Tchem MAP3K8 Mitogen-activated protein kinase kinase kinase 8

Protein Classes

DTO Classes

Protein / Kinase / Protein Kinase / Ste Group / Ste-unique Family / Mitogen-activated Protein Kinase Kinase Kinase 8

Protein Summary

Description

Required for lipopolysaccharide (LPS)-induced, TLR4-mediated activation of the MAPK/ERK pathway in macrophages, thus being critical for production of the proinflammatory cytokine TNF-alpha (TNF) during immune responses. Involved in the regulation of T-helper cell differentiation and IFNG expression in T-cells. Involved in mediating host resistance to bacterial infection through negative regulation of type I interferon (IFN) production. In vitro, activates MAPK/ERK pathway in response to IL1 in an IRAK1-independent manner, leading to up-regulation of IL8 and CCL4. Transduces CD40 and TNFRSF1A signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production. May also play a role in the transduction of TNF signals that activate JNK and NF-kappa-B in some cell types. In adipocytes, activates MAPK/ERK pathway in an IKBKB-dependent manner in response to IL1B and TNF, but not insulin, leading to induction of lipolysis. Plays a role in the cell cycle. Isoform 1 shows some transforming activity, although it is much weaker than that of the activated oncogenic variant. This gene is an oncogene that encodes a member of the serine/threonine protein kinase family. The encoded protein localizes to the cytoplasm and can activate both the MAP kinase and JNK kinase pathways. This protein was shown to activate IkappaB kinases, and thus induce the nuclear production of NF-kappaB. This protein was also found to promote the production of TNF-alpha and IL-2 during T lymphocyte activation. This gene may also utilize a downstream in-frame translation start codon, and thus produce an isoform containing a shorter N-terminus. The shorter isoform has been shown to display weaker transforming activity. Alternate splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Sep 2011]

Uniprot Accession IDs

• P41279
• A8K2Q5
• D3DRX1
• Q14275
• Q5T855
• Q9HC81

Gene Name

• MAP3K8

Ensembl ID

• ENST00000263056
• ENSP00000263056
• ENSG00000107968
• ENST00000375321
• ENSP00000364470
• ENST00000542547
• ENSP00000443610

Symbol

• COT
• ESTF
• COT
• EST
• ESTF
• TPL2
• AURA2
• MEKK8
• Tpl-2
• c-COT

Knowledge Table

Most Knowledge About	Knowledge Value (0 to 1 scale)
hub protein	1
molecular function	0.98
virus perturbation	0.97
PubMedID	0.94
transcription factor binding site profile	0.88

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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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: 220.14   (req: < 5)

Gene RIFs: 72   (req: <= 3)

Antibodies: 552   (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: 220.14   (req: >= 5)

Gene RIFs: 72   (req: > 3)

Antibodies: 552   (req: > 50)

- OR - satisfy the following criterion:

Gene Ontology Terms: 12

Tchem

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

Active Ligands: 54

Tclin

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

Active Drug: 0

Active Ligands (54)

Explore Active Ligands

1 – 10 of 54

MEK inhibitor II

MAP3K8Tchem Kinase

IC50 : 7.30000019

Tpl2 kinase inhibitor

MAP3K8Tchem Kinase

IC50 : 7.30000019

CHEMBL527026

MAP3K8Tchem Kinase

IC50 : 8.8

CHEMBL371658

MAP3K8Tchem Kinase

IC50 : 8.7

CHEMBL230117

MAP3K8Tchem Kinase

IC50 : 8.7

CHEMBL498071

MAP3K8Tchem Kinase

IC50 : 8.7

CHEMBL498029

MAP3K8Tchem Kinase

IC50 : 8.66

CHEMBL219682

MAP3K8Tchem Kinase

IC50 : 8.52

CHEMBL221221

MAP3K8Tchem Kinase

IC50 : 8.52

CHEMBL482863

MAP3K8Tchem Kinase

IC50 : 8.52

GWAS Traits (3)

• Explore on Target Illumination GWAS Analytics (TIGA)

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1 – 3 of 3

GWAS Trait	EFO ID	Study Count	SNP Count	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
inflammatory bowel disease	EFO_0003767	1	1	0	1.1	46.5
Crohn's disease	EFO_0000384	1	1	0	1.1	33.1
C-reactive protein measurement	EFO_0004458	1	1	1		12.7

• Explore on Target Illumination GWAS Analytics (TIGA)

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GWAS Trait	EFO ID	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
inflammatory bowel disease	EFO_0003767	0	1.1	46.5
Crohn's disease	EFO_0000384	0	1.1	33.1
C-reactive protein measurement	EFO_0004458	1		12.7

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Orthologs (14)

1 – 5 of 14

Species	Name	Source ID	Gene ID	OMA	EggNOG	Inparanoid
Chimp	mitogen-activated protein kinase kinase kinase 8	VGNC:7238	450384
Macaque	mitogen-activated protein kinase kinase kinase 8		696936
Mouse	mitogen-activated protein kinase kinase kinase 8	MGI:1346878	26410
Rat	mitogen-activated protein kinase kinase kinase 8	RGD:620969	116596
Dog	mitogen-activated protein kinase kinase kinase 8	VGNC:42979	487085

