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

MAPK8 (P45983) - Overview - Molecular Target Synopsis

Protein


MAPK8, Mitogen-activated protein kinase 8
Enzyme Classification 2.7.11.24
UniProt P45983

Also Known as MK08_HUMAN, MAPK8, JNK1, PRKM8, SAPK1, SAPK1C

Serine/threonine-protein kinase involved in various processes such as cell proliferation, differentiation, migration, transformation and programmed cell death. Extracellular stimuli such as proinflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK8/JNK1. In turn, MAPK8/JNK1 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN, JDP2 and ATF2 and thus regulates AP-1 transcriptional activity. Phosphorylates the replication licensing factor CDT1, inhibiting the interaction between CDT1 and the histone H4 acetylase HBO1 to replication origins. Loss of this interaction abrogates the acetylation required for replication initiation. Promotes stressed cell apoptosis by phosphorylating key regulatory factors including p53/TP53 and Yes-associates protein YAP1. In T-cells, MAPK8 and MAPK9 are required for polarized differentiation of T-helper cells into Th1 cells. Contributes to the survival of erythroid cells by phosphorylating the antagonist of cell death BAD upon EPO stimulation. Mediates starvation-induced BCL2 phosphorylation, BCL2 dissociation from BECN1, and thus activation of autophagy. Phosphorylates STMN2 and hence regulates microtubule dynamics, controlling neurite elongation in cortical neurons. In the developing brain, through its cytoplasmic activity on STMN2, negatively regulates the rate of exit from multipolar stage and of radial migration from the ventricular zone. Phosphorylates several other substrates including heat shock factor protein 4 (HSF4), the deacetylase SIRT1, ELK1, or the E3 ligase ITCH. Phosphorylates the CLOCK-ARNTL/BMAL1 heterodimer and plays a role in the regulation of the circadian clock (PubMed:22441692). Phosphorylates the heat shock transcription factor HSF1, suppressing HSF1-induced transcriptional activity (PubMed:10747973). Phosphorylates POU5F1, which results in the inhibition of POU5F1's transcriptional activity and enhances its proteosomal degradation., JNK1 isoforms display different binding patterns: beta-1 preferentially binds to c-Jun, whereas alpha-1, alpha-2, and beta-2 have a similar low level of binding to both c-Jun or ATF2. However, there is no correlation between binding and phosphorylation, which is achieved at about the same efficiency by all isoforms. Binds to at least four scaffolding proteins, MAPK8IP1/JIP-1, MAPK8IP2/JIP-2, MAPK8IP3/JIP-3/JSAP1 and SPAG9/MAPK8IP4/JIP-4 (PubMed:15693750). These proteins also bind other components of the JNK signaling pathway. Interacts with TP53 and WWOX (PubMed:12514174). Interacts with JAMP (By similarity). Forms a complex with MAPK8IP1 and ARHGEF28 (By similarity). Interacts with HSF1 (via D domain and preferentially with hyperphosphorylated form); this interaction occurs under both normal growth conditions and immediately upon heat shock (PubMed:10747973). Interacts (phosphorylated form) with NFE2; the interaction phosphorylates NFE2 in undifferentiated cells (By similarity). Interacts with NFATC4 (PubMed:17875713). Interacts with MECOM; regulates JNK signaling (PubMed:10856240). Interacts with PIN1; this interaction mediates MAPK8 conformational changes leading to the binding of MAPK8 to its substrates (PubMed:21660049). Interacts with GRIPAP1 (PubMed:17761173). Interacts with POU5F1; phosphorylates POU5F1 at 'Ser-355'. Found in a complex with SH3RF1, RAC1, MAP3K11/MLK3, MAP2K7/MKK7 and MAPK8IP1/JIP1. Found in a complex with SH3RF1, RAC2, MAP3K7/TAK1, MAP2K7/MKK7, MAPK8IP1/JIP1 and MAPK9/JNK2.

5LW1
CRYSTAL STRUCTURE OF DARPIN-DARPIN RIGID FUSION, VARIANT DD_232_11_D12 IN COMPLEX JNK1A1 AND JIP1 PEPTIDE
RCSB/PDB
Inspect Structure
See all 3D Structures for MAPK8

Isoforms / Transcripts (Protein Coding)


Sub-cellular localization


UniProt: MAPK8 is active in the following subcellular-locations: cytoplasm, nucleus.
GO terms: MAPK8 is active in the following subcellular-locations: axon, basal dendrite, cytoplasm, cytosol, mitochondrion, neuron projection, nucleoplasm, nucleus.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project MAPK8 has gain in 1 cell-lines, loss in 2 cell-lines and no signal in 1002 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: OVCAR_8, DU_145, K_562

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: MHH-NB-11, SW 1573, SK-N-DZ

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, K562, AG445

(see details)

RNA Interference


MAPK8 was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: PCI30, OVTOKO. (see details)

3D Structures


For MAPK8 there are:
32 structures (46 chains) solved
22 are solved in complex with at least one small molecule ligand
1 are solved with an approved drug

MAPK8 is solved in complex with the approved drug(s):

ADN/ADENOSINE (5LW1_B, 5LW1_E, 5LW1_H).

(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


MAPK8 has been screened with 2417 compounds (3597 bioactivities), 813 compounds have bioactivities that show binding affinity of <= 500nM (1073 bioactivities). (see details)