CDK9_MOUSE - PTM Information in dbPTM

Basic Information of Protein

• UniProt ID: CDK9_MOUSE
• UniProt AC: Q99J95
• Protein Name: Cyclin-dependent kinase 9
• Gene Name: Cdk9
• Organism: Mus musculus (Mouse).
• Sequence Length: 372
• Subcellular Localization: Nucleus . Cytoplasm. Nucleus, PML body. 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 Description: 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)..
• Protein Sequence: MAKQYDSVECPFCDEVTKYEKLAKIGQGTFGEVFKAKHRQTGQKVALKKVLMENEKEGFPITALREIKILQLLKHENVVNLIEICRTKASPYNRCKGSIYLVFDFCEHDLAGLLSNVLVKFTLSEIKRVMQMLLNGLYYIHRNKILHRDMKAANVLITRDGVLKLADFGLARAFSLAKNSQPNRYTNRVVTLWYRPPELLLGERDYGPPIDLWGAGCIMAEMWTRSPIMQGNTEQHQLALISQLCGSITPEVWPNVDKYELFEKLELVKGQKRKVKDRLKAYVRDPYALDLIDKLLVLDPAQRIDSDDALNHDFFWSDPMPSDLKGMLSTHLTSMFEYLAPPRRKGSQITQQSTNQSRNPATTNQTEFERVF

Overview of Protein Modification Sites with Functional and Structural Information

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
3	Acetylation	-----MAKQYDSVEC -----CCCCCCCCCC	48.36	22826441
29	Phosphorylation	LAKIGQGTFGEVFKA HHHHCCCCHHHHHHH	22.15	-
44	Acetylation	KHRQTGQKVALKKVL HHCHHCCEEHHHHHH	30.71	-
48	Acetylation	TGQKVALKKVLMENE HCCEEHHHHHHHHCC	30.97	-
49	Malonylation	GQKVALKKVLMENEK CCEEHHHHHHHHCCC	41.26	26320211
49	Ubiquitination	GQKVALKKVLMENEK CCEEHHHHHHHHCCC	41.26	27667366
68	Ubiquitination	ITALREIKILQLLKH CHHHHHHHHHHHHCC	32.39	-
139	Phosphorylation	MLLNGLYYIHRNKIL HHHHHHHHHHHCCCC	8.69	29895711
148	Dimethylation	HRNKILHRDMKAANV HHCCCCCCCHHHHCE	42.12	-
164	Ubiquitination	ITRDGVLKLADFGLA EECCCHHHHHHHHHH	38.94	-
175	Phosphorylation	FGLARAFSLAKNSQP HHHHHHHHHHHCCCC	26.82	-
178	Ubiquitination	ARAFSLAKNSQPNRY HHHHHHHHCCCCCCC	63.53	27667366
180	Phosphorylation	AFSLAKNSQPNRYTN HHHHHHCCCCCCCCC	46.43	26060331
185	Phosphorylation	KNSQPNRYTNRVVTL HCCCCCCCCCCEEEE	18.27	24899341
186	Phosphorylation	NSQPNRYTNRVVTLW CCCCCCCCCCEEEEE	17.20	26824392
191	Phosphorylation	RYTNRVVTLWYRPPE CCCCCEEEEEECCHH	14.55	27600695
264	Ubiquitination	DKYELFEKLELVKGQ CHHHHHHHHHHHCCC	39.67	-
287	Phosphorylation	KAYVRDPYALDLIDK HHHHCCHHHHHHHHH	24.88	-
347	Phosphorylation	APPRRKGSQITQQST CCCCCCCCCCCCCCC	22.80	25521595
350	Phosphorylation	RRKGSQITQQSTNQS CCCCCCCCCCCCCCC	16.96	25159016
353	Phosphorylation	GSQITQQSTNQSRNP CCCCCCCCCCCCCCC	21.36	29514104
354	Phosphorylation	SQITQQSTNQSRNPA CCCCCCCCCCCCCCC	32.70	23684622
357	Phosphorylation	TQQSTNQSRNPATTN CCCCCCCCCCCCCCC	35.77	29514104
362	Phosphorylation	NQSRNPATTNQTEFE CCCCCCCCCCCCHHH	27.77	-
363	Phosphorylation	QSRNPATTNQTEFER CCCCCCCCCCCHHHH	27.69	-

Upstream regulatory proteins (kinases for phosphorylation sites, E3 ubiquitin ligases of ubiquitination sites, ...)

