M3K8_MOUSE
ID M3K8_MOUSE Reviewed; 467 AA.
AC Q07174;
DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1995, sequence version 1.
DT 03-AUG-2022, entry version 171.
DE RecName: Full=Mitogen-activated protein kinase kinase kinase 8;
DE EC=2.7.11.25;
DE AltName: Full=Cancer Osaka thyroid oncogene;
DE AltName: Full=Proto-oncogene c-Cot;
DE AltName: Full=Serine/threonine-protein kinase cot;
DE AltName: Full=Tumor progression locus 2;
DE Short=TPL-2;
GN Name=Map3k8; Synonyms=Cot, Tpl2;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=C57BL/6 X CBA; TISSUE=Thymus;
RX PubMed=8320169; DOI=10.1111/j.1349-7006.1993.tb00170.x;
RA Ohara R., Miyoshi J., Aoki M., Toyoshima K.;
RT "The murine cot proto-oncogene: genome structure and tissue-specific
RT expression.";
RL Jpn. J. Cancer Res. 84:518-525(1993).
RN [2]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=11163183; DOI=10.1016/s0092-8674(00)00210-5;
RA Dumitru C.D., Ceci J.D., Tsatsanis C., Kontoyiannis D., Stamatakis K.,
RA Lin J.H., Patriotis C., Jenkins N.A., Copeland N.G., Kollias G.,
RA Tsichlis P.N.;
RT "TNF-alpha induction by LPS is regulated posttranscriptionally via a
RT Tpl2/ERK-dependent pathway.";
RL Cell 103:1071-1083(2000).
RN [3]
RP FUNCTION, AND INTERACTION WITH CD40 AND TRAF6.
RX PubMed=12881420; DOI=10.1093/emboj/cdg386;
RA Eliopoulos A.G., Wang C.C., Dumitru C.D., Tsichlis P.N.;
RT "Tpl2 transduces CD40 and TNF signals that activate ERK and regulates IgE
RT induction by CD40.";
RL EMBO J. 22:3855-3864(2003).
RN [4]
RP FUNCTION, INTERACTION WITH NFKB1, AND TISSUE SPECIFICITY.
RX PubMed=12667451; DOI=10.1016/s1097-2765(03)00070-4;
RA Waterfield M.R., Zhang M., Norman L.P., Sun S.C.;
RT "NF-kappaB1/p105 regulates lipopolysaccharide-stimulated MAP kinase
RT signaling by governing the stability and function of the Tpl2 kinase.";
RL Mol. Cell 11:685-694(2003).
RN [5]
RP FUNCTION.
RX PubMed=15833743; DOI=10.1074/jbc.m412837200;
RA Das S., Cho J., Lambertz I., Kelliher M.A., Eliopoulos A.G., Du K.,
RA Tsichlis P.N.;
RT "Tpl2/cot signals activate ERK, JNK, and NF-kappaB in a cell-type and
RT stimulus-specific manner.";
RL J. Biol. Chem. 280:23748-23757(2005).
RN [6]
RP FUNCTION, INDUCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=19001140; DOI=10.1084/jem.20081461;
RA Watford W.T., Hissong B.D., Durant L.R., Yamane H., Muul L.M., Kanno Y.,
RA Tato C.M., Ramos H.L., Berger A.E., Mielke L., Pesu M., Solomon B.,
RA Frucht D.M., Paul W.E., Sher A., Jankovic D., Tsichlis P.N., O'Shea J.J.;
RT "Tpl2 kinase regulates T cell interferon-gamma production and host
RT resistance to Toxoplasma gondii.";
RL J. Exp. Med. 205:2803-2812(2008).
RN [7]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=19808894; DOI=10.2337/db09-0470;
RA Jager J., Gremeaux T., Gonzalez T., Bonnafous S., Debard C., Laville M.,
RA Vidal H., Tran A., Gual P., Le Marchand-Brustel Y., Cormont M., Tanti J.F.;
RT "Tpl2 kinase is upregulated in adipose tissue in obesity and may mediate
RT interleukin-1beta and tumor necrosis factor-{alpha} effects on
RT extracellular signal-regulated kinase activation and lipolysis.";
RL Diabetes 59:61-70(2010).