Species	Name	OMA	EggNOG	Inparanoid
Chimp	mitogen-activated protein kinase kinase kinase 8
Macaque	mitogen-activated protein kinase kinase kinase 8
Mouse	mitogen-activated protein kinase kinase kinase 8
Rat	mitogen-activated protein kinase kinase kinase 8
Dog	mitogen-activated protein kinase kinase kinase 8

Protein Structure (3 Structures, 1 AlphaFold Model)

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Representation

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Color Scheme

  target   atomindex   bfactor   chainname   electrostatic   element   hydrophobicity   resname   sstruc

Click on a row in the table to change the structure displayed.
More information can be found at RCSB PDB

AF-P41279-F1-model_v1

AlphaFold Structures Developed by DeepMind and EMBL-EBI

1 – 3 of 3

PDB Structure Id	Ligand	Method	Resolution (Å)	Residues	Fraction of Total Protein	Pub Year	Title

PDB Structure Id	Fraction of Total Protein	Resolution	Pub Year

Pathways (67)

Reactome (29)

KEGG (4)

PathwayCommons (14)

WikiPathways (20)

Adaptive Immune System (R-HSA-1280218)

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Data Source	Name	Explore in Pharos	Explore in Source
Reactome	Adaptive Immune System	894 targets	R-HSA-1280218
Reactome	CD28 co-stimulation	33 targets	R-HSA-389356
Reactome	CD28 dependent PI3K/Akt signaling	22 targets	R-HSA-389357
Reactome	Costimulation by the CD28 family	88 targets	R-HSA-388841
Reactome	Cytokine Signaling in Immune system	922 targets	R-HSA-1280215

Name	Explore in Pharos	Explore in Source
Adaptive Immune System	894 targets	R-HSA-1280218
CD28 co-stimulation	33 targets	R-HSA-389356
CD28 dependent PI3K/Akt signaling	22 targets	R-HSA-389357
Costimulation by the CD28 family	88 targets	R-HSA-388841
Cytokine Signaling in Immune system	922 targets	R-HSA-1280215

Gene Ontology Terms (14)

Functions (4)

Components (2)

Processes (8)

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10

1 – 4 of 4

GO Term	Evidence	Assigned by
protein serine/threonine kinase activity	Inferred from Biological aspect of Ancestor (IBA)	GO_Central
MAP kinase kinase kinase activity	Traceable Author Statement (TAS)	Reactome
ATP binding	Inferred from Electronic Annotation (IEA)	UniProtKB-KW
magnesium ion binding	Inferred from Electronic Annotation (IEA)	InterPro

Protein-Protein Interactions (88)

Explore Interacting Targets

1 – 10 of 88

• See Interactions on String-DB

TNIP2

Tbio

Novelty:  0.03640252

Score:  0.988

Data Source:  Reactome,STRINGDB

NFKB1

Tclin

Family:  TF

Novelty:  0.00198195

Score:  0.976

Data Source:  Reactome,STRINGDB

MAP2K1

Tclin

Family:  Kinase

Novelty:  0.0005278

Score:  0.957

Data Source:  Reactome,STRINGDB

AKT1

Tchem

Family:  Kinase

Novelty:  0.00003185

Score:  0.954

Data Source:  Reactome,STRINGDB

MAP2K4

Tchem

Family:  Kinase

Novelty:  0.00252847

Score:  0.952

Data Source:  Reactome,STRINGDB

MAP3K14

Tchem

Family:  Kinase

Novelty:  0.0350173

Score:  0.949

Data Source:  Reactome,STRINGDB

CHUK

Tchem

Family:  Kinase

Novelty:  0.00151532

Score:  0.947

Data Source:  STRINGDB

MAP2K7

Tchem

Family:  Kinase

Novelty:  0.00916401

Score:  0.94

Data Source:  STRINGDB

IKBKG

Tbio

Family:  Kinase

Novelty:  0.0006149

Score:  0.935

Data Source:  STRINGDB

MAP2K5

Tchem

Family:  Kinase

Novelty:  0.00587774

Score:  0.923

Data Source:  STRINGDB

Publication Statistics

PubMed Score  220.14

PubMed score by year

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PubTator Score  126.82

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Patents

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Amino Acid Sequence

Residue Counts

Protein Sequence

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Ortholog Sequence Conservation

WebLogo Color Code

PolarG S T Y C

NeutralQ N

BasicK R H

AcidicD E

HydrophobicA V L I P W F M

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Structural Annotations

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UniProt Keyword Find Similar Targets

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3D-structure
Alternative initiation
ATP-binding
Cell cycle
Complete proteome
Cytoplasm
Immunity
Kinase
Magnesium
Metal-binding

GWAS Trait Find Similar Targets

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C-reactive protein measurement
Crohn's disease
inflammatory bowel disease

MGI Phenotype Find Similar Targets

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behavior/neurological phenotype
cardiovascular system phenotype
cellular phenotype
digestive/alimentary phenotype
endocrine/exocrine gland phenotype
growth/size/body region phenotype
hematopoietic system phenotype
homeostasis/metabolism phenotype
immune system phenotype
mortality/aging