdk9 phosphorylated at threonine 186.";
Li Q., Price J.P., Byers S.A., Cheng D., Peng J., Price D.H.;
J. Biol. Chem. 280:28819-28826(2005).
Cited for: IDENTIFICATION IN INACTIVE 7SK SNRNP COMPLEX, AND PHOSPHORYLATION ATTHR-186.
"Proteomics analysis of protein kinases by target class-selectiveprefractionation and tandem mass spectrometry.";
Wissing J., Jaensch L., Nimtz M., Dieterich G., Hornberger R.,Keri G., Wehland J., Daub H.;
Mol. Cell. Proteomics 6:537-547(2007).
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-186, AND MASSSPECTROMETRY.
"PP2B and PP1alpha cooperatively disrupt 7SK snRNP to release P-TEFbfor transcription in response to Ca2+ signaling.";
Chen R., Liu M., Li H., Xue Y., Ramey W.N., He N., Ai N., Luo H.,Zhu Y., Zhou N., Zhou Q.;
Genes Dev. 22:1356-1368(2008).
Cited for: PHOSPHORYLATION AT THR-186, DEPHOSPHORYLATION BY PPP1CA, P-TEFB/7SKSNRNP COMPLEX, SUBUNIT, INTERACTION WITH BRD4, AND ENZYME REGULATION.
"Phosphatase PPM1A regulates phosphorylation of Thr-186 in the Cdk9 T-loop.";
Wang Y., Dow E.C., Liang Y.Y., Ramakrishnan R., Liu H., Sung T.L.,Lin X., Rice A.P.;
J. Biol. Chem. 283:33578-33584(2008).
Cited for: PHOSPHORYLATION AT THR-186, AND DEPHOSPHORYLATION BY PPM1A AND PPM1B.
"Kinase-selective enrichment enables quantitative phosphoproteomics ofthe kinome across the cell cycle.";
Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,Greff Z., Keri G., Stemmann O., Mann M.;
Mol. Cell 31:438-448(2008).
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-186; SER-347 ANDSER-353, PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-27; SER-35;SER-52 AND SER-56 (ISOFORM 2), AND MASS SPECTROMETRY.
"Large-scale proteomics analysis of the human kinome.";
Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,Mann M., Daub H.;
Mol. Cell. Proteomics 8:1751-1764(2009).
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-185; THR-186; SER-347;THR-350 AND SER-353, PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-27;SER-35; SER-43; SER-52; THR-54; THR-55 AND SER-56; (ISOFORM 2), ANDMASS SPECTROMETRY.
"Cdk9 T-loop phosphorylation is regulated by the calcium signalingpathway.";
Ramakrishnan R., Rice A.P.;
J. Cell. Physiol. 227:609-617(2012).
Cited for: PHOSPHORYLATION AT THR-186, ENZYME REGULATION, DEGRADATION BYPROTEASOME, AND MUTAGENESIS OF THR-186.
"Protein phosphatase-1 activates CDK9 by dephosphorylating Ser175.";
Ammosova T., Obukhov Y., Kotelkin A., Breuer D., Beullens M.,Gordeuk V.R., Bollen M., Nekhai S.;
PLoS ONE 6:E18985-E18985(2011).
Cited for: DEPHOSPHORYLATION AT SER-175 BY PP1, AND MUTAGENESIS OF SER-175.
"Crystal structure of HIV-1 Tat complexed with human P-TEFb.";
Tahirov T.H., Babayeva N.D., Varzavand K., Cooper J.J., Sedore S.C.,Price D.H.;
Nature 465:747-751(2010).
Cited for: X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 1-345 IN COMPLEX WITH HIV-1TAT AND CCNT1, AND PHOSPHORYLATION AT THR-186.
"The structure of P-TEFb (CDK9/cyclin T1), its complex withflavopiridol and regulation by phosphorylation.";
Baumli S., Lolli G., Lowe E.D., Troiani S., Rusconi L., Bullock A.N.,Debreczeni J.E., Knapp S., Johnson L.N.;
EMBO J. 27:1907-1918(2008).
Cited for: X-RAY CRYSTALLOGRAPHY (2.48 ANGSTROMS) OF 2-330 IN COMPLEX WITHINHIBITOR FLAVOPIRIDOL; ATP AND CCNT1, PHOSPHORYLATION AT THR-186SER347; THR362 AND THR363, AUTOPHOSPHORYLATION, AND MUTAGENESIS OFTHR-186.
"Halogen bonds form the basis for selective P-TEFb inhibition byDRB.";
Baumli S., Endicott J.A., Johnson L.N.;
Chem. Biol. 17:931-936(2010).
Cited for: X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) OF 2-330 IN COMPLEX WITHINHIBITOR DRB, AND PHOSPHORYLATION AT THR-186.
"CDK inhibitors roscovitine and CR8 trigger Mcl-1 down-regulation andapoptotic cell death in neuroblastoma cells.";
Bettayeb K., Baunbaek D., Delehouze C., Loaec N., Hole A.J.,Baumli S., Endicott J.A., Douc-Rasy S., Benard J., Oumata N.,Galons H., Meijer L.;
Genes Cancer 1:369-380(2010).
Cited for: X-RAY CRYSTALLOGRAPHY (3.00 ANGSTROMS) OF 2-330 IN COMPLEX WITH CCNT1;INHIBITORS ROSCOVITINE AND CR8, PHOSPHORYLATION AT THR-186, AND ENZYMEREGULATION.
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Basic Information | Overview of PTM Sites | Experimental PTM Sites | Protein-Protein Interactions | Drug and Disease Associations | Related Literatures