Reviewed, UniProtKB/Swiss-Prot P49336 (CDK8_HUMAN)

Names and origin

Protein names

Recommended name:
    Cell division protein kinase 8
    EC=2.7.11.22
    EC=2.7.11.23
Alternative name(s):
    Cyclin-dependent kinase 8
    Mediator of RNA polymerase II transcription subunit CDK8
    Mediator complex subunit CDK8
    Protein kinase K35

Gene names

Name:

CDK8

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	464 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex. Phosphorylates CCNH leading to down-regulation of the TFIIH complex and transcriptional repression. Recruited through interaction with MAML1 to hyperphosphorylate the intracellular domain of NOTCH, leading to its degradation. Ref.8 Ref.9
Catalytic activity	ATP + a protein = ADP + a phosphoprotein. Ref.8 ATP + [DNA-directed RNA polymerase] = ADP + [DNA-directed RNA polymerase] phosphate. Ref.8
Cofactor	Magnesium By similarity.
Subunit structure	Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. The cylin/CDK pair formed by CCNC/CDK8 also associates with the large subunit of RNA polymerase II. Interacts with CTNNB1, GLI3 and MAML1. Ref.9 Ref.12
Subcellular location	Nucleus Probable.
Sequence similarities	Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily. Contains 1 protein kinase domain.

Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Ligand	ATP-binding Nucleotide-binding
Molecular function	Activator Kinase Repressor Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	Complete proteome
Gene Ontology (GO)
Biological process	protein amino acid phosphorylation Inferred from electronic annotation. Source: InterPro regulation of transcription Inferred from electronic annotation. Source: UniProtKB-KW transcription Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	mediator complex Inferred from direct assay. Source: MGI
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW RNA polymerase II carboxy-terminal domain kinase activity Inferred from electronic annotation. Source: EC cyclin-dependent protein kinase activity Inferred from electronic annotation. Source: EC protein binding Ref.1 Ref.9 Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CCNC	P24863	2	EBI-394377,EBI-395261

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P49336-1)

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: P49336-2)

The sequence of this isoform differs from the canonical sequence as follows:
     370-370: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 464	464	Cell division protein kinase 8		PRO_0000085797
Regions
	Domain	21 – 335	315	Protein kinase
	Nucleotide binding	27 – 35	9	ATP By similarity
	Compositional bias	373 – 377	5	Poly-Gln
Sites
	Active site	151	1	Proton acceptor By similarity
	Binding site	52	1	ATP By similarity
Amino acid modifications
	Modified residue	410	1	Phosphothreonine
	Modified residue	413	1	Phosphoserine
Natural variations
	Alternative sequence	370	1	Missing in isoform 2.		VSP_029970
	Natural variant	189	1	D → N in a lung neuroendocrine carcinoma sample; somatic mutation. Ref.14		VAR_041980
	Natural variant	424	1	R → C in a colorectal adenocarcinoma sample; somatic mutation. Ref.14		VAR_041981
Experimental info
	Mutagenesis	173	1	D → A: Abrogates kinase activity and TFIIH-dependent transcriptional repression. Ref.8

