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Protein

Mitogen-activated protein kinase 8

Gene

Mapk8

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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 (By similarity). 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 (By similarity).By similarity6 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Cofactori

Mg2+1 Publication

Enzyme regulationi

Inhibited by SERPINB3 (By similarity). Activated by threonine and tyrosine phosphorylation by either of two dual specificity kinases, MAP2K4 and MAP2K7. MAP2K4 shows a strong preference for Tyr-185 while MAP2K7 phosphorylates Tyr-183 preferentially. Inhibited by dual specificity phosphatases, such as DUSP1.By similarity1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei55ATPPROSITE-ProRule annotation1
Active sitei151Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi32 – 40ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • enzyme binding Source: MGI
  • histone deacetylase binding Source: MGI
  • histone deacetylase regulator activity Source: MGI
  • JUN kinase activity Source: UniProtKB
  • kinase activity Source: MGI
  • protein kinase activity Source: MGI
  • protein serine/threonine kinase activity Source: MGI

GO - Biological processi

  • cellular response to amino acid starvation Source: MGI
  • cellular response to cadmium ion Source: MGI
  • cellular response to hydrogen peroxide Source: MGI
  • cellular response to lipopolysaccharide Source: MGI
  • cellular response to nitric oxide Source: MGI
  • cellular response to organic substance Source: GO_Central
  • cellular response to reactive oxygen species Source: MGI
  • dendrite morphogenesis Source: CACAO
  • determination of dorsal identity Source: MGI
  • JNK cascade Source: UniProtKB
  • JUN phosphorylation Source: MGI
  • negative regulation of apoptotic process Source: MGI
  • negative regulation of protein binding Source: MGI
  • neuronal stem cell population maintenance Source: MGI
  • neuron migration Source: CACAO
  • ossification Source: MGI
  • peptidyl-serine phosphorylation Source: MGI
  • peptidyl-threonine phosphorylation Source: MGI
  • positive regulation of apoptotic process Source: Reactome
  • positive regulation of apoptotic signaling pathway Source: MGI
  • positive regulation of cyclase activity Source: MGI
  • positive regulation of deacetylase activity Source: MGI
  • positive regulation of determination of dorsal identity Source: MGI
  • positive regulation of gene expression Source: MGI
  • positive regulation of podosome assembly Source: MGI
  • positive regulation of protein metabolic process Source: MGI
  • programmed necrotic cell death Source: MGI
  • protein localization to tricellular tight junction Source: MGI
  • protein phosphorylation Source: MGI
  • regulation of circadian rhythm Source: UniProtKB
  • regulation of DNA replication origin binding Source: MGI
  • regulation of gene expression Source: MGI
  • regulation of protein localization Source: MGI
  • response to cadmium ion Source: MGI
  • response to mechanical stimulus Source: GO_Central
  • response to UV Source: MGI
  • rhythmic process Source: UniProtKB-KW
  • stress-activated MAPK cascade Source: MGI

Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase
Biological processBiological rhythms
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.11.24. 3474.
ReactomeiR-MMU-111446. Activation of BIM and translocation to mitochondria.
R-MMU-139910. Activation of BMF and translocation to mitochondria.
R-MMU-193648. NRAGE signals death through JNK.
R-MMU-205043. NRIF signals cell death from the nucleus.
R-MMU-2559580. Oxidative Stress Induced Senescence.
R-MMU-2871796. FCERI mediated MAPK activation.
R-MMU-376172. DSCAM interactions.
R-MMU-450321. JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
R-MMU-450341. Activation of the AP-1 family of transcription factors.
R-MMU-5693565. Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks.

Names & Taxonomyi

Protein namesi
Recommended name:
Mitogen-activated protein kinase 8 (EC:2.7.11.24)
Short name:
MAP kinase 8
Short name:
MAPK 8
Alternative name(s):
Stress-activated protein kinase JNK1
c-Jun N-terminal kinase 1
Gene namesi
Name:Mapk8
Synonyms:Jnk1, Prkm8
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 14

Organism-specific databases

MGIiMGI:1346861. Mapk8.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: MGI
  • cytosol Source: MGI
  • mitochondrion Source: MGI
  • neuron projection Source: GO_Central
  • nucleus Source: MGI
  • podosome Source: MGI

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Disruption phenotypei

At 14.5 dpc, brain intermediate zone and cortical plate are significantly thicker in mutant mice compared to wild type. The number of neuronal cells is increased in the cortical plate and intermediate zone. Cell cycle exit is decreased by 13% in the ventricular and subventricular zones. In 17.5 dpc brains, the ventricular zone was thinner in mutant mice compared to wild type animals, consistent with the increased number of neurons in the cortical plate. TUBB3 is consistently more diffuse and less structured in mutant telencephalon than in wild type.1 Publication

Chemistry databases

ChEMBLiCHEMBL1795174.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001862631 – 384Mitogen-activated protein kinase 8Add BLAST384

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei116S-nitrosocysteineBy similarity1
Modified residuei183Phosphothreonine; by MAP2K71 Publication1
Modified residuei185Phosphotyrosine; by MAP2K41 Publication1
Modified residuei377PhosphoserineCombined sources1

Post-translational modificationi

Phosphorylated by TAOK2 (By similarity). Dually phosphorylated on Thr-183 and Tyr-185 by MAP2K7 and MAP2K4, which activates the enzyme.By similarity1 Publication

Keywords - PTMi

Phosphoprotein, S-nitrosylation

Proteomic databases

MaxQBiQ91Y86.
PaxDbiQ91Y86.
PRIDEiQ91Y86.

