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P49185

- MK08_RAT

UniProt

P49185 - MK08_RAT

Protein

Mitogen-activated protein kinase 8

Gene

Mapk8

Organism
Rattus norvegicus (Rat)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 139 (01 Oct 2014)
      Sequence version 1 (01 Feb 1996)
      Previous versions | rss
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    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 By similarity.By similarity

    Catalytic activityi

    ATP + a protein = ADP + a phosphoprotein.

    Cofactori

    Magnesium.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)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei55 – 551ATPPROSITE-ProRule annotation
    Active sitei151 – 1511Proton acceptorPROSITE-ProRule annotation

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi32 – 409ATPPROSITE-ProRule annotation

    GO - Molecular functioni

    1. ATP binding Source: UniProtKB-KW
    2. JUN kinase activity Source: UniProtKB
    3. protein binding Source: IntAct

    GO - Biological processi

    1. inflammatory response Source: RGD
    2. JNK cascade Source: UniProtKB
    3. JUN phosphorylation Source: GOC
    4. negative regulation of apoptotic process Source: RGD
    5. neuron projection development Source: RGD
    6. positive regulation of apoptotic process Source: RGD
    7. positive regulation of cell migration Source: RGD
    8. positive regulation of DNA replication Source: RGD
    9. positive regulation of microtubule polymerization Source: RGD
    10. regulation of transcription, DNA-templated Source: RGD
    11. response to heat Source: RGD
    12. response to hydrogen peroxide Source: RGD
    13. response to osmotic stress Source: RGD
    14. response to steroid hormone Source: RGD
    15. signal transduction Source: RGD

    Keywords - Molecular functioni

    Kinase, Serine/threonine-protein kinase, Transferase

    Keywords - Ligandi

    ATP-binding, Nucleotide-binding

    Enzyme and pathway databases

    BRENDAi2.7.11.24. 5301.

    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 lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
    ProteomesiUP000002494: Unplaced

    Organism-specific databases

    RGDi621506. Mapk8.

    Subcellular locationi

    Cytoplasm 1 Publication. Nucleus By similarity
    Note: In the cortical neurons, predominantly cytoplasmic and associated with the Golgi apparatus and endosomal fraction.

    GO - Cellular componenti

    1. axon Source: RGD
    2. cytoplasm Source: RGD
    3. cytosol Source: Reactome
    4. dendrite cytoplasm Source: RGD
    5. mitochondrion Source: RGD
    6. nucleus Source: RGD
    7. perikaryon Source: RGD
    8. vesicle Source: RGD

    Keywords - Cellular componenti

    Cytoplasm, Nucleus

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi116 – 1161C → S: Abolished inhibitory effect of IFN-gamma on JNK1 activity. 1 Publication

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 411411Mitogen-activated protein kinase 8PRO_0000186264Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei116 – 1161S-nitrosocysteine; in inhibited form1 Publication
    Modified residuei183 – 1831Phosphothreonine; by MAP2K7By similarity
    Modified residuei185 – 1851Phosphotyrosine; by MAP2K4By similarity
    Modified residuei377 – 3771PhosphoserineBy similarity

    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.1 Publication

    Keywords - PTMi

    Phosphoprotein, S-nitrosylation

    Proteomic databases

    PaxDbiP49185.
    PRIDEiP49185.

    PTM databases

    PhosphoSiteiP49185.

    Expressioni

    Gene expression databases

    GenevestigatoriP49185.

    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. Forms a complex with MAPK8IP1 and ARHGEF28. Interacts with STMN2, STMN3 and STMN4.By similarity2 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    Gria2P19491-32EBI-7456505,EBI-9118256
    Gria4P194932EBI-7456505,EBI-7761834
    JunP173252EBI-7456505,EBI-7709365
    Syt4P502325EBI-7456505,EBI-540118

    Protein-protein interaction databases

    IntActiP49185. 6 interactions.
    MINTiMINT-1500743.
    STRINGi10116.ENSRNOP00000027338.

    Structurei

    3D structure databases

    ProteinModelPortaliP49185.
    SMRiP49185. Positions 7-364.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini26 – 321296Protein kinasePROSITE-ProRule annotationAdd
    BLAST

    Motif

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Motifi183 – 1853TXY

    Domaini

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

    Sequence similaritiesi

    Contains 1 protein kinase domain.PROSITE-ProRule annotation

    Phylogenomic databases

    eggNOGiCOG0515.
    HOGENOMiHOG000233024.
    HOVERGENiHBG014652.
    InParanoidiP49185.
    KOiK04440.
    PhylomeDBiP49185.

    Family and domain databases

    InterProiIPR011009. 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]
    PfamiPF00069. Pkinase. 1 hit.
    [Graphical view]
    PRINTSiPR01772. JNKMAPKINASE.
    SMARTiSM00220. S_TKc. 1 hit.
    [Graphical view]
    SUPFAMiSSF56112. SSF56112. 1 hit.
    PROSITEiPS01351. MAPK. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS00108. PROTEIN_KINASE_ST. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    P49185-1 [UniParc]FASTAAdd to Basket

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    MSRSKRDNNF YSVEIADSTF TVLKRYQNLK PIGSGAQGIV CAAYDAILER    50
    NVAIKKLSRP FQNQTHAKRA YRELVLMKCV NHKNIIGLLN VFTPQKSLEE 100
    FQDVYIVMEL MDANLCQVIQ MELDHERMSY LLYQMLCGIK HLHSAGIIHR 150
    DLKPSNIVVK SDCTLKILDF GLARTAGTSF MMTPYVVTRY YRAPEVILGM 200
    GYKENVDLWS VGCIMGEMVC LKILFPGRDY IDQWNKVIEQ LGTPCPEFMK 250
    KLQPTVRTYV ENRPKYAGYS FEKLFPDVLF PADSEHNKLK ASQARDLLSK 300
    MLVIDASKRI SVDEALQHPY INVWYDPSEA EAPPPKIPDK QLDEREHTIE 350
    EWKELIYKEV MDLEERTKNG VIRGQPSPLG AAVINGSQHP VSSPSVNDMS 400
    SMSTDPTLAS D 411
    Length:411
    Mass (Da):46,807
    Last modified:February 1, 1996 - v1
    Checksum:i04E388B4F94633D4
    GO

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    L27129 mRNA. Translation: AAA42111.1.
    PIRiS43970.
    RefSeqiNP_446281.1. NM_053829.1.
    UniGeneiRn.4090.

    Genome annotation databases

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

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    L27129 mRNA. Translation: AAA42111.1 .
    PIRi S43970.
    RefSeqi NP_446281.1. NM_053829.1.
    UniGenei Rn.4090.

    3D structure databases

    ProteinModelPortali P49185.
    SMRi P49185. Positions 7-364.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    IntActi P49185. 6 interactions.
    MINTi MINT-1500743.
    STRINGi 10116.ENSRNOP00000027338.

    Chemistry

    ChEMBLi CHEMBL5718.

    PTM databases

    PhosphoSitei P49185.

    Proteomic databases

    PaxDbi P49185.
    PRIDEi P49185.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    GeneIDi 116554.
    KEGGi rno:116554.
    UCSCi RGD:621506. rat.

    Organism-specific databases

    CTDi 5599.
    RGDi 621506. Mapk8.

    Phylogenomic databases

    eggNOGi COG0515.
    HOGENOMi HOG000233024.
    HOVERGENi HBG014652.
    InParanoidi P49185.
    KOi K04440.
    PhylomeDBi P49185.

    Enzyme and pathway databases

    BRENDAi 2.7.11.24. 5301.

    Gene expression databases

    Genevestigatori P49185.

    Family and domain databases

    InterProi IPR011009. 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 ]
    Pfami PF00069. Pkinase. 1 hit.
    [Graphical view ]
    PRINTSi PR01772. JNKMAPKINASE.
    SMARTi SM00220. S_TKc. 1 hit.
    [Graphical view ]
    SUPFAMi SSF56112. SSF56112. 1 hit.
    PROSITEi PS01351. MAPK. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS00108. PROTEIN_KINASE_ST. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. 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. Cited for: FUNCTION.

    Entry informationi

    Entry nameiMK08_RAT
    AccessioniPrimary (citable) accession number: P49185
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: February 1, 1996
    Last sequence update: February 1, 1996
    Last modified: October 1, 2014
    This is version 139 of the entry and version 1 of the sequence. [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

    External Data

    Dasty 3