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified February 1, 1996. Version 1. Checksum: 00CBAB6CE354605F	FASTA	464	53,284
	10 20 30 40 50 60 MDYDFKVKLS SERERVEDLF EYEGCKVGRG TYGHVYKAKR KDGKDDKDYA LKQIEGTGIS 70 80 90 100 110 120 MSACREIALL RELKHPNVIS LQKVFLSHAD RKVWLLFDYA EHDLWHIIKF HRASKANKKP 130 140 150 160 170 180 VQLPRGMVKS LLYQILDGIH YLHANWVLHR DLKPANILVM GEGPERGRVK IADMGFARLF 190 200 210 220 230 240 NSPLKPLADL DPVVVTFWYR APELLLGARH YTKAIDIWAI GCIFAELLTS EPIFHCRQED 250 260 270 280 290 300 IKTSNPYHHD QLDRIFNVMG FPADKDWEDI KKMPEHSTLM KDFRRNTYTN CSLIKYMEKH 310 320 330 340 350 360 KVKPDSKAFH LLQKLLTMDP IKRITSEQAM QDPYFLEDPL PTSDVFAGCQ IPYPKREFLT 370 380 390 400 410 420 EEEPDDKGDK KNQQQQQGNN HTNGTGHPGN QDSSHTQGPP LKKVRVVPPT TTSGGLIMTS 430 440 450 460 DYQRSNPHAA YPNPGPSTSQ PQSSMGYSAT SQQPPQYSHQ THRY
	Isoform 2. Checksum: 8C74EEBD24CBA5DB	FASTA	463	53,156
	10 20 30 40 50 60 MDYDFKVKLS SERERVEDLF EYEGCKVGRG TYGHVYKAKR KDGKDDKDYA LKQIEGTGIS 70 80 90 100 110 120 MSACREIALL RELKHPNVIS LQKVFLSHAD RKVWLLFDYA EHDLWHIIKF HRASKANKKP 130 140 150 160 170 180 VQLPRGMVKS LLYQILDGIH YLHANWVLHR DLKPANILVM GEGPERGRVK IADMGFARLF 190 200 210 220 230 240 NSPLKPLADL DPVVVTFWYR APELLLGARH YTKAIDIWAI GCIFAELLTS EPIFHCRQED 250 260 270 280 290 300 IKTSNPYHHD QLDRIFNVMG FPADKDWEDI KKMPEHSTLM KDFRRNTYTN CSLIKYMEKH 310 320 330 340 350 360 KVKPDSKAFH LLQKLLTMDP IKRITSEQAM QDPYFLEDPL PTSDVFAGCQ IPYPKREFLT 370 380 390 400 410 420 EEEPDDKGDK NQQQQQGNNH TNGTGHPGNQ DSSHTQGPPL KKVRVVPPTT TSGGLIMTSD 430 440 450 460 YQRSNPHAAY PNPGPSTSQP QSSMGYSATS QQPPQYSHQT HRY