Modified Location	Modified Residue	Modification	Type of Upstream Proteins	Gene Name of Upstream Proteins	UniProt AC of Upstream Proteins	Sources
186	T	Phosphorylation	Kinase	CAMK1D	Q8BW96	Uniprot
347	S	Phosphorylation	Kinase	CDK9	Q99J95	Uniprot
347	S	Phosphorylation	Kinase	PKA	-	Uniprot
350	T	Phosphorylation	Kinase	CDK9	Q99J95	Uniprot
353	S	Phosphorylation	Kinase	CDK9	Q99J95	Uniprot
354	T	Phosphorylation	Kinase	CDK9	Q99J95	Uniprot
357	S	Phosphorylation	Kinase	CDK9	Q99J95	Uniprot
362	T	Phosphorylation	Kinase	CDK9	Q99J95	Uniprot
363	T	Phosphorylation	Kinase	CDK9	Q99J95	Uniprot

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Function	Reference
2	S	Acetylation	Deacetylated by SIRT7, promoting the kinase activity and subsequent 'Ser-2' phosphorylation of the C-terminal domain (CTD) of RNA polymerase II.	-
2	S	Phosphorylation	Deacetylated by SIRT7, promoting the kinase activity and subsequent 'Ser-2' phosphorylation of the C-terminal domain (CTD) of RNA polymerase II.	-
2	S	Phosphorylation	This ubiquitination is promoted by TFIIS/TCEA1 and favors 'Ser-2' phosphorylation of RPB1/POLR2A CTD (By similarity).	-
2	S	ubiquitylation	This ubiquitination is promoted by TFIIS/TCEA1 and favors 'Ser-2' phosphorylation of RPB1/POLR2A CTD (By similarity).	-
29	T	Phosphorylation	This inhibition is relieved by Thr-29 dephosphorylation.	-
44	K	Acetylation	N6-acetylation of Lys-44 promotes kinase activity, whereas acetylation of both Lys-44 and Lys-48 mediated by PCAF/KAT2B and GCN5/KAT2A reduces kinase activity.	-
48	K	Acetylation	N6-acetylation of Lys-44 promotes kinase activity, whereas acetylation of both Lys-44 and Lys-48 mediated by PCAF/KAT2B and GCN5/KAT2A reduces kinase activity.	-
175	S	Phosphorylation	Phosphorylation at Ser-175 inhibits kinase activity.	-
186	T	Phosphorylation	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.	-
186	T	Phosphorylation	Dephosphorylation of Thr-186 by PPM1A and PPM1B blocks CDK9 activity and may lead to CDK9 proteasomal degradation.	-
186	T	Phosphorylation	However, PPP1CA-mediated Thr-186 dephosphorylation is required to release P-TEFb from its inactive P-TEFb/7SK snRNP complex.	-
186	T	Phosphorylation	Thr-186 phosphorylation requires the calcium Ca(2+) signaling pathway, including CaMK1D and calmodulin.	-
347	S	Phosphorylation	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.	-
350	T	Phosphorylation	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.	-
353	S	Phosphorylation	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.	-
354	T	Phosphorylation	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.	-
357	S	Phosphorylation	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.	-
362	T	Phosphorylation	Can be phosphorylated on either Thr-362 or Thr-363 but not on both simultaneously (By similarity).	-
363	T	Phosphorylation	Can be phosphorylated on either Thr-362 or Thr-363 but not on both simultaneously (By similarity).	-

Disease-associated PTM Sites based on SAP

* Distance = the distance between SAP position and PTM sites.

Oops, there are no SNP-PTM records of CDK9_MOUSE !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
CCNT1_HUMAN	CCNT1	physical	20081228
GATA4_HUMAN	GATA4	physical	20081228
ACTB_HUMAN	ACTB	physical	20081228
EP300_HUMAN	EP300	physical	20081228
TRAF2_MOUSE	Traf2	physical	9827693
RB_MOUSE	Rb1	physical	9827693

Drug and Disease Associations

• Kegg Drug
• DrugBank
• There are no disease associations of PTM sites.