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Q07174 (M3K8_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 116. 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·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended 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 names
Name:Map3k8
Synonyms:Cot, Tpl2
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length467 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.2 Ref.3 Ref.4 Ref.5 Ref.6 Ref.7 Ref.8

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Cofactor

Magnesium By similarity.

Subunit structure

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. Ref.3 Ref.4

Subcellular location

Cytoplasm.

Tissue specificity

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. Ref.4 Ref.7

Induction

Up-regulated by Il12 in T-lymphocytes. Up-regulated during in vitro adipocyte differentiation. Up-regulated in epididymal adipose tissue of obese mice. Ref.6

Post-translational modification

Autophosphorylated By similarity.

Disruption phenotype

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. Ref.2 Ref.6 Ref.8

Sequence similarities

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

Contains 1 protein kinase domain.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 467467Mitogen-activated protein kinase kinase kinase 8
PRO_0000086256

Regions

Domain138 – 388251Protein kinase
Nucleotide binding144 – 1529ATP By similarity

Sites

Active site2531Proton acceptor By similarity
Binding site1671ATP By similarity

Amino acid modifications

Modified residue621Phosphoserine By similarity
Modified residue801Phosphothreonine By similarity
Modified residue2901Phosphothreonine By similarity
Modified residue4001Phosphoserine By similarity
Modified residue4431Phosphoserine By similarity

Sequences

Sequence LengthMass (Da)Tools
Q07174 [UniParc].

Last modified February 1, 1995. Version 1.
Checksum: 60C2A34E530866BE

FASTA46752,942
        10         20         30         40         50         60 
MEYMSTGSDE KEEIDLLIKH LNVSEVIDIM ENLYASEEPG VYEPSLMTMY PDSNQNEERS 

        70         80         90        100        110        120 
ESLLRSGQEV PWLSSVRYGT VEDLLAFANH VSNMTKHFYG RRPQECGILL NMVISPQNGR 

       130        140        150        160        170        180 
YQIDSDVLLV PWKLTYRNIG SGFVPRGAFG KVYLAQDMKT KKRMACKLIP IDQFKPSDVE 

       190        200        210        220        230        240 
IQACFRHENI AELYGAVLWG DTVHLFMEAG EGGSVLEKLE SCGPMREFEI IWVTKHILKG 

       250        260        270        280        290        300 
LDFLHSKKVI HHDIKPSNIV FMSTKAVLVD FGLSVKMTED VYLPKDLRGT EIYMSPEVIL 

       310        320        330        340        350        360 
CRGHSTKADI YSLGATLIHM QTGTPPWVKR YPRSAYPSYL YIIHKQAPPL EDIAGDCSPG 

       370        380        390        400        410        420 
MRELIEAALE RNPNHRPKAA DLLKHEALNP PREDQPRCQS LDSALFERKR LLSRKELQLP 

       430        440        450        460 
ENIADSSCTG STEESEVLRR QRSLYIDLGA LAGYFNIVRG PPTLEYG 

« Hide

References

[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]"Tpl2 kinase regulates T cell interferon-gamma production and host resistance to Toxoplasma gondii."
Watford W.T., Hissong B.D., Durant L.R., Yamane H., Muul L.M., Kanno Y., Tato C.M., Ramos H.L., Berger A.E., Mielke L., Pesu M., Solomon B., Frucht D.M., Paul W.E., Sher A., Jankovic D., Tsichlis P.N., O'Shea J.J.
J. Exp. Med. 205:2803-2812(2008) [PubMed] [Europe PMC] [Abstract]
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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
D13759 mRNA. Translation: BAA02905.1.
PIRI49609.
RefSeqNP_031772.1. NM_007746.2.
UniGeneMm.3275.

3D structure databases

ProteinModelPortalQ07174.
SMRQ07174. Positions 88-415.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid204963. 2 interactions.
IntActQ07174. 5 interactions.

PTM databases

PhosphoSiteQ07174.

Proteomic databases

PaxDbQ07174.
PRIDEQ07174.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000025078; ENSMUSP00000025078; ENSMUSG00000024235.
GeneID26410.
KEGGmmu:26410.
UCSCuc008dye.1. mouse.

Organism-specific databases

CTD1326.
MGIMGI:1346878. Map3k8.

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000285978.
HOVERGENHBG006306.
InParanoidQ07174.
KOK04415.
OMADDCSPGM.
OrthoDBEOG71P29J.
PhylomeDBQ07174.
TreeFamTF105117.

Gene expression databases

ArrayExpressQ07174.
BgeeQ07174.
CleanExMM_MAP3K8.
GenevestigatorQ07174.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR017424. MAPKKK8.
IPR000719. Prot_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
PIRSFPIRSF038171. MAPKKK8. 1 hit.
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio304397.
PROQ07174.
SOURCESearch...

Entry information

Entry nameM3K8_MOUSE
AccessionPrimary (citable) accession number: Q07174
Entry history
Integrated into UniProtKB/Swiss-Prot: February 1, 1995
Last sequence update: February 1, 1995
Last modified: April 16, 2014
This is version 116 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