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Identification of human cyclin-dependent kinase 8, a putative protein kinase partner for cyclin C." Tassan J.-P., Jaquenoud M., Leopold P., Schultz S.J., Nigg E.A. Proc. Natl. Acad. Sci. U.S.A. 92:8871-8875(1995) [PubMed: 7568034] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Testis.
[2]	"The DNA sequence and analysis of human chromosome 13." Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L., Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E., Griffiths-Jones S., Jones M.C., Keenan S.J., Oliver K., Scott C.E., Ainscough R., Almeida J.P., Ambrose K.D., Andrews D.T. , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Bannerjee R., Barlow K.F., Bates K., Beasley H., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P., Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M., Clegg S.C., Cobley V., Collins J.E., Corby N., Coville G.J., Deloukas P., Dhami P., Dunham I., Dunn M., Earthrowl M.E., Ellington A.G., Faulkner L., Frankish A.G., Frankland J., French L., Garner P., Garnett J., Gilbert J.G.R., Gilson C.J., Ghori J., Grafham D.V., Gribble S.M., Griffiths C., Hall R.E., Hammond S., Harley J.L., Hart E.A., Heath P.D., Howden P.J., Huckle E.J., Hunt P.J., Hunt A.R., Johnson C., Johnson D., Kay M., Kimberley A.M., King A., Laird G.K., Langford C.J., Lawlor S., Leongamornlert D.A., Lloyd D.M., Lloyd C., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S., Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K.M., Rice C.M., Searle S., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Steward C.A., Sycamore N., Tester J., Thomas D.W., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., Whitehead S.L., Willey D.L., Wilming L., Wray P.W., Wright M.W., Young L., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Beck S., Bentley D.R., Rogers J., Ross M.T. Nature 428:522-528(2004) [PubMed: 15057823] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
[5]	"NAT, a human complex containing Srb polypeptides that functions as a negative regulator of activated transcription." Sun X., Zhang Y., Cho H., Rickert P., Lees E., Lane W.S., Reinberg D. Mol. Cell 2:213-222(1998) [PubMed: 9734358] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY, IDENTIFICATION IN THE MEDIATOR COMPLEX.
[6]	"A novel human SRB/MED-containing cofactor complex, SMCC, involved in transcription regulation." Gu W., Malik S., Ito M., Yuan C.-X., Fondell J.D., Zhang X., Martinez E., Qin J., Roeder R.G. Mol. Cell 3:97-108(1999) [PubMed: 10024883] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY, IDENTIFICATION IN THE SMCC COMPLEX.
[7]	Erratum Gu W., Malik S., Ito M., Yuan C.-X., Fondell J.D., Zhang X., Martinez E., Qin J., Roeder R.G. Mol. Cell 3:541-541(1999)
[8]	"TFIIH is negatively regulated by cdk8-containing mediator complexes." Akoulitchev S., Chuikov S., Reinberg D. Nature 407:102-106(2000) [PubMed: 10993082] [Abstract] Cited for: FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF ASP-173.
[9]	"Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover." Fryer C.J., White J.B., Jones K.A. Mol. Cell 16:509-520(2004) [PubMed: 15546612] [Abstract] Cited for: FUNCTION, INTERACTION WITH MAML1.
[10]	"A set of consensus mammalian mediator subunits identified by multidimensional protein identification technology." Sato S., Tomomori-Sato C., Parmely T.J., Florens L., Zybailov B., Swanson S.K., Banks C.A.S., Jin J., Cai Y., Washburn M.P., Conaway J.W., Conaway R.C. Mol. Cell 14:685-691(2004) [PubMed: 15175163] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY, IDENTIFICATION IN THE MEDIATOR COMPLEX.
[11]	"MED1/TRAP220 exists predominantly in a TRAP/Mediator subpopulation enriched in RNA polymerase II and is required for ER-mediated transcription." Zhang X., Krutchinsky A., Fukuda A., Chen W., Yamamura S., Chait B.T., Roeder R.G. Mol. Cell 19:89-100(2005) [PubMed: 15989967] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY, IDENTIFICATION IN THE MEDIATOR COMPLEX, ASSOCIATION OF THE MEDIATOR COMPLEX WITH RNA POLYMERASE II.
[12]	"Mediator modulates Gli3-dependent Sonic hedgehog signaling." Zhou H., Kim S., Ishii S., Boyer T.G. Mol. Cell. Biol. 26:8667-8682(2006) [PubMed: 17000779] [Abstract] Cited for: INTERACTION WITH CTNNB1; GLI3; MED1; MED6; MED12 AND MED23.
[13]	"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) [PubMed: 19369195] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-410 AND SER-413, MASS SPECTROMETRY.
[14]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed: 17344846] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] ASN-189 AND CYS-424.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	X85753 mRNA. Translation: CAA59754.1. AL590108, AL159159 Genomic DNA. Translation: CAH72300.1. AL159159, AL590108 Genomic DNA. Translation: CAI16960.1. CH471075 Genomic DNA. Translation: EAX08386.1. CH471075 Genomic DNA. Translation: EAX08387.1. BC069634 mRNA. Translation: AAH69634.1. BC104492 mRNA. Translation: AAI04493.1. BC105950 mRNA. Translation: AAI05951.1. BC107601 mRNA. Translation: AAI07602.1.
IPI	IPI00026791. IPI00879595.
PIR	I37227.
RefSeq	NP_001251.1.
UniGene	Hs.382306
3D structure databases
SMR	P49336. Positions 22-343.
ModBase	Search...
Protein-protein interaction databases
IntAct	P49336. 12 interactions.
STRING	P49336.
PTM databases
PhosphoSite	P49336.
Proteomic databases
PRIDE	P49336.
Genome annotation databases
Ensembl	ENST00000381527; ENSP00000370938; ENSG00000132964; Homo sapiens. [Genome view]
GeneID	1024.
KEGG	hsa:1024.
UCSC	uc001uqr.1. human. uc001uqs.1. human.
Organism-specific databases
CTD	1024.
GeneCards	GC13P025726.
H-InvDB	HIX0037326.
HGNC	HGNC:1779. CDK8.
MIM	603184. gene.
PharmGKB	PA26315.
GenAtlas	Search...
Phylogenomic databases
eggNOG	prNOG05645.
HOGENOM	HBG755340.
HOVERGEN	P49336.
InParanoid	P49336.
OMA	GQPQMGQ.
OrthoDB	EOG91G5PZ.
PhylomeDB	P49336.
Enzyme and pathway databases
BRENDA	2.7.11.22. 247. 2.7.11.23. 247.
Reactome	REACT_71. Gene Expression.
Gene expression databases
ArrayExpress	P49336.
Bgee	P49336.
CleanEx	HS_CDK8.
Genevestigator	P49336.
GermOnline	ENSG00000132964. Homo sapiens.
Family and domain databases
InterPro	IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR017442. Se/Thr_prot_kinase-like_dom. IPR008271. Ser/Thr_prot_kinase_AS. IPR002290. Ser/Thr_prot_kinase_dom. [Graphical view]
Pfam	PF00069. Pkinase. 1 hit. [Graphical view]
SMART	SM00220. S_TKc. 1 hit. [Graphical view]
PROSITE	PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	4301.
SOURCE	Search...

Entry information

Entry name

CDK8_HUMAN

Accession

Primary (citable) accession number: P49336
Secondary accession number(s): Q5VUF3, Q6ISB5

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1996
Last sequence update:	February 1, 1996
Last modified:	February 9, 2010
This is version 90 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.