Tchem CDK8 Cyclin-dependent kinase 8

Protein Summary

Description

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. This gene encodes a member of the cyclin-dependent protein kinase (CDK) family. CDK family members are known to be important regulators of cell cycle progression. This kinase and its regulatory subunit, cyclin C, are components of the Mediator transcriptional regulatory complex, involved in both transcriptional activation and repression by phosphorylation of the carboxy-terminal domain of the largest subunit of RNA polymerase II. This kinase regulates transcription by targeting the cyclin-dependent kinase 7 subunits of the general transcription initiation factor IIH, thus providing a link between the Mediator complex and the basal transcription machinery. Multiple pseudogenes of this gene have been identified. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2016]

Uniprot Accession IDs

• P49336
• Q5VUF3
• Q6ISB5

Gene Name

• CDK8

Ensembl ID

• ENST00000381527
• ENSP00000370938
• ENSG00000132964

Symbol

• K35

Knowledge Table

Most Knowledge About	Knowledge Value (0 to 1 scale)
molecular function	0.95
disease perturbation	0.93
transcription factor binding site profile	0.88
histone modification site profile	0.84
trait	0.75

Protein Classes

PANTHER Classes

Protein / Transferase / Kinase / Protein Kinase / Non-receptor Tyrosine Protein Kinase / Cyclin-dependent Kinase 8

Protein / Transferase / Kinase / Protein Kinase / Non-receptor Serine/threonine Protein Kinase / Cyclin-dependent Kinase 8

DTO Classes

Protein / Kinase / Protein Kinase / Cmgc Group / Cdk Family / Cdk8 Subfamily / Cyclin-dependent Kinase 8

IDG Development Level Summary

Tdark

These are targets about which virtually nothing is known. They do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 233.53   (req: < 5)

Gene RIFs: 51   (req: <= 3)

Antibodies: 408   (req: <= 50)

Tbio

These targets do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 233.53   (req: >= 5)

Gene RIFs: 51   (req: > 3)

Antibodies: 408   (req: > 50)

- OR - satisfy the following criterion:

Gene Ontology Terms: 8

Tchem

Target has at least one ChEMBL compound with an activity cutoff of < 30 nM - AND - satisfies the preceding conditions

Active Ligands: 190

Tclin

Target has at least one approved drug - AND - satisfies the preceding conditions

Active Drugs: 2

Protein Sequence and Structure

Residue Counts

Protein Sequence

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Expression Data (0 Tissues)

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No expression data found

Related Tools

ProKinO

The ProKinO is a protein kinase-specific ontology, which provides a controlled vocabulary of terms, their hierarchy, and relationships unifying sequence, structure, function, mutation and pathway information on kinases.

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Target Illumination GWAS Analytics (TIGA)

TIGA scores and ranks GWAS discovered associations according to the quantity and quality of the evidence supporting the association.

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GENEVA

GENEVA (GENe Expression Variance Analysis) allows you to identify RNA-sequencing datasets from the Gene Expression Omnibus (GEO) that contain conditions modulating a gene or a gene signature.

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GlyGen

GlyGen is a data integration and dissemination project for carbohydrate and glycoconjugate related data.

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ARCHS4

ARCHS4 provides access to gene-function predictions based on RNA-seq co-expression, and gene expression levels across cell and tissues.

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Approved Drugs (2)

Explore Approved Drugs

1 – 2 of 2

ponatinib

CDK8Tchem Kinase

INHIBITOR pKi : 8.8

sorafenib

CDK8Tchem Kinase

INHIBITOR pKd : 7.8

Active Ligands (190)

Explore Active Ligands

1 – 10 of 190

SID103905531

CDK8Tchem Kinase

pKi : 9.5

AST-487

CDK8Tchem Kinase

pKd : 7.77

SID103904479

CDK8Tchem Kinase

pKi : 9

SID103904480

CDK8Tchem Kinase

pKi : 8.4

SID103904190

CDK8Tchem Kinase

pKi : 8.5

SID103904323

CDK8Tchem Kinase

pKi : 9.2

SID103904984

CDK8Tchem Kinase

pKi : 9.7

SID103904189

CDK8Tchem Kinase

pKi : 8

SID103905453

CDK8Tchem Kinase

pKi : 7.7

linifanib

CDK8Tchem Kinase

pKi : 7.06

Protein-Protein Interactions (191)

