UniProtKB - Q07174 (M3K8_MOUSE)
Protein
Mitogen-activated protein kinase kinase kinase 8
Gene
Map3k8
Organism
Mus musculus (Mouse)
Status
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. 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
Cofactori
Mg2+By similarity
Sites
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Binding sitei | 167 | ATPPROSITE-ProRule annotation | 1 | |
Active sitei | 253 | Proton acceptorPROSITE-ProRule annotation | 1 |
Regions
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Nucleotide bindingi | 144 – 152 | ATPPROSITE-ProRule annotation | 9 |
GO - Molecular functioni
- ATP binding Source: UniProtKB-KW
- magnesium ion binding Source: InterPro
- MAP kinase kinase kinase activity Source: MGI
GO - Biological processi
- cell cycle Source: UniProtKB-KW
- immune system process Source: UniProtKB-KW
Keywordsi
Molecular function | Kinase, Serine/threonine-protein kinase, Transferase |
Biological process | Cell cycle, Immunity |
Ligand | ATP-binding, Magnesium, Metal-binding, Nucleotide-binding |
Enzyme and pathway databases
Reactomei | R-MMU-389357, CD28 dependent PI3K/Akt signaling R-MMU-5684264, MAP3K8 (TPL2)-dependent MAPK1/3 activation |
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 |
Organismi | Mus musculus (Mouse) |
Taxonomic identifieri | 10090 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Myomorpha › Muroidea › Muridae › Murinae › Mus › Mus |
Proteomesi |
|
Organism-specific databases
MGIi | MGI:1346878, Map3k8 |
Subcellular locationi
Other locations
Cytosol
- cytosol Source: MGI
Keywords - Cellular componenti
CytoplasmPathology & 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-oncogenePTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
ChainiPRO_0000086256 | 1 – 467 | Mitogen-activated protein kinase kinase kinase 8Add BLAST | 467 |
Amino acid modifications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Modified residuei | 80 | PhosphothreonineBy similarity | 1 | |
Modified residuei | 141 | PhosphoserineBy similarity | 1 | |
Modified residuei | 290 | PhosphothreonineBy similarity | 1 | |
Modified residuei | 400 | PhosphoserineBy similarity | 1 | |
Modified residuei | 443 | PhosphoserineBy similarity | 1 |
Post-translational modificationi
Autophosphorylated.By similarity
Keywords - PTMi
PhosphoproteinProteomic databases
EPDi | Q07174 |
PaxDbi | Q07174 |
PRIDEi | Q07174 |
PTM databases
iPTMneti | Q07174 |
PhosphoSitePlusi | Q07174 |
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
Bgeei | ENSMUSG00000024235, Expressed in colon and 163 other tissues |
ExpressionAtlasi | Q07174, baseline and differential |
Genevisiblei | Q07174, MM |
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 PublicationsProtein-protein interaction databases
BioGRIDi | 204963, 2 interactors |
IntActi | Q07174, 5 interactors |
MINTi | Q07174 |
STRINGi | 10090.ENSMUSP00000025078 |
Miscellaneous databases
RNActi | Q07174, protein |
Family & Domainsi
Domains and Repeats
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Domaini | 138 – 388 | Protein kinasePROSITE-ProRule annotationAdd BLAST | 251 |
Sequence similaritiesi
Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily.Curated
Phylogenomic databases
eggNOGi | KOG0201, Eukaryota |
GeneTreei | ENSGT00940000158806 |
HOGENOMi | CLU_047137_0_0_1 |
InParanoidi | Q07174 |
OMAi | MACKLVP |
OrthoDBi | 681235at2759 |
PhylomeDBi | Q07174 |
TreeFami | TF105117 |
Family and domain databases
InterProi | View protein in InterPro IPR011009, Kinase-like_dom_sf IPR017424, MAPKKK8 IPR000719, Prot_kinase_dom IPR008271, Ser/Thr_kinase_AS |
Pfami | View protein in Pfam PF00069, Pkinase, 1 hit |
PIRSFi | PIRSF038171, MAPKKK8, 1 hit |
SMARTi | View protein in SMART SM00220, S_TKc, 1 hit |
SUPFAMi | SSF56112, SSF56112, 1 hit |
PROSITEi | View protein in PROSITE PS50011, PROTEIN_KINASE_DOM, 1 hit PS00108, PROTEIN_KINASE_ST, 1 hit |
(1+)i Sequence
Sequence statusi: Complete.