RN [8]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=23842752; DOI=10.4049/jimmunol.1300146;
RA McNab F.W., Ewbank J., Rajsbaum R., Stavropoulos E., Martirosyan A.,
RA Redford P.S., Wu X., Graham C.M., Saraiva M., Tsichlis P., Chaussabel D.,
RA Ley S.C., O'Garra A.;
RT "TPL-2-ERK1/2 signaling promotes host resistance against intracellular
RT bacterial infection by negative regulation of type I IFN production.";
RL J. Immunol. 191:1732-1743(2013).
CC -!- FUNCTION: Required for lipopolysaccharide (LPS)-induced, TLR4-mediated
CC activation of the MAPK/ERK pathway in macrophages, thus being critical
CC for production of the pro-inflammatory cytokine TNF-alpha (TNF) during
CC immune responses. Involved in the regulation of T-helper cell
CC differentiation and IFNG expression in T-cells. Involved in mediating
CC host resistance to bacterial infection through negative regulation of
CC type I interferon (IFN) production. Transduces CD40 and TNFRSF1A
CC signals that activate ERK in B-cells and macrophages, and thus may play
CC a role in the regulation of immunoglobulin production. May also play a
CC role in the transduction of TNF signals that activate JNK and NF-kappa-
CC B in some cell types. In adipocytes, activates MAPK/ERK pathway in an
CC IKBKB-dependent manner in response to IL1B and TNF, but not insulin,
CC leading to induction of lipolysis. Plays a role in the cell cycle.
CC {ECO:0000269|PubMed:11163183, ECO:0000269|PubMed:12667451,
CC ECO:0000269|PubMed:12881420, ECO:0000269|PubMed:15833743,
CC ECO:0000269|PubMed:19001140, ECO:0000269|PubMed:19808894,
CC ECO:0000269|PubMed:23842752}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.25;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.25;
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000250};
CC -!- SUBUNIT: Forms a ternary complex with NFKB1/p105 and TNIP2. Interacts
CC with NFKB1; the interaction increases the stability of MAP3K8 but
CC inhibits its MEK phosphorylation activity, whereas loss of interaction
CC following LPS stimulation leads to its degradation. Interacts with CD40
CC and TRAF6; the interaction is required for ERK activation. Interacts
CC with KSR2; the interaction inhibits ERK and NF-kappa-B activation.
CC {ECO:0000269|PubMed:12667451, ECO:0000269|PubMed:12881420}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- TISSUE SPECIFICITY: Expressed in bone marrow-derived macrophages,
CC peritoneal macrophages, splenocytes and 3T3-L1 fibroblasts and
CC differentiated adipocytes (at protein level). Highly expressed in adult
CC submandibular gland, thymus, spleen and newborn digestive tract.
CC {ECO:0000269|PubMed:12667451, ECO:0000269|PubMed:19808894}.
CC -!- INDUCTION: Up-regulated by Il12 in T-lymphocytes. Up-regulated during
CC in vitro adipocyte differentiation. Up-regulated in epididymal adipose
CC tissue of obese mice. {ECO:0000269|PubMed:19001140}.
CC -!- PTM: Autophosphorylated. {ECO:0000250}.
CC -!- DISRUPTION PHENOTYPE: Mutant mice develop normally and show
CC histologically normal bone marrow, thymus, spleen and lymph nodes. Mice
CC are resistant to the induction of endotoxin shock due to defect in the
CC induction of Tnf in response to LPS. Mice display impaired host defense
CC against T.gondii with reduced parasite clearance and decreased Ifng
CC production. Mice also show increased susceptibility to M.tuberculosis
CC and L.monocytogenes infection. {ECO:0000269|PubMed:11163183,
CC ECO:0000269|PubMed:19001140, ECO:0000269|PubMed:23842752}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. MAP kinase kinase kinase subfamily.
CC {ECO:0000305}.
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DR EMBL; D13759; BAA02905.1; -; mRNA.
DR CCDS; CCDS29036.1; -.
DR PIR; I49609; I49609.
DR RefSeq; NP_031772.1; NM_007746.2.
DR AlphaFoldDB; Q07174; -.
DR SMR; Q07174; -.
DR BioGRID; 204963; 2.
DR IntAct; Q07174; 5.
DR MINT; Q07174; -.
DR STRING; 10090.ENSMUSP00000025078; -.
DR iPTMnet; Q07174; -.
DR PhosphoSitePlus; Q07174; -.
DR EPD; Q07174; -.
