Molecule Information

General Information of the Molecule (ID: Mol04374)

• Name: Mitogen-activated protein kinase 8 (MAPK8) ,Homo sapiens
• Synonyms: JNK-46; Stress-activated protein kinase 1c; Stress-activated protein kinase JNK1; c-Jun N-terminal kinase 1
• Molecule Type: Protein
• Gene Name: MAPK8
• Gene ID: 5599
• Sequence:
  MSRSKRDNNFYSVEIGDSTFTVLKRYQNLKPIGSGAQGIVCAAYDAILERNVAIKKLSRP
  FQNQTHAKRAYRELVLMKCVNHKNIIGLLNVFTPQKSLEEFQDVYIVMELMDANLCQVI
  Q MELDHERMSYLLYQMLCGIKHLHSAGIIHRDLKPSNIVVKSDCTLKILDFGLARTAGT
  SF MMTPYVVTRYYRAPEVILGMGYKENVDLWSVGCIMGEMVCHKILFPGRDYIDQWNKV
  IEQ LGTPCPEFMKKLQPTVRTYVENRPKYAGYSFEKLFPDVLFPADSEHNKLKASQARD
  LLSK MLVIDASKRISVDEALQHPYINVWYDPSEAEAPPPKIPDKQLDEREHTIEEWKEL
  IYKEV MDLEERTKNGVIRGQPSPLGAAVINGSQHPSSSSSVNDVSSMSTDPTLASDTDS
  SLEAAA GPLGCCR
• Function: Serine/threonine-protein kinase involved in various processessuch as cell proliferation, differentiation, migration, transformationand programmed cell death. Extracellular stimuli such as pro-inflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase signalingpathway . In this cascade, two dual specificitykinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activateMAPK8/JNK1. In turn, MAPK8/JNK1 phosphorylates a number oftranscription factors, primarily components of AP-1 such as JUN, JDP2and ATF2 and thus regulates AP-1 transcriptional activity. Phosphorylates the replication licensing factorCDT1, inhibiting the interaction between CDT1 and the histone H4acetylase HBO1 to replication origins . Loss of thisinteraction abrogates the acetylation required for replicationinitiation . Promotes stressed cell apoptosis byphosphorylating key regulatory factors including p53/TP53 and Yes-associates protein YAP1 . In T-cells, MAPK8 and MAPK9are required for polarized differentiation of T-helper cells into Th1cells. Contributes to the survival of erythroid cells byphosphorylating 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 microtubuledynamics, controlling neurite elongation in cortical neurons . In the developing brain, through its cytoplasmic activityon STMN2, negatively regulates the rate of exit from multipolar stageand of radial migration from the ventricular zone .Phosphorylates several other substrates including heat shock factorprotein 4 , the deacetylase SIRT1, ELK1, or the E3 ligase ITCH. Phosphorylates theCLOCK-BMAL1 heterodimer and plays a role in the regulation of thecircadian clock . Phosphorylates the heat shocktranscription factor HSF1, suppressing HSF1-induced transcriptionalactivity . Phosphorylates POU5F1, which results in theinhibition of POU5F1's transcriptional activity and enhances itsproteasomal degradation . Phosphorylates JUND and thisphosphorylation is inhibited in the presence of MEN1 .In neurons, phosphorylates SYT4 which captures neuronal dense corevesicles at synapses . Phosphorylates EIF4ENIF1/4-ET inresponse to oxidative stress, promoting P-body assembly. Phosphorylates SIRT6 in response to oxidativestress, stimulating its mono-ADP-ribosyltransferase activity. Phosphorylates NLRP3, promoting assembly of theNLRP3 inflammasome . Phosphorylates ALKBH5 in responseto reactive oxygen species , promoting ALKBH5 sumoylation andinactivation . {ECO:0000250|UniProtKB:P49185,ECO:0000250|UniProtKB:Q91Y86, ECO:0000269|PubMed:10747973,ECO:0000269|PubMed:16581800, ECO:0000269|PubMed:17296730,ECO:0000269|PubMed:18307971, ECO:0000269|PubMed:18570871,ECO:0000269|PubMed:20027304, ECO:0000269|PubMed:21095239,ECO:0000269|PubMed:21364637, ECO:0000269|PubMed:21856198,ECO:0000269|PubMed:22327296, ECO:0000269|PubMed:22441692,ECO:0000269|PubMed:22966201, ECO:0000269|PubMed:27568560,ECO:0000269|PubMed:28943315, ECO:0000269|PubMed:34048572}.; JNK1 isoforms display different binding patterns: beta-1preferentially binds to c-Jun, whereas alpha-1, alpha-2, and beta-2have a similar low level of binding to both c-Jun or ATF2. However,there is no correlation between binding and phosphorylation, which isachieved at about the same efficiency by all isoforms.
• Uniprot ID: MK08_HUMAN
• Ensembl ID: ENSG0000010764317
• 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

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Clinical Trial Drug(s) 1 drug(s) in total

Vemurafenib/Cobimetinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [ICD-11: 2C30.0] [1]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Vemurafenib/Cobimetinib
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• In Vitro Model: Hs294T R cells; Skin; Homo sapiens (Human); CVCL_E3AI
• In Vitro Model: WM9 R cells; melanoma; Homo sapiens (Human); CVCL_E3AH
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: XTT assay
• Mechanism Description: Obtained resistant melanoma cells exhibit increased activation of signaling pathways, including JNK, which raised activation in resistant to BRAFi/MEKi melanoma cells is demonstrated here for the first time.

References

• Ref 1: Characterization of two melanoma cell lines resistant to BRAF/MEK inhibitors (vemurafenib and cobimetinib). Cell Commun Signal. 2024 Aug 23;22(1):410.