PTM databases

iPTMnetiQ91Y86.
PhosphoSitePlusiQ91Y86.

Expressioni

Tissue specificityi

Brain (at protein level).1 Publication

Developmental stagei

At 15.5 dpc, mid to low expression throughout the midbrain, with more prominent levels in the telencephalon, especially in the intermediate zone, the midbrain roof, the olfactory epithelium, the inferior colliculus, and the medulla oblongata. telencephalon revealed concentrated (at protein level).1 Publication

Inductioni

In T-cells, following T-cell receptor (TCR) activation. Levels peak 48 hours after TCR and CD-28 costimulation.1 Publication

Gene expression databases

BgeeiENSMUSG00000021936.
CleanExiMM_MAPK8.
ExpressionAtlasiQ91Y86. baseline and differential.
GenevisibleiQ91Y86. MM.

Interactioni

Subunit structurei

Binds to at least four scaffolding proteins, MAPK8IP1/JIP-1, MAPK8IP2/JIP-2, MAPK8IP3/JIP-3/JSAP1 and SPAG9/MAPK8IP4/JIP-4. These proteins also bind other components of the JNK signaling pathway. Forms a complex with MAPK8IP1 and ARHGEF28. Interacts with TP53 and WWOX. Interacts with JAMP. Interacts with NFATC4. Interacts with MECOM; regulates JNK signaling. Interacts with PIN1; this interaction mediates MAPK8 conformational changes leading to the binding of MAPK8 to its substrates (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 (By similarity). Interacts (phosphorylated form) with NFE2; the interaction phosphorylates NFE2 in undifferentiated cells.By similarity6 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
JunP056272EBI-298784,EBI-764369

GO - Molecular functioni

Protein-protein interaction databases

BioGridi204971. 20 interactors.
DIPiDIP-31075N.
IntActiQ91Y86. 7 interactors.
MINTiMINT-1204569.
STRINGi10090.ENSMUSP00000107576.

Structurei

3D structure databases

ProteinModelPortaliQ91Y86.
SMRiQ91Y86.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini26 – 321Protein kinasePROSITE-ProRule annotationAdd BLAST296

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi183 – 185TXY3

Domaini

The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.

Sequence similaritiesi

Phylogenomic databases

eggNOGiKOG0665. Eukaryota.
ENOG410XSHI. LUCA.
GeneTreeiENSGT00550000074271.
HOGENOMiHOG000233024.
HOVERGENiHBG014652.
InParanoidiQ91Y86.
KOiK04440.
PhylomeDBiQ91Y86.
TreeFamiTF105100.

Family and domain databases

InterProiView protein in InterPro
IPR011009. Kinase-like_dom.
IPR003527. MAP_kinase_CS.
IPR008351. MAPK_JNK.
IPR000719. Prot_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
PfamiView protein in Pfam
PF00069. Pkinase. 1 hit.
PRINTSiPR01772. JNKMAPKINASE.
SMARTiView protein in SMART
SM00220. S_TKc. 1 hit.
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiView protein in PROSITE
PS01351. MAPK. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.

Sequencei

Sequence statusi: Complete.

Q91Y86-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSRSKRDNNF YSVEIGDSTF TVLKRYQNLK PIGSGAQGIV CAAYDAILER
60 70 80 90 100
NVAIKKLSRP FQNQTHAKRA YRELVLMKCV NHKNIIGLLN VFTPQKSLEE
110 120 130 140 150
FQDVYIVMEL MDANLCQVIQ MELDHERMSY LLYQMLCGIK HLHSAGIIHR
160 170 180 190 200
DLKPSNIVVK SDCTLKILDF GLARTAGTSF MMTPYVVTRY YRAPEVILGM
210 220 230 240 250
GYKENVDLWS VGCIMGEMVC HKILFPGRDY IDQWNKVIEQ LGTPCPEFMK
260 270 280 290 300
KLQPTVRTYV ENRPKYAGYS FEKLFPDVLF PADSEHNKLK ASQARDLLSK
310 320 330 340 350
MLVIDASKRI SVDEALQHPY INVWYDPSEA EAPPPKIPDK QLDEREHTIE
360 370 380
EWKELIYKEV MDLEERTKNG VIRGQPSPLA QVQQ
Length:384
Mass (Da):44,229
Last modified:December 1, 2001 - v1
Checksum:iA7320EF933E9CF85
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB005663 mRNA. Translation: BAA85875.1.
CCDSiCCDS36869.1.
RefSeqiNP_057909.1. NM_016700.4.
UniGeneiMm.21495.

Genome annotation databases

EnsembliENSMUST00000111945; ENSMUSP00000107576; ENSMUSG00000021936.
GeneIDi26419.
KEGGimmu:26419.
UCSCiuc007szt.3. mouse.

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.

Entry informationi

Entry nameiMK08_MOUSE
AccessioniPrimary (citable) accession number: Q91Y86
Entry historyiIntegrated into UniProtKB/Swiss-Prot: August 30, 2002
Last sequence update: December 1, 2001
Last modified: June 7, 2017
This is version 168 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families