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

MAP2K4 (P45985) - Overview - Molecular Target Synopsis

Protein


MAP2K4, Dual specificity mitogen-activated protein kinase kinase 4
Enzyme Classification 2.7.12.2
UniProt P45985

Also Known as MP2K4_HUMAN, MAP2K4, JNKK1, MEK4, MKK4, PRKMK4, SEK1, SERK1, SKK1

Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K7/MKK7, is the one of the only known kinase to directly activate the stress-activated protein kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they differ in their preference for the phosphorylation site in the Thr-Pro-Tyr motif. MAP2K4 shows preference for phosphorylation of the Tyr residue and MAP2K7/MKK7 for the Thr residue. The phosphorylation of the Thr residue by MAP2K7/MKK7 seems to be the prerequisite for JNK activation at least in response to proinflammatory cytokines, while other stimuli activate both MAP2K4/MKK4 and MAP2K7/MKK7 which synergistically phosphorylate JNKs. MAP2K4 is required for maintaining peripheral lymphoid homeostasis. The MKK/JNK signaling pathway is also involved in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis. Whereas MAP2K7/MKK7 exclusively activates JNKs, MAP2K4/MKK4 additionally activates the p38 MAPKs MAPK11, MAPK12, MAPK13 and MAPK14. Interacts with SPAG9 (By similarity). Interacts (via its D domain) with its substrates MAPK8/JNK1, MAPK9/JNK2, MAPK10/JNK3, MAPK11 and MAPK14. Interacts (via its DVD domain) with MAP3Ks activators like MAP3K1/MEKK1 and MAP3K11/MLK3. Interacts with ARRB1, ARRB2 and MAPK8IP3/JIP3.

3VUT
CRYSTAL STRUCTURES OF NON-PHOSPHORYLATED MAP2K4
RCSB/PDB
Inspect Structure
See all 3D Structures for MAP2K4

Isoforms / Transcripts (Protein Coding)


Sub-cellular localization


UniProt: MAP2K4 is active in the following subcellular-locations: cytoplasm, nucleus.
GO terms: MAP2K4 is active in the following subcellular-locations: axon, cytoplasm, cytosol, dendrite cytoplasm, nucleus, perikaryon.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project MAP2K4 has gain in 1 cell-lines, loss in 18 cell-lines and no signal in 986 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: U251, HOP_62, MDA_MB_231

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: SNU-182, KYSE-30, HCC1576

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: NHLF, HMEC, HSMM

(see details)

RNA Interference


MAP2K4 was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: CAL120, MDAMB134VI. (see details)

3D Structures


For MAP2K4 there are:
3 structures (6 chains) solved
2 are solved in complex with at least one small molecule ligand



(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


MAP2K4 has been screened with 162 compounds (204 bioactivities), 8 compounds have bioactivities that show binding affinity of <= 500nM (11 bioactivities). (see details)