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Q91Y86 (MK08_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 139. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Mitogen-activated protein kinase 8

Short name=MAP kinase 8
Short name=MAPK 8
EC=2.7.11.24
Alternative name(s):
Stress-activated protein kinase JNK1
c-Jun N-terminal kinase 1
Gene names
Name:Mapk8
Synonyms:Jnk1, Prkm8
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length384 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.2 Ref.5 Ref.6 Ref.13 Ref.14

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Cofactor

Magnesium. Ref.4

Enzyme regulation

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. Ref.5

Subunit structure

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 (phosphorylated form) with NFE2; the interaction phosphorylates NFE2 in undifferentiated cells. Ref.1 Ref.7 Ref.8 Ref.9 Ref.11 Ref.13

Subcellular location

Cytoplasm. Nucleus By similarity Ref.12.

Developmental stage

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). Ref.12

Induction

In T-cells, following T-cell receptor (TCR) activation. Levels peak 48 hours after TCR and CD-28 costimulation. Ref.3 Ref.4 Ref.5

Domain

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

Post-translational modification

Phosphorylated by TAOK2 By similarity. Dually phosphorylated on Thr-183 and Tyr-185 by MAP2K7 and MAP2K4, which activates the enzyme. Ref.7

Disruption phenotype

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. Ref.14

Sequence similarities

Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily.

Contains 1 protein kinase domain.

Ontologies

Keywords
   Cellular componentCytoplasm
Nucleus
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMPhosphoprotein
S-nitrosylation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processJNK cascade

Inferred from direct assay Ref.5. Source: UniProtKB

JUN phosphorylation

Inferred from mutant phenotype PubMed 14967141. Source: MGI

cellular response to hydrogen peroxide

Inferred from direct assay PubMed 20808772. Source: MGI

cellular response to lipopolysaccharide

Inferred from sequence orthology PubMed 23776175. Source: MGI

cellular response to mechanical stimulus

Inferred from electronic annotation. Source: Ensembl

cellular response to nitric oxide

Inferred from mutant phenotype PubMed 18007661. Source: MGI

determination of dorsal identity

Inferred from sequence orthology PubMed 17681137. Source: MGI

negative regulation of apoptotic process

Inferred from electronic annotation. Source: Ensembl

negative regulation of protein binding

Inferred from electronic annotation. Source: Ensembl

ossification

Inferred from mutant phenotype PubMed 15820682. Source: MGI

peptidyl-serine phosphorylation

Inferred from electronic annotation. Source: Ensembl

peptidyl-threonine phosphorylation

Inferred from mutant phenotype PubMed 14967141. Source: MGI

positive regulation of apoptotic signaling pathway

Inferred from genetic interaction PubMed 16458303. Source: MGI

positive regulation of deacetylase activity

Inferred from electronic annotation. Source: Ensembl

positive regulation of determination of dorsal identity

Inferred from direct assay PubMed 18316368. Source: MGI

positive regulation of gene expression

Inferred from electronic annotation. Source: Ensembl

programmed necrotic cell death

Inferred from mutant phenotype PubMed 18007661. Source: MGI

protein phosphorylation

Inferred from direct assay PubMed 15767678. Source: MGI

regulation of gene expression

Inferred from mutant phenotype PubMed 19289495. Source: MGI

regulation of protein localization

Inferred from electronic annotation. Source: Ensembl

response to UV

Inferred from electronic annotation. Source: Ensembl

response to cadmium ion

Inferred from genetic interaction PubMed 16458303. Source: MGI

   Cellular_componentcytoplasm

Inferred from direct assay PubMed 15030387. Source: MGI

cytosol

Inferred from direct assay PubMed 11884367. Source: MGI

mitochondrion

Inferred from direct assay PubMed 11884367. Source: MGI

nucleus

Inferred from direct assay PubMed 15030387PubMed 15483136. Source: MGI

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

JUN kinase activity

Inferred from direct assay Ref.5. Source: UniProtKB

histone deacetylase regulator activity

Inferred from electronic annotation. Source: Ensembl

kinase activity

Inferred from direct assay PubMed 12808090PubMed 15483136PubMed 15767678. Source: MGI

protein binding

Inferred from physical interaction PubMed 10629060Ref.7. Source: UniProtKB

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

JunP056272EBI-298784,EBI-764369

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 384384Mitogen-activated protein kinase 8
PRO_0000186263

Regions

Domain26 – 321296Protein kinase
Nucleotide binding32 – 409ATP By similarity
Motif183 – 1853TXY

Sites

Active site1511Proton acceptor By similarity
Binding site551ATP By similarity

Amino acid modifications

Modified residue1161S-nitrosocysteine By similarity
Modified residue1831Phosphothreonine; by MAP2K7 Ref.7
Modified residue1851Phosphotyrosine; by MAP2K4 Ref.7
Modified residue3771Phosphoserine Ref.10

Sequences

Sequence LengthMass (Da)Tools
Q91Y86 [UniParc].

