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Q07174

- M3K8_MOUSE

UniProt

Q07174 - M3K8_MOUSE

Protein

Mitogen-activated protein kinase kinase kinase 8

Gene

Map3k8

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 121 (01 Oct 2014)
      Sequence version 1 (01 Feb 1995)
      Previous versions | rss
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    Functioni

    Required for lipopolysaccharide (LPS)-induced, TLR4-mediated activation of the MAPK/ERK pathway in macrophages, thus being critical for production of the proinflammatory cytokine TNF-alpha (TNF) during immune responses. Involved in the regulation of T-helper cell differentiation and IFNG expression in T-cells. Involved in mediating host resistance to bacterial infection through negative regulation of type I interferon (IFN) production. In vitro, activates MAPK/ERK pathway in response to IL1 in an IRAK1-independent manner, leading to up-regulation of IL8 and CCL4. Transduces CD40 and TNFRSF1A signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production. May also play a role in the transduction of TNF signals that activate JNK and NF-kappa-B in some cell types. In adipocytes, activates MAPK/ERK pathway in an IKBKB-dependent manner in response to IL1B and TNF, but not insulin, leading to induction of lipolysis. Plays a role in the cell cycle.7 Publications

    Catalytic activityi

    ATP + a protein = ADP + a phosphoprotein.

    Cofactori

    Magnesium.By similarity

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei167 – 1671ATPPROSITE-ProRule annotation
    Active sitei253 – 2531Proton acceptorPROSITE-ProRule annotation

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi144 – 1529ATPPROSITE-ProRule annotation

    GO - Molecular functioni

    1. ATP binding Source: UniProtKB-KW
    2. magnesium ion binding Source: InterPro
    3. MAP kinase kinase kinase activity Source: UniProtKB-EC

    GO - Biological processi

    1. cell cycle Source: UniProtKB-KW
    2. immune system process Source: UniProtKB-KW

    Keywords - Molecular functioni

    Kinase, Serine/threonine-protein kinase, Transferase

    Keywords - Biological processi

    Cell cycle, Immunity

    Keywords - Ligandi

    ATP-binding, Magnesium, Metal-binding, Nucleotide-binding

    Enzyme and pathway databases

    ReactomeiREACT_224208. Interleukin-1 signaling.
    REACT_226151. CD28 dependent PI3K/Akt signaling.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Mitogen-activated protein kinase kinase kinase 8 (EC:2.7.11.25)
    Alternative name(s):
    Cancer Osaka thyroid oncogene
    Proto-oncogene c-Cot
    Serine/threonine-protein kinase cot
    Tumor progression locus 2
    Short name:
    TPL-2
    Gene namesi
    Name:Map3k8
    Synonyms:Cot, Tpl2
    OrganismiMus musculus (Mouse)
    Taxonomic identifieri10090 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
    ProteomesiUP000000589: Chromosome 18

    Organism-specific databases

    MGIiMGI:1346878. Map3k8.

    Subcellular locationi

    GO - Cellular componenti

    1. cytoplasm Source: UniProtKB-SubCell

    Keywords - Cellular componenti

    Cytoplasm

    Pathology & Biotechi

    Disruption phenotypei

    Mutant mice develop normally and show histologically normal bone marrow, thymus, spleen and lymph nodes. Mice are resistant to the induction of endotoxin shock due to defect in the induction of Tnf in response to LPS. Mice display impaired host defense against T.gondii with reduced parasite clearance and decreased Ifng production. Mice also show increased susceptibility to M.tuberculosis and L.monocytogenes infection.3 Publications

    Keywords - Diseasei

    Proto-oncogene

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 467467Mitogen-activated protein kinase kinase kinase 8PRO_0000086256Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei62 – 621PhosphoserineBy similarity
    Modified residuei80 – 801PhosphothreonineBy similarity
    Modified residuei290 – 2901PhosphothreonineBy similarity
    Modified residuei400 – 4001PhosphoserineBy similarity
    Modified residuei443 – 4431PhosphoserineBy similarity

    Post-translational modificationi

    Autophosphorylated.By similarity

    Keywords - PTMi

    Phosphoprotein

    Proteomic databases

    PaxDbiQ07174.
    PRIDEiQ07174.

    PTM databases

    PhosphoSiteiQ07174.