Explore Interacting Targets

1 – 10 of 191

• See Interactions on String-DB

CCNC

Tbio

Novelty:  0.00585842

p_int:  1

Score:  0.999

Data Source:  BioPlex,Reactome,STRINGDB

CDK19

Tchem

Family:  Kinase

Novelty:  0.03132669

p_int:  1

Score:  0.982

Data Source:  BioPlex,STRINGDB

MED1

Tbio

Family:  Enzyme

Novelty:  0.00852082

p_int:  0.999999829

p_ni:  1.71e-7

Score:  0.994

Data Source:  BioPlex,STRINGDB

MED21

Tbio

Family:  Enzyme

Novelty:  0.06996616

p_int:  0.999997249

p_ni:  0.000002751

Score:  0.993

Data Source:  BioPlex,STRINGDB

MED19

Tbio

Family:  Enzyme

Novelty:  0.03926689

p_int:  0.999994863

p_ni:  0.000005137

Score:  0.995

Data Source:  BioPlex,STRINGDB

MED6

Tbio

Family:  Enzyme

Novelty:  0.05215086

p_int:  0.999993113

p_ni:  0.000006887

Score:  0.996

Data Source:  BioPlex,STRINGDB

MED8

Tbio

Family:  Enzyme

Novelty:  0.06648307

p_int:  0.999927198

p_ni:  0.000072204

p_wrong:  5.98e-7

Score:  0.993

Data Source:  BioPlex,STRINGDB

MED13

Tbio

Family:  Enzyme

Novelty:  0.02090708

p_int:  0.999926571

p_ni:  0.000073428

p_wrong:  1e-9

Score:  0.998

Data Source:  BioPlex,STRINGDB

MED24

Tbio

Family:  Enzyme

Novelty:  0.05466084

p_int:  0.999920819

p_ni:  0.000079181

Score:  0.99

Data Source:  BioPlex,STRINGDB

MED12L

Tdark

Family:  Enzyme

Novelty:  0.09658419

p_int:  0.999918151

p_ni:  0.000081849

Score:  0.978

Data Source:  BioPlex,STRINGDB

Nearest Tclin Targets

Nearest Tclin calculations are only available for targets with KEGG Pathway annotations.

Pathways (33)

Reactome (24)

PathwayCommons (6)

WikiPathways (3)

Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862)

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Data Source	Name	Explore in Pharos	Explore in Source
Reactome	Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	58 targets	R-HSA-2894862
Reactome	Constitutive Signaling by NOTCH1 PEST Domain Mutants	58 targets	R-HSA-2644606
Reactome	Developmental Biology	1055 targets	R-HSA-1266738
Reactome	Disease	1105 targets	R-HSA-1643685
Reactome	Diseases of signal transduction	387 targets	R-HSA-5663202

Name	Explore in Pharos	Explore in Source
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	58 targets	R-HSA-2894862
Constitutive Signaling by NOTCH1 PEST Domain Mutants	58 targets	R-HSA-2644606
Developmental Biology	1055 targets	R-HSA-1266738
Disease	1105 targets	R-HSA-1643685
Diseases of signal transduction	387 targets	R-HSA-5663202

Viral Interactions (0)

No viral interactions found

Gene Ontology Terms (13)

Functions (5)

Components (5)

Processes (3)

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1 – 5 of 5

GO Term	Evidence	Assigned by
cyclin-dependent protein serine/threonine kinase activity	Inferred from Biological aspect of Ancestor (IBA)	GO_Central
protein kinase activity	Traceable Author Statement (TAS)	ProtInc
protein serine/threonine kinase activity	Traceable Author Statement (TAS)	Reactome
ATP binding	Inferred from Electronic Annotation (IEA)	UniProtKB-KW
RNA polymerase II CTD heptapeptide repeat kinase activity	Inferred from Electronic Annotation (IEA)	UniProtKB-EC

Disease Associations ()

No disease associations found

GWAS Traits (6)

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1 – 5 of 6

GWAS Trait	EFO ID	Study Count	SNP Count	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
type II diabetes mellitus	EFO_0001360	6	4	3	1.1	95.6
glucose measurement	EFO_0004468	1	1	1		64.4
Pituitary Gland Adenoma	EFO_1000478	1	1	0	1.4	21.5
sex hormone-binding globulin measurement	EFO_0004696	1	1	1		9.2
appendicular lean mass	EFO_0004980	1	1	1		9

• Explore on Target Illumination GWAS Analytics (TIGA)

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5

1 – 5 of 6

GWAS Trait	EFO ID	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
type II diabetes mellitus	EFO_0001360	3	1.1	95.6
glucose measurement	EFO_0004468	1		64.4
Pituitary Gland Adenoma	EFO_1000478	0	1.4	21.5
sex hormone-binding globulin measurement	EFO_0004696	1		9.2
appendicular lean mass	EFO_0004980	1		9

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UniProt Keyword Find Similar Targets

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3D-structure
Activator
Alternative splicing
ATP-binding
Complete proteome
Kinase
Nucleotide-binding
Nucleus
Polymorphism
Reference proteome

GWAS Trait Find Similar Targets

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appendicular lean mass
glucose measurement
mathematical ability
Pituitary Gland Adenoma
sex hormone-binding globulin measurement
type II diabetes mellitus

MGI Phenotype Find Similar Targets

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cardiovascular system phenotype
embryo phenotype
growth/size/body region phenotype
mortality/aging
nervous system phenotype

IDG Resources

No IDG generated resources found

Orthologs (14)

1 – 5 of 14

Species	Name	Source ID	Gene ID	OMA	EggNOG	Inparanoid
Chimp	cyclin dependent kinase 8	VGNC:7829	452501
Macaque	cyclin dependent kinase 8		709761
Mouse	cyclin-dependent kinase 8	MGI:1196224	264064
Dog	cyclin dependent kinase 8	VGNC:39061	486035
Horse	cyclin dependent kinase 8	VGNC:16356	100050819

Species	Name	OMA	EggNOG	Inparanoid
Chimp	cyclin dependent kinase 8
Macaque	cyclin dependent kinase 8
Mouse	cyclin-dependent kinase 8
Dog	cyclin dependent kinase 8
Horse	cyclin dependent kinase 8

Publication Statistics

PubMed Score 233.53

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PubTator Score 108.47

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Related Publications

Text Mined References (84)

GeneRif Annotations (51)

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PMID	Year	Title