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Protein

Mitogen-activated protein kinase 8

Gene

Mapk8

Organism
Rattus norvegicus (Rat)
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 (By similarity). Phosphorylates the heat shock transcription factor HSF1, suppressing HSF1-induced transcriptional activity (By similarity).By similarity3 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Cofactori

Mg2+1 Publication

Enzyme regulationi

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. Inhibited by SERPINB3 (By similarity). Inhibited by IFN-gamma-induced S-nitrosylation.By similarity

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
  • JUN kinase activity Source: RGD
  • kinesin binding Source: RGD

GO - Biological processi

  • cellular response to amyloid-beta Source: RGD
  • cellular response to interleukin-1 Source: RGD
  • glial cell apoptotic process Source: RGD
  • inflammatory response Source: RGD
  • JNK cascade Source: UniProtKB
  • negative regulation of apoptotic process Source: RGD
  • neuronal stem cell population maintenance Source: MGI
  • neuron development Source: RGD
  • neuron projection development Source: RGD
  • positive regulation of apoptotic process Source: RGD
  • positive regulation of cardiac muscle cell apoptotic process Source: RGD
  • positive regulation of cell migration Source: RGD
  • positive regulation of DNA replication Source: RGD
  • positive regulation of glial cell apoptotic process Source: RGD
  • positive regulation of microtubule polymerization Source: RGD
  • positive regulation of neuroblast proliferation Source: RGD
  • positive regulation of neuron apoptotic process Source: RGD
  • positive regulation of neuron migration Source: RGD
  • regulation of centrosome cycle Source: RGD
  • regulation of circadian rhythm Source: UniProtKB
  • regulation of neuron differentiation Source: RGD
  • regulation of transcription, DNA-templated Source: RGD
  • response to heat Source: RGD
  • response to hydrogen peroxide Source: RGD
  • response to mechanical stimulus Source: GO_Central
  • response to osmotic stress Source: RGD
  • response to steroid hormone Source: RGD
  • rhythmic process Source: UniProtKB-KW
  • signal transduction Source: RGD
  • type B pancreatic cell apoptotic process Source: CACAO

Keywordsi

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

Enzyme and pathway databases

BRENDAi2.7.11.24. 5301.
ReactomeiR-RNO-193648. NRAGE signals death through JNK.

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):
SAPK gamma
Stress-activated protein kinase JNK1
c-Jun N-terminal kinase 1
p54 gamma
Gene namesi
Name:Mapk8
Synonyms:Jnk1, Prkm8
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Unplaced

Organism-specific databases

RGDi621506. Mapk8.

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi116C → S: Abolished inhibitory effect of IFN-gamma on JNK1 activity. 1 Publication1

Chemistry databases

ChEMBLiCHEMBL5718.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001862641 – 411Mitogen-activated protein kinase 8Add BLAST411

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei116S-nitrosocysteine; in inhibited form1 Publication1
Modified residuei183Phosphothreonine; by MAP2K7By similarity1
Modified residuei185Phosphotyrosine; by MAP2K4By similarity1
Modified residuei377PhosphoserineBy similarity1

Post-translational modificationi

Dually phosphorylated on Thr-183 and Tyr-185 by MAP2K7 and MAP2K4, which activates the enzyme. Phosphorylated by TAOK2 (By similarity).By similarity
Nitrosylated upon IFN-gamma-induced endogenous NO production, which inhibits the enzyme (PubMed:11121042). May be phosphorylated at Thr-183 and Tyr-185 by MAP3K1/MEKK1 (By similarity).By similarity1 Publication

Keywords - PTMi

Phosphoprotein, S-nitrosylation

Proteomic databases

PRIDEiP49185.

PTM databases

iPTMnetiP49185.
PhosphoSitePlusiP49185.

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. Interacts with TP53, WWOX and JAMP. Interacts with NFATC4. Interacts (phosphorylated form) with NFE2; the interaction phosphorylates NFE2 in undifferentiated cells. 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). Forms a complex with MAPK8IP1 and ARHGEF28 (PubMed:14499478). Interacts with STMN2, STMN3 and STMN4 (PubMed:16618812). Interacts with GRIPAP1 (PubMed:17761173).By similarity3 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • kinesin binding Source: RGD

Protein-protein interaction databases

IntActiP49185. 6 interactors.
MINTiMINT-1500743.

Chemistry databases

BindingDBiP49185.

Structurei

3D structure databases

ProteinModelPortaliP49185.
SMRiP49185.
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

HOGENOMiHOG000233024.
HOVERGENiHBG014652.
InParanoidiP49185.
KOiK04440.
PhylomeDBiP49185.

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.

P49185-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSRSKRDNNF YSVEIADSTF 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 LKILFPGRDY IDQWNKVIEQ LGTPCPEFMK
260 270 280 290 300
KLQPTVRTYV ENRPKYAGYS FEKLFPDVLF PADSEHNKLK ASQARDLLSK
310 320 330 340 350
MLVIDASKRI SVDEALQHPY INVWYDPSEA EAPPPKIPDK QLDEREHTIE
360 370 380 390 400
EWKELIYKEV MDLEERTKNG VIRGQPSPLG AAVINGSQHP VSSPSVNDMS
410
SMSTDPTLAS D
Length:411
Mass (Da):46,807
Last modified:February 1, 1996 - v1
Checksum:i04E388B4F94633D4
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L27129 mRNA. Translation: AAA42111.1.
PIRiS43970.
RefSeqiNP_446281.2. NM_053829.2.
UniGeneiRn.4090.

Genome annotation databases

GeneIDi116554.
KEGGirno:116554.
UCSCiRGD:621506. rat.

Similar proteinsi

Entry informationi

Entry nameiMK08_RAT
AccessioniPrimary (citable) accession number: P49185
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1996
Last sequence update: February 1, 1996
Last modified: October 25, 2017
This is version 166 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. SIMILARITY comments
    Index of protein domains and families