    Expressioni

    Tissue specificityi

    Expressed in bone marrow-derived macrophages, peritoneal macrophages, splenocytes and 3T3-L1 fibroblasts and differentiated adipocytes (at protein level). Highly expressed in adult submandibular gland, thymus, spleen and newborn digestive tract.2 Publications

    Inductioni

    Up-regulated by Il12 in T-lymphocytes. Up-regulated during in vitro adipocyte differentiation. Up-regulated in epididymal adipose tissue of obese mice.1 Publication

    Gene expression databases

    ArrayExpressiQ07174.
    BgeeiQ07174.
    CleanExiMM_MAP3K8.
    GenevestigatoriQ07174.

    Interactioni

    Subunit structurei

    Forms a ternary complex with NFKB1/p105 and TNIP2. Interacts with NFKB1; the interaction increases the stability of MAP3K8 but inhibits its MEK phosphorylation activity, whereas loss of interaction following LPS stimulation leads to its degradation. Interacts with CD40 and TRAF6; the interaction is required for ERK activation. Interacts with KSR2; the interaction inhibits ERK and NF-kappa-B activation.2 Publications

    Protein-protein interaction databases

    BioGridi204963. 2 interactions.
    IntActiQ07174. 5 interactions.

    Structurei

    3D structure databases

    ProteinModelPortaliQ07174.
    SMRiQ07174. Positions 107-421.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini138 – 388251Protein kinasePROSITE-ProRule annotationAdd
    BLAST

    Sequence similaritiesi

    Contains 1 protein kinase domain.PROSITE-ProRule annotation

    Phylogenomic databases

    eggNOGiCOG0515.
    HOGENOMiHOG000285978.
    HOVERGENiHBG006306.
    InParanoidiQ07174.
    KOiK04415.
    OMAiIHLFMEA.
    OrthoDBiEOG71P29J.
    PhylomeDBiQ07174.
    TreeFamiTF105117.

    Family and domain databases

    InterProiIPR011009. Kinase-like_dom.
    IPR017424. MAPKKK8.
    IPR000719. Prot_kinase_dom.
    IPR008271. Ser/Thr_kinase_AS.
    [Graphical view]
    PfamiPF00069. Pkinase. 1 hit.
    [Graphical view]
    PIRSFiPIRSF038171. MAPKKK8. 1 hit.
    SUPFAMiSSF56112. SSF56112. 1 hit.
    PROSITEiPS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS00108. PROTEIN_KINASE_ST. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    Q07174-1 [UniParc]FASTAAdd to Basket

    « Hide

    MEYMSTGSDE KEEIDLLIKH LNVSEVIDIM ENLYASEEPG VYEPSLMTMY    50
    PDSNQNEERS ESLLRSGQEV PWLSSVRYGT VEDLLAFANH VSNMTKHFYG 100
    RRPQECGILL NMVISPQNGR YQIDSDVLLV PWKLTYRNIG SGFVPRGAFG 150
    KVYLAQDMKT KKRMACKLIP IDQFKPSDVE IQACFRHENI AELYGAVLWG 200
    DTVHLFMEAG EGGSVLEKLE SCGPMREFEI IWVTKHILKG LDFLHSKKVI 250
    HHDIKPSNIV FMSTKAVLVD FGLSVKMTED VYLPKDLRGT EIYMSPEVIL 300
    CRGHSTKADI YSLGATLIHM QTGTPPWVKR YPRSAYPSYL YIIHKQAPPL 350
    EDIAGDCSPG MRELIEAALE RNPNHRPKAA DLLKHEALNP PREDQPRCQS 400
    LDSALFERKR LLSRKELQLP ENIADSSCTG STEESEVLRR QRSLYIDLGA 450
    LAGYFNIVRG PPTLEYG 467
    Length:467
    Mass (Da):52,942
    Last modified:February 1, 1995 - v1
    Checksum:i60C2A34E530866BE
    GO

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    D13759 mRNA. Translation: BAA02905.1.
    CCDSiCCDS29036.1.
    PIRiI49609.
    RefSeqiNP_031772.1. NM_007746.2.
    UniGeneiMm.3275.

    Genome annotation databases

    EnsembliENSMUST00000025078; ENSMUSP00000025078; ENSMUSG00000024235.
    GeneIDi26410.
    KEGGimmu:26410.
    UCSCiuc008dye.1. mouse.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    D13759 mRNA. Translation: BAA02905.1 .
    CCDSi CCDS29036.1.
    PIRi I49609.
    RefSeqi NP_031772.1. NM_007746.2.
    UniGenei Mm.3275.

    3D structure databases

    ProteinModelPortali Q07174.
    SMRi Q07174. Positions 107-421.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 204963. 2 interactions.
    IntActi Q07174. 5 interactions.

    PTM databases

    PhosphoSitei Q07174.

