Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
Chemistry
Ligand Efficiency Plot
Pathways
Family Cladogram
Interaction Network
Gene Expression
Gene Copy Number Variation
RNAi
Mutations
Germline Genetics

MAP3K8 (P41279) - Overview - Molecular Target Synopsis

Protein


MAP3K8, Mitogen-activated protein kinase kinase kinase 8
Enzyme Classification 2.7.11.25
UniProt P41279

Also Known as M3K8_HUMAN, MAP3K8, COT, ESTF

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. Forms a ternary complex with NFKB1/p105 and TNIP2. Interacts with NFKB1; the interaction increases the stability of MAP3K8 but inhibits its MEK phosphorylation activity, whereas loss of interaction following LPS stimulation leads to its degradation. Interacts with CD40 and TRAF6; the interaction is required for ERK activation. Interacts with KSR2; the interaction inhibits ERK and NF-kappa-B activation.

5IU2
DISCOVERY OF IMIDAZOQUINOLINES AS A NOVEL CLASS OF POTENT, SELECTIVE AND IN VIVO EFFICACIOUS COT KINASE INHIBITORS
RCSB/PDB
Inspect Structure
See all 3D Structures for MAP3K8

Isoforms / Transcripts (Protein Coding)


Sub-cellular localization


UniProt: MAP3K8 is active in the following subcellular-locations: cytoplasm.
GO terms: MAP3K8 is active in the following subcellular-locations: cytoplasm, cytosol.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project MAP3K8 has gain in 5 cell-lines, loss in 7 cell-lines and no signal in 993 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: A549, EKVX, MCF7

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: PLC/PRF/5, KARPAS-1106P, COR-L26

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: SK-N-SH, A549, NHLF

(see details)

RNA Interference


MAP3K8 was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: OV90, SKBR3. (see details)

3D Structures


For MAP3K8 there are:
3 structures (8 chains) solved
3 are solved in complex with at least one small molecule ligand



(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


MAP3K8 has been screened with 334 compounds (460 bioactivities), 120 compounds have bioactivities that show binding affinity of <= 500nM (207 bioactivities). (see details)