Last modified December 1, 2001. Version 1.
Checksum: A7320EF933E9CF85

FASTA38444,229
        10         20         30         40         50         60 
MSRSKRDNNF YSVEIGDSTF TVLKRYQNLK PIGSGAQGIV CAAYDAILER NVAIKKLSRP 

        70         80         90        100        110        120 
FQNQTHAKRA YRELVLMKCV NHKNIIGLLN VFTPQKSLEE FQDVYIVMEL MDANLCQVIQ 

       130        140        150        160        170        180 
MELDHERMSY LLYQMLCGIK HLHSAGIIHR DLKPSNIVVK SDCTLKILDF GLARTAGTSF 

       190        200        210        220        230        240 
MMTPYVVTRY YRAPEVILGM GYKENVDLWS VGCIMGEMVC HKILFPGRDY IDQWNKVIEQ 

       250        260        270        280        290        300 
LGTPCPEFMK KLQPTVRTYV ENRPKYAGYS FEKLFPDVLF PADSEHNKLK ASQARDLLSK 

       310        320        330        340        350        360 
MLVIDASKRI SVDEALQHPY INVWYDPSEA EAPPPKIPDK QLDEREHTIE EWKELIYKEV 

       370        380 
MDLEERTKNG VIRGQPSPLA QVQQ 

« Hide

References

« Hide 'large scale' references
[1]"JSAP1, a novel jun N-terminal protein kinase (JNK)-binding protein that functions as a scaffold factor in the JNK signaling pathway."
Ito M., Yoshioka K., Akechi M., Yamashita S., Takamatsu N., Sugiyama K., Hibi M., Nakabeppu Y., Shiba T., Yamamoto K.
Mol. Cell. Biol. 19:7539-7548(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], INTERACTION WITH MAPK8IP3.
Tissue: Brain.
[2]"JNK1, JNK2 and JNK3 are p53 N-terminal serine 34 kinases."
Hu M.C., Qiu W.R., Wang Y.P.
Oncogene 15:2277-2287(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF TP53.
[3]"Targeted disruption of the MKK4 gene causes embryonic death, inhibition of c-Jun NH2-terminal kinase activation, and defects in AP-1 transcriptional activity."
Yang D., Tournier C., Wysk M., Lu H.-T., Xu J., Davis R.J., Flavell R.A.
Proc. Natl. Acad. Sci. U.S.A. 94:3004-3009(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: REGULATION BY MAP2K4.
Tissue: Embryonic stem cell.
[4]"Mitogen-activated protein kinase kinase 7 is an activator of the c-Jun NH2-terminal kinase."
Tournier C., Whitmarsh A.J., Cavanagh J., Barrett T., Davis R.J.
Proc. Natl. Acad. Sci. U.S.A. 94:7337-7342(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: REGULATION BY MAP2K7, COFACTOR.
[5]"JNK is required for effector T-cell function but not for T-cell activation."
Dong C., Yang D.D., Tournier C., Whitmarsh A.J., Xu J., Davis R.J., Flavell R.A.
Nature 405:91-94(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, ENZYME REGULATION, INDUCTION.
Tissue: Embryonic stem cell and T-cell.
[6]"The AP-1 repressor, JDP2, is a bona fide substrate for the c-Jun N-terminal kinase."
Katz S., Heinrich R., Aronheim A.
FEBS Lett. 506:196-200(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF JDP2.
[7]"Requirement of the JIP1 scaffold protein for stress-induced JNK activation."
Whitmarsh A.J., Kuan C.-Y., Kennedy N.J., Kelkar N., Haydar T.F., Mordes J.P., Appel M., Rossini A.A., Jones S.N., Flavell R.A., Rakic P., Davis R.J.
Genes Dev. 15:2421-2432(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBUNIT, PHOSPHORYLATION AT THR-183 AND TYR-185.
Tissue: Hippocampus.
[8]"JLP: a scaffolding protein that tethers JNK/p38MAPK signaling modules and transcription factors."
Lee C.M., Onesime D., Reddy C.D., Dhanasekaran N., Reddy E.P.
Proc. Natl. Acad. Sci. U.S.A. 99:14189-14194(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH SPAG9.
[9]"Cytoplasmic retention sites in p190RhoGEF confer anti-apoptotic activity to an EGFP-tagged protein."
Wu J., Zhai J., Lin H., Nie Z., Ge W.-W., Garcia-Bermejo L., Muschel R.J., Schlaepfer W.W., Canete-Soler R.
Brain Res. Mol. Brain Res. 117:27-38(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION IN A COMPLEX WITH MAPK8IP1 AND ARHGEF28.
[10]"Phosphoproteomic analysis of the developing mouse brain."
Ballif B.A., Villen J., Beausoleil S.A., Schwartz D., Gygi S.P.
Mol. Cell. Proteomics 3:1093-1101(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-377, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Embryonic brain.
[11]"JAMP, a Jun N-terminal kinase 1 (JNK1)-associated membrane protein, regulates duration of JNK activity."
Kadoya T., Khurana A., Tcherpakov M., Bromberg K.D., Didier C., Broday L., Asahara T., Bhoumik A., Ronai Z.
Mol. Cell. Biol. 25:8619-8630(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH JAMP.
[12]"JNK1 phosphorylation of SCG10 determines microtubule dynamics and axodendritic length."
Tararuk T., Ostman N., Li W., Bjorkblom B., Padzik A., Zdrojewska J., Hongisto V., Herdegen T., Konopka W., Courtney M.J., Coffey E.T.
J. Cell Biol. 173:265-277(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, DEVELOPMENTAL STAGE.
[13]"JNK-mediated turnover and stabilization of the transcription factor p45/NF-E2 during differentiation of murine erythroleukemia cells."
Lee T.L., Shyu Y.C., Hsu P.H., Chang C.W., Wen S.C., Hsiao W.Y., Tsai M.D., Shen C.K.
Proc. Natl. Acad. Sci. U.S.A. 107:52-57(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH NFE2, FUNCTION.
[14]"Phosphorylation of SCG10/stathmin-2 determines multipolar stage exit and neuronal migration rate."
Westerlund N., Zdrojewska J., Padzik A., Komulainen E., Bjorkblom B., Rannikko E., Tararuk T., Garcia-Frigola C., Sandholm J., Nguyen L., Kallunki T., Courtney M.J., Coffey E.T.
Nat. Neurosci. 14:305-313(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, DISRUPTION PHENOTYPE.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AB005663 mRNA. Translation: BAA85875.1.
CCDSCCDS36869.1.
RefSeqNP_057909.1. NM_016700.4.
UniGeneMm.21495.