    Proteomic databases

    PaxDbi Q07174.
    PRIDEi Q07174.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSMUST00000025078 ; ENSMUSP00000025078 ; ENSMUSG00000024235 .
    GeneIDi 26410.
    KEGGi mmu:26410.
    UCSCi uc008dye.1. mouse.

    Organism-specific databases

    CTDi 1326.
    MGIi MGI:1346878. Map3k8.

    Phylogenomic databases

    eggNOGi COG0515.
    HOGENOMi HOG000285978.
    HOVERGENi HBG006306.
    InParanoidi Q07174.
    KOi K04415.
    OMAi IHLFMEA.
    OrthoDBi EOG71P29J.
    PhylomeDBi Q07174.
    TreeFami TF105117.

    Enzyme and pathway databases

    Reactomei REACT_224208. Interleukin-1 signaling.
    REACT_226151. CD28 dependent PI3K/Akt signaling.

    Miscellaneous databases

    NextBioi 304397.
    PROi Q07174.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi Q07174.
    Bgeei Q07174.
    CleanExi MM_MAP3K8.
    Genevestigatori Q07174.

    Family and domain databases

    InterProi IPR011009. Kinase-like_dom.
    IPR017424. MAPKKK8.
    IPR000719. Prot_kinase_dom.
    IPR008271. Ser/Thr_kinase_AS.
    [Graphical view ]
    Pfami PF00069. Pkinase. 1 hit.
    [Graphical view ]
    PIRSFi PIRSF038171. MAPKKK8. 1 hit.
    SUPFAMi SSF56112. SSF56112. 1 hit.
    PROSITEi PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS00108. PROTEIN_KINASE_ST. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "The murine cot proto-oncogene: genome structure and tissue-specific expression."
      Ohara R., Miyoshi J., Aoki M., Toyoshima K.
      Jpn. J. Cancer Res. 84:518-525(1993) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
      Strain: C57BL/6 X CBA.
      Tissue: Thymus.
    2. "TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway."
      Dumitru C.D., Ceci J.D., Tsatsanis C., Kontoyiannis D., Stamatakis K., Lin J.H., Patriotis C., Jenkins N.A., Copeland N.G., Kollias G., Tsichlis P.N.
      Cell 103:1071-1083(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, DISRUPTION PHENOTYPE.
    3. "Tpl2 transduces CD40 and TNF signals that activate ERK and regulates IgE induction by CD40."
      Eliopoulos A.G., Wang C.C., Dumitru C.D., Tsichlis P.N.
      EMBO J. 22:3855-3864(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, INTERACTION WITH CD40 AND TRAF6.
    4. "NF-kappaB1/p105 regulates lipopolysaccharide-stimulated MAP kinase signaling by governing the stability and function of the Tpl2 kinase."
      Waterfield M.R., Zhang M., Norman L.P., Sun S.C.
      Mol. Cell 11:685-694(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, INTERACTION WITH NFKB1, TISSUE SPECIFICITY.
    5. "Tpl2/cot signals activate ERK, JNK, and NF-kappaB in a cell-type and stimulus-specific manner."
      Das S., Cho J., Lambertz I., Kelliher M.A., Eliopoulos A.G., Du K., Tsichlis P.N.
      J. Biol. Chem. 280:23748-23757(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION.
    6. Cited for: FUNCTION, INDUCTION, DISRUPTION PHENOTYPE.
    7. "Tpl2 kinase is upregulated in adipose tissue in obesity and may mediate interleukin-1beta and tumor necrosis factor-{alpha} effects on extracellular signal-regulated kinase activation and lipolysis."
      Jager J., Gremeaux T., Gonzalez T., Bonnafous S., Debard C., Laville M., Vidal H., Tran A., Gual P., Le Marchand-Brustel Y., Cormont M., Tanti J.F.
      Diabetes 59:61-70(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, TISSUE SPECIFICITY.
    8. "TPL-2-ERK1/2 signaling promotes host resistance against intracellular bacterial infection by negative regulation of type I IFN production."
      McNab F.W., Ewbank J., Rajsbaum R., Stavropoulos E., Martirosyan A., Redford P.S., Wu X., Graham C.M., Saraiva M., Tsichlis P., Chaussabel D., Ley S.C., O'Garra A.
      J. Immunol. 191:1732-1743(2013) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, DISRUPTION PHENOTYPE.

    Entry informationi

    Entry nameiM3K8_MOUSE
    AccessioniPrimary (citable) accession number: Q07174
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: February 1, 1995
    Last sequence update: February 1, 1995
    Last modified: October 1, 2014
    This is version 121 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. 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

    External Data

    Dasty 3