This entry has 1 described isoform and 1 potential isoform that is computationally mapped.Show allAlign All
Q07174-1 [UniParc]FASTAAdd to basket
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
Computationally mapped potential isoform sequencesi
There is 1 potential isoform mapped to this entry.BLASTAlignShow allAdd to basketG3UWY2 | G3UWY2_MOUSE | Mitogen-activated protein kinase ki... | Map3k8 | 181 | Annotation score: |
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 |
Genome annotation databases
Ensembli | ENSMUST00000025078; ENSMUSP00000025078; ENSMUSG00000024235 |
GeneIDi | 26410 |
KEGGi | mmu:26410 |
UCSCi | uc008dye.1, mouse |
Similar proteinsi
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 |
3D structure databases
SMRi | Q07174 |
ModBasei | Search... |
Protein-protein interaction databases
BioGRIDi | 204963, 2 interactors |
IntActi | Q07174, 5 interactors |
MINTi | Q07174 |
STRINGi | 10090.ENSMUSP00000025078 |
PTM databases
iPTMneti | Q07174 |
PhosphoSitePlusi | Q07174 |
Proteomic databases
EPDi | Q07174 |
PaxDbi | Q07174 |
PRIDEi | Q07174 |
Protocols and materials databases
Antibodypediai | 2836, 581 antibodies |
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 | KOG0201, Eukaryota |
GeneTreei | ENSGT00940000158806 |
HOGENOMi | CLU_047137_0_0_1 |
InParanoidi | Q07174 |
OMAi | MACKLVP |
OrthoDBi | 681235at2759 |
PhylomeDBi | Q07174 |
TreeFami | TF105117 |
Enzyme and pathway databases
Reactomei | R-MMU-389357, CD28 dependent PI3K/Akt signaling R-MMU-5684264, MAP3K8 (TPL2)-dependent MAPK1/3 activation |
Miscellaneous databases
BioGRID-ORCSi | 26410, 0 hits in 17 CRISPR screens |
ChiTaRSi | Map3k8, mouse |
PROi | PR:Q07174 |
RNActi | Q07174, protein |
SOURCEi | Search... |
Gene expression databases
Bgeei | ENSMUSG00000024235, Expressed in colon and 163 other tissues |
ExpressionAtlasi | Q07174, baseline and differential |
Genevisiblei | Q07174, MM |
Family and domain databases
InterProi | View protein in InterPro IPR011009, Kinase-like_dom_sf IPR017424, MAPKKK8 IPR000719, Prot_kinase_dom IPR008271, Ser/Thr_kinase_AS |
Pfami | View protein in Pfam PF00069, Pkinase, 1 hit |
PIRSFi | PIRSF038171, MAPKKK8, 1 hit |
SMARTi | View protein in SMART SM00220, S_TKc, 1 hit |
SUPFAMi | SSF56112, SSF56112, 1 hit |
PROSITEi | View protein in PROSITE PS50011, PROTEIN_KINASE_DOM, 1 hit PS00108, PROTEIN_KINASE_ST, 1 hit |
ProtoNeti | Search... |
MobiDBi | Search... |
Entry informationi
Entry namei | M3K8_MOUSE | |
Accessioni | Q07174Primary (citable) accession number: Q07174 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | February 1, 1995 |
Last sequence update: | February 1, 1995 | |
Last modified: | December 2, 2020 | |
This is version 165 of the entry and version 1 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Chordata Protein Annotation Program |
Miscellaneousi
Keywords - Technical termi
Reference proteomeDocuments
- MGD cross-references
Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot - SIMILARITY comments
Index of protein domains and families - Human and mouse protein kinases
Human and mouse protein kinases: classification and index