Molecule Information

General Information of the Molecule (ID: Mol02115)

• Name: Mitogen-activated protein kinase 8 (MAPK8) ,Homo sapiens
• Synonyms: Mitogen-activated protein kinase 8 (MAP kinase 8) (MAPK 8) (EC 2.7.11.24) (JNK-46) (Stress-activated protein kinase 1c) (SAPK1c) (Stress-activated protein kinase JNK1) (c-Jun N-terminal kinase 1); MAPK8; JNK1; PRKM8; SAPK1; SAPK1C
• Molecule Type: Protein
• Gene Name: MAPK8
• Gene ID: 5599
• Location: Chromosome 10: 48,306,639-48,439,360 forward strand
• Sequence:
  MSRSKRDNNFYSVEIGDSTFTVLKRYQNLKPIGSGAQGIVCAAYDAILERNVAIKKLSRP
  FQNQTHAKRAYRELVLMKCVNHKNIIGLLNVFTPQKSLEEFQDVYIVMELMDANLCQVIQ
  MELDHERMSYLLYQMLCGIKHLHSAGIIHRDLKPSNIVVKSDCTLKILDFGLARTAGTSF
  MMTPYVVTRYYRAPEVILGMGYKENVDLWSVGCIMGEMVCHKILFPGRDYIDQWNKVIEQ
  LGTPCPEFMKKLQPTVRTYVENRPKYAGYSFEKLFPDVLFPADSEHNKLKASQARDLLSK
  MLVIDASKRISVDEALQHPYINVWYDPSEAEAPPPKIPDKQLDEREHTIEEWKELIYKEV
  MDLEERTKNGVIRGQPSPLGAAVINGSQHPSSSSSVNDVSSMSTDPTLASDTDSSLEAAA
  GPLGCCR
• 3D-structure: PDB ID: 3V3V; Classification: Transferase/transferase inhibitor; Method: X-ray diffraction; Resolution: 2.70 Å
• Function: Serine/threonine-protein kinase involved in various processes such as cell proliferation, differentiation, migration, transformation and programmed cell death. Extracellular stimuli such as pro-inflammatory 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. Phosphorylates the heat shock transcription factor HSF1, suppressing HSF1-induced transcriptional activity. Phosphorylates POU5F1, which results in the inhibition of POU5F1's transcriptional activity and enhances its proteosomal degradation. Phosphorylates JUND and this phosphorylation is inhibited in the presence of MEN1. In neurons, phosphorylates SYT4 which captures neuronal dense core vesicles at synapses. Phosphorylates EIF4ENIF1/4-ET in response to oxidative stress, promoting P-body assembly. Phosphorylates SIRT6 in response to oxidative stress, stimulating its mono-ADP-ribosyltransferase activity.
• Uniprot ID: MK08_HUMAN
• Ensembl ID: ENSG00000107643
• HGNC ID: HGNC:6881

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Olanzapine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Schizophrenia [ICD-11: 6A20.0] [1]

• Resistant Disease: Schizophrenia [ICD-11: 6A20.0]
• Resistant Drug: Olanzapine
• Molecule Alteration: Function; Activation
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vivo Model: Female C57BL/6J mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: Flow cytometry
• Mechanism Description: JNK downregulation improves olanzapine-induced insulin resistance by suppressing IRS1Ser307 phosphorylation and reducing inflammation.

Preclinical Drug(s) 1 drug(s) in total

JNK1 inhibitors

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Chronic lymphocytic leukemia [ICD-11: 2A82.0] [2]

• Sensitive Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Sensitive Drug: JNK1 inhibitors
• Molecule Alteration: Phosphorylation; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: B cell receptor signaling pathway; Inhibition; hsa04662
• In Vitro Model: 3T3-msCD40L cells; Embryo; Homo sapiens (Human); CVCL_1H10
• In Vitro Model: M2-10B4 cells; Bone marrow; Homo sapiens (Human); CVCL_5794
• In Vivo Model: NOG mice; Eu-TCL1-tg mice; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: JNK1 inhibition affects BCL2 and MCL1 expression in CLL;JNK1 inhibition reduces CLL cell viability preferentially in IGHV unmutated CLLs and overcomes stromal protective effects;JNK1 is a crucial downstream mediator of BCR signaling in CLL.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 06

Schizophrenia [ICD-11: 6A20]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Superior temporal cortex
• The Specified Disease: Schizophrenia
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.59E-01; Fold-change: 6.76E-02; Z-score: 3.10E-01
• The Studied Tissue: Pre-frontal cortex
• The Specified Disease: Schizophrenia
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.74E-04; Fold-change: -1.74E-01; Z-score: -4.16E-01

References

• Ref 1: JNK downregulation improves olanzapine-induced insulin resistance by suppressing IRS1(Ser307) phosphorylation and reducing inflammation .Biomed Pharmacother. 2021 Oct;142:112071. doi: 10.1016/j.biopha.2021.112071. Epub 2021 Aug 26. 10.1016/j.biopha.2021.112071
• Ref 2: JNK1 inhibitors target distal B cell receptor signaling and overcome BTK-inhibitor resistance in CLL. J Exp Med. 2025 Jan 6;222(1):e20230681.