3D structure databases

ProteinModelPortalQ91Y86.
SMRQ91Y86. Positions 7-364.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid204971. 16 interactions.
IntActQ91Y86. 6 interactions.
MINTMINT-1204569.
STRING10090.ENSMUSP00000022504.

Chemistry

BindingDBQ91Y86.
ChEMBLCHEMBL1795174.

PTM databases

PhosphoSiteQ91Y86.

Proteomic databases

PaxDbQ91Y86.
PRIDEQ91Y86.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000111945; ENSMUSP00000107576; ENSMUSG00000021936.
GeneID26419.
KEGGmmu:26419.
UCSCuc007szt.3. mouse.

Organism-specific databases

CTD5599.
MGIMGI:1346861. Mapk8.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00550000074271.
HOGENOMHOG000233024.
HOVERGENHBG014652.
KOK04440.
OrthoDBEOG7PCJGV.
PhylomeDBQ91Y86.
TreeFamTF105100.

Enzyme and pathway databases

BRENDA2.7.11.24. 3474.
ReactomeREACT_188257. Signal Transduction.

Gene expression databases

ArrayExpressQ91Y86.
BgeeQ91Y86.
CleanExMM_MAPK8.
GenevestigatorQ91Y86.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR003527. MAP_kinase_CS.
IPR008351. MAPK_JNK.
IPR000719. Prot_kinase_dom.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
PRINTSPR01772. JNKMAPKINASE.
SMARTSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS01351. MAPK. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio304433.
PROQ91Y86.
SOURCESearch...

Entry information

Entry nameMK08_MOUSE
AccessionPrimary (citable) accession number: Q91Y86
Entry history
Integrated into UniProtKB/Swiss-Prot: August 30, 2002
Last sequence update: December 1, 2001
Last modified: July 9, 2014
This is version 139 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot