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P49185 (MK08_RAT) Reviewed, UniProtKB/Swiss-Prot

Last modified June 11, 2014. Version 137. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (1) | 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):
SAPK gamma
Stress-activated protein kinase JNK1
c-Jun N-terminal kinase 1
p54 gamma
Gene names
Name:Mapk8
Synonyms:Jnk1, Prkm8
OrganismRattus norvegicus (Rat) [Reference proteome]
Taxonomic identifier10116 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus

Protein attributes

Sequence length411 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 By similarity. Ref.2 Ref.5 Ref.6

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Cofactor

Magnesium. Ref.2

Enzyme regulation

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.

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. 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. Forms a complex with MAPK8IP1 and ARHGEF28. Interacts with STMN2, STMN3 and STMN4. Ref.4 Ref.5

Subcellular location

Cytoplasm. Nucleus By similarity. Note: In the cortical neurons, predominantly cytoplasmic and associated with the Golgi apparatus and endosomal fraction. Ref.5

Domain

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

Post-translational modification

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

Nitrosylated upon IFN-gamma-induced endogenous NO production, which inhibits the enzyme.

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 sequence or structural similarity. Source: UniProtKB

JUN phosphorylation

Inferred from direct assay PubMed 11849756PubMed 17064355. Source: GOC

inflammatory response

Inferred from direct assay PubMed 11435459. Source: RGD

negative regulation of apoptotic process

Inferred from direct assay PubMed 15309413. Source: RGD

neuron projection development

Inferred from mutant phenotype Ref.5. Source: RGD

positive regulation of DNA replication

Inferred from mutant phenotype PubMed 9487126. Source: RGD

positive regulation of apoptotic process

Inferred from expression pattern PubMed 16699462. Source: RGD

positive regulation of cell migration

Inferred from direct assay PubMed 12853963. Source: RGD

positive regulation of microtubule polymerization

Inferred from mutant phenotype Ref.5. Source: RGD

regulation of transcription, DNA-templated

Inferred from direct assay PubMed 12011047. Source: RGD

response to heat

Inferred from direct assay PubMed 10772775. Source: RGD

response to hydrogen peroxide

Inferred from direct assay PubMed 14707549. Source: RGD

response to osmotic stress

Inferred from direct assay PubMed 10781376. Source: RGD

response to steroid hormone

Inferred from expression pattern PubMed 14512437. Source: RGD

signal transduction

Inferred from direct assay PubMed 12011047. Source: RGD

   Cellular_componentaxon

Inferred from direct assay PubMed 9714150. Source: RGD

cytoplasm

Inferred from direct assay PubMed 10773432PubMed 15504737. Source: RGD

cytosol

Traceable author statement. Source: Reactome

dendrite cytoplasm

Inferred from direct assay PubMed 9714150. Source: RGD

mitochondrion

Inferred from direct assay PubMed 15504737. Source: RGD

nucleus

Inferred from direct assay PubMed 10773432PubMed 15504737PubMed 16699462. Source: RGD

perikaryon

Inferred from direct assay PubMed 9714150. Source: RGD

vesicle

Inferred from direct assay Ref.5. Source: RGD

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

JUN kinase activity

Inferred from sequence or structural similarity. Source: UniProtKB

protein binding

Inferred from physical interaction PubMed 18046461PubMed 18188153. Source: IntAct

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 411411Mitogen-activated protein kinase 8
PRO_0000186264

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; in inhibited form Ref.3
Modified residue1831Phosphothreonine; by MAP2K7 By similarity
Modified residue1851Phosphotyrosine; by MAP2K4 By similarity
Modified residue3771Phosphoserine By similarity

Experimental info

Mutagenesis1161C → S: Abolished inhibitory effect of IFN-gamma on JNK1 activity. Ref.3

Sequences

Sequence LengthMass (Da)Tools
P49185 [UniParc].

Last modified February 1, 1996. Version 1.
Checksum: 04E388B4F94633D4

FASTA41146,807
        10         20         30         40         50         60 
MSRSKRDNNF YSVEIADSTF 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 LKILFPGRDY 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        390        400        410 
MDLEERTKNG VIRGQPSPLG AAVINGSQHP VSSPSVNDMS SMSTDPTLAS D 

« Hide

References

[1]"The stress-activated protein kinase subfamily of c-Jun kinases."
Kyriakis J.M., Banerjee P., Nikolakaki E., Dai T., Rubie E.A., Ahmad M.F., Avruch J., Woodgett J.R.
Nature 369:156-160(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Brain.
[2]"Stimulation of 'stress-regulated' mitogen-activated protein kinases (stress-activated protein kinases/c-Jun N-terminal kinases and p38-mitogen-activated protein kinases) in perfused rat hearts by oxidative and other stresses."
Clerk A., Fuller S.J., Michael A., Sugden P.H.
J. Biol. Chem. 273:7228-7234(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, COFACTOR.
Tissue: Heart.
[3]"Nitric oxide negatively regulates c-Jun N-terminal kinase/stress-activated protein kinase by means of S-nitrosylation."
Park H.S., Huh S.H., Kim M.S., Lee S.H., Choi E.J.
Proc. Natl. Acad. Sci. U.S.A. 97:14382-14387(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: S-NITROSYLATION AT CYS-116, MUTAGENESIS OF CYS-116.
[4]"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.
[5]"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: FUNCTION, INTERACTION WITH MAPK8IP1; STMN2; STMN3 AND STMN4, SUBCELLULAR LOCATION.
[6]"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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
L27129 mRNA. Translation: AAA42111.1.
PIRS43970.
RefSeqNP_446281.1. NM_053829.1.
UniGeneRn.4090.

3D structure databases

ProteinModelPortalP49185.
SMRP49185. Positions 7-364.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

IntActP49185. 6 interactions.
MINTMINT-1500743.
STRING10116.ENSRNOP00000027338.

Chemistry

ChEMBLCHEMBL5718.

PTM databases

PhosphoSiteP49185.

Proteomic databases

PaxDbP49185.
PRIDEP49185.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

GeneID116554.
KEGGrno:116554.
UCSCRGD:621506. rat.

Organism-specific databases

CTD5599.
RGD621506. Mapk8.

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000233024.
HOVERGENHBG014652.
InParanoidP49185.
KOK04440.
PhylomeDBP49185.

Enzyme and pathway databases

BRENDA2.7.11.24. 5301.
ReactomeREACT_212996. Signal Transduction.

Gene expression databases

GenevestigatorP49185.

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...

Entry information

Entry nameMK08_RAT
AccessionPrimary (citable) accession number: P49185
Entry history
Integrated into UniProtKB/Swiss-Prot: February 1, 1996
Last sequence update: February 1, 1996
Last modified: June 11, 2014
This is version 137 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