DR PaxDb; Q07174; -.
DR PRIDE; Q07174; -.
DR ProteomicsDB; 292140; -.
DR Antibodypedia; 2836; 621 antibodies from 37 providers.
DR DNASU; 26410; -.
DR Ensembl; ENSMUST00000025078; ENSMUSP00000025078; ENSMUSG00000024235.
DR GeneID; 26410; -.
DR KEGG; mmu:26410; -.
DR UCSC; uc008dye.1; mouse.
DR CTD; 1326; -.
DR MGI; MGI:1346878; Map3k8.
DR VEuPathDB; HostDB:ENSMUSG00000024235; -.
DR eggNOG; KOG0201; Eukaryota.
DR GeneTree; ENSGT00940000158806; -.
DR HOGENOM; CLU_047137_0_0_1; -.
DR InParanoid; Q07174; -.
DR OMA; FPWRLTY; -.
DR OrthoDB; 681235at2759; -.
DR PhylomeDB; Q07174; -.
DR TreeFam; TF105117; -.
DR Reactome; R-MMU-389357; CD28 dependent PI3K/Akt signaling.
DR Reactome; R-MMU-5684264; MAP3K8 (TPL2)-dependent MAPK1/3 activation.
DR BioGRID-ORCS; 26410; 3 hits in 74 CRISPR screens.
DR ChiTaRS; Map3k8; mouse.
DR PRO; PR:Q07174; -.
DR Proteomes; UP000000589; Chromosome 18.
DR RNAct; Q07174; protein.
DR Bgee; ENSMUSG00000024235; Expressed in granulocyte and 135 other tissues.
DR ExpressionAtlas; Q07174; baseline and differential.
DR Genevisible; Q07174; MM.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0000287; F:magnesium ion binding; IEA:InterPro.
DR GO; GO:0004709; F:MAP kinase kinase kinase activity; ISO:MGI.
DR GO; GO:0004672; F:protein kinase activity; ISO:MGI.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:1990349; P:gap junction-mediated intercellular transport; ISO:MGI.
DR GO; GO:0002376; P:immune system process; IEA:UniProtKB-KW.
DR GO; GO:0000165; P:MAPK cascade; IBA:GO_Central.
DR GO; GO:0006468; P:protein phosphorylation; IBA:GO_Central.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR017424; MAPKKK8.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00069; Pkinase; 1.
DR PIRSF; PIRSF038171; MAPKKK8; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Cell cycle; Cytoplasm; Immunity; Kinase; Magnesium;
KW Metal-binding; Nucleotide-binding; Phosphoprotein; Proto-oncogene;
KW Reference proteome; Serine/threonine-protein kinase; Transferase.
FT CHAIN 1..467
FT /note="Mitogen-activated protein kinase kinase kinase 8"
FT /id="PRO_0000086256"
FT DOMAIN 138..388
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT ACT_SITE 253
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 144..152
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 167
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 80
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P41279"
FT MOD_RES 141
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P41279"
FT MOD_RES 290
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P41279"
FT MOD_RES 400
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P41279"
FT MOD_RES 443
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P41279"
SQ SEQUENCE 467 AA; 52942 MW; 60C2A34E530866BE CRC64;
MEYMSTGSDE KEEIDLLIKH LNVSEVIDIM ENLYASEEPG VYEPSLMTMY PDSNQNEERS
ESLLRSGQEV PWLSSVRYGT VEDLLAFANH VSNMTKHFYG RRPQECGILL NMVISPQNGR
YQIDSDVLLV PWKLTYRNIG SGFVPRGAFG KVYLAQDMKT KKRMACKLIP IDQFKPSDVE
IQACFRHENI AELYGAVLWG DTVHLFMEAG EGGSVLEKLE SCGPMREFEI IWVTKHILKG
LDFLHSKKVI HHDIKPSNIV FMSTKAVLVD FGLSVKMTED VYLPKDLRGT EIYMSPEVIL
CRGHSTKADI YSLGATLIHM QTGTPPWVKR YPRSAYPSYL YIIHKQAPPL EDIAGDCSPG
MRELIEAALE RNPNHRPKAA DLLKHEALNP PREDQPRCQS LDSALFERKR LLSRKELQLP
ENIADSSCTG STEESEVLRR QRSLYIDLGA LAGYFNIVRG PPTLEYG
