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Q07174

- M3K8_MOUSE

UniProt

Q07174 - M3K8_MOUSE

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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

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

Mg2+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
Complete GO annotation...

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-KW
Complete GO annotation...

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

BgeeiQ07174.
CleanExiMM_MAP3K8.
ExpressionAtlasiQ07174. baseline and differential.
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 88-421.
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

        10         20         30         40         50
MEYMSTGSDE KEEIDLLIKH LNVSEVIDIM ENLYASEEPG VYEPSLMTMY
60 70 80 90 100
PDSNQNEERS ESLLRSGQEV PWLSSVRYGT VEDLLAFANH VSNMTKHFYG
110 120 130 140 150
RRPQECGILL NMVISPQNGR YQIDSDVLLV PWKLTYRNIG SGFVPRGAFG
160 170 180 190 200
KVYLAQDMKT KKRMACKLIP IDQFKPSDVE IQACFRHENI AELYGAVLWG
210 220 230 240 250
DTVHLFMEAG EGGSVLEKLE SCGPMREFEI IWVTKHILKG LDFLHSKKVI
260 270 280 290 300
HHDIKPSNIV FMSTKAVLVD FGLSVKMTED VYLPKDLRGT EIYMSPEVIL
310 320 330 340 350
CRGHSTKADI YSLGATLIHM QTGTPPWVKR YPRSAYPSYL YIIHKQAPPL
360 370 380 390 400
EDIAGDCSPG MRELIEAALE RNPNHRPKAA DLLKHEALNP PREDQPRCQS
410 420 430 440 450
LDSALFERKR LLSRKELQLP ENIADSSCTG STEESEVLRR QRSLYIDLGA
460
LAGYFNIVRG PPTLEYG
Length:467
Mass (Da):52,942
Last modified:February 1, 1995 - v1
Checksum:i60C2A34E530866BE
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
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:
EMBLi
GenBanki
DDBJi
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 88-421.
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

Bgeei Q07174.
CleanExi MM_MAP3K8.
ExpressionAtlasi Q07174. baseline and differential.
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: November 26, 2014
This is version 123 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