M3K8_RAT
ID M3K8_RAT Reviewed; 467 AA.
AC Q63562;
DT 26-SEP-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 142.
DE RecName: Full=Mitogen-activated protein kinase kinase kinase 8;
DE EC=2.7.11.25;
DE AltName: Full=Tumor progression locus 2;
DE Short=TPL-2;
GN Name=Map3k8; Synonyms=Tpl2;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND TISSUE SPECIFICITY.
RC STRAIN=Long Evans; TISSUE=Liver;
RX PubMed=7681591; DOI=10.1073/pnas.90.6.2251;
RA Patriotis C., Makris A., Bear S.E., Tsichlis P.N.;
RT "Tumor progression locus 2 (Tpl-2) encodes a protein kinase involved in the
RT progression of rodent T-cell lymphomas and in T-cell activation.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:2251-2255(1993).
RN [2]
RP INTERACTION WITH NFKB1.
RX PubMed=9950430; DOI=10.1038/16946;
RA Belich M.P., Salmeron A., Johnston L.H., Ley S.C.;
RT "TPL-2 kinase regulates the proteolysis of the NF-kappaB-inhibitory protein
RT NF-kappaB1 p105.";
RL Nature 397:363-368(1999).
RN [3]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-138 AND SER-141, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
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:7681591}.
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:9950430}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}.
CC -!- TISSUE SPECIFICITY: Expressed in spleen, thymus, liver and lung.
CC {ECO:0000269|PubMed:7681591}.
CC -!- PTM: Autophosphorylated. {ECO:0000250}.
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; M94454; AAA42185.1; -; mRNA.
DR PIR; A47388; A47388.
DR RefSeq; NP_446299.1; NM_053847.1.
DR AlphaFoldDB; Q63562; -.
DR SMR; Q63562; -.
DR STRING; 10116.ENSRNOP00000022190; -.
DR iPTMnet; Q63562; -.
DR PhosphoSitePlus; Q63562; -.
DR PaxDb; Q63562; -.
DR GeneID; 116596; -.
DR KEGG; rno:116596; -.
DR UCSC; RGD:620969; rat.
DR CTD; 1326; -.
DR RGD; 620969; Map3k8.
DR eggNOG; KOG0201; Eukaryota.
DR InParanoid; Q63562; -.
DR PhylomeDB; Q63562; -.
DR Reactome; R-RNO-389357; CD28 dependent PI3K/Akt signaling.
DR PRO; PR:Q63562; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; IDA:RGD.
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; IDA:RGD.
DR GO; GO:0004672; F:protein kinase activity; IDA:RGD.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0003231; P:cardiac ventricle development; IEP:RGD.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:1990349; P:gap junction-mediated intercellular transport; IMP:RGD.
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_0000086257"
FT DOMAIN 146..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 138
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 141
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
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; 52807 MW; 454E0E32768A4ABD CRC64;
MEYMSTGSDE KEEIDLLINH LNVSEVLDIM ENLYASEEPA VYEPSLMTMC PDSNQNKEHS
ESLLRSGQEV PWLSSVRYGT VEDLLAFANH ISNTTKHFYR CRPQESGILL NMVISPQNGR
YQIDSDVLLV PWKLTYRSIG SGFVPRGAFG KVYLAQDMKT KKRMACKLIP VDQFKPSDVE
IQACFRHENI AELYGAVLWG DTVHLFMEAG EGGSVLEKLE SCGPMREFEI IWVTKHVLKG
LDFLHSKKVI HHDIKPSNIV FMSTKAVLVD FGLSVQMTED VYLPKDLRGT EIYMSPEVIL
CRGHSTKADI YSLGATLIHM QTGTPPWVKR YPRSAYPSYL YIIHKQAPPL EDIAGDCSPG
MRELIEAALE RNPNHRPKAA DLLKHEALNP PREDQPRCQS LDSALFDRKR LLSRKELELP
ENIADSSCTG STEESEVLRR QRSLYIDLGA LAGYFNIVRG PPTLEYG
