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Protein

Mitogen-activated protein kinase kinase kinase 8

Gene

Map3k8

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 4 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.1 Publication

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

GO - Biological processi

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

Names & Taxonomyi

Protein namesi
Recommended name:
Mitogen-activated protein kinase kinase kinase 8 (EC:2.7.11.25)
Alternative name(s):
Tumor progression locus 2
Short name:
TPL-2
Gene namesi
Name:Map3k8
Synonyms:Tpl2
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Unplaced

Organism-specific databases

RGDi620969. Map3k8.

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm

Pathology & Biotechi

Keywords - Diseasei

Proto-oncogene

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 467467Mitogen-activated protein kinase kinase kinase 8PRO_0000086257Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei62 – 621PhosphoserineBy similarity
Modified residuei80 – 801PhosphothreonineBy similarity
Modified residuei138 – 1381PhosphoserineCombined sources
Modified residuei141 – 1411PhosphoserineCombined sources
Modified residuei290 – 2901PhosphothreonineBy similarity
Modified residuei400 – 4001PhosphoserineBy similarity
Modified residuei443 – 4431PhosphoserineBy similarity

Post-translational modificationi

Autophosphorylated.By similarity

Keywords - PTMi

Phosphoprotein

Proteomic databases

PaxDbiQ63562.
PRIDEiQ63562.

PTM databases

PhosphoSiteiQ63562.

Expressioni

Tissue specificityi

Expressed in spleen, thymus, liver and lung.1 Publication

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.1 Publication

Protein-protein interaction databases

STRINGi10116.ENSRNOP00000022190.

Structurei

3D structure databases

ProteinModelPortaliQ63562.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini146 – 388243Protein kinasePROSITE-ProRule annotationAdd
BLAST

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG0201. Eukaryota.
ENOG410XP9G. LUCA.
HOGENOMiHOG000285978.
HOVERGENiHBG006306.
InParanoidiQ63562.
KOiK04415.
PhylomeDBiQ63562.

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.
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q63562-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MEYMSTGSDE KEEIDLLINH LNVSEVLDIM ENLYASEEPA VYEPSLMTMC
60 70 80 90 100
PDSNQNKEHS ESLLRSGQEV PWLSSVRYGT VEDLLAFANH ISNTTKHFYR
110 120 130 140 150
CRPQESGILL NMVISPQNGR YQIDSDVLLV PWKLTYRSIG SGFVPRGAFG
160 170 180 190 200
KVYLAQDMKT KKRMACKLIP VDQFKPSDVE IQACFRHENI AELYGAVLWG
210 220 230 240 250
DTVHLFMEAG EGGSVLEKLE SCGPMREFEI IWVTKHVLKG LDFLHSKKVI
260 270 280 290 300
HHDIKPSNIV FMSTKAVLVD FGLSVQMTED 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
LDSALFDRKR LLSRKELELP ENIADSSCTG STEESEVLRR QRSLYIDLGA
460
LAGYFNIVRG PPTLEYG
Length:467
Mass (Da):52,807
Last modified:November 1, 1996 - v1
Checksum:i454E0E32768A4ABD
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M94454 mRNA. Translation: AAA42185.1.
PIRiA47388.
RefSeqiNP_446299.1. NM_053847.1.
UniGeneiRn.9939.

Genome annotation databases

GeneIDi116596.
KEGGirno:116596.
UCSCiRGD:620969. rat.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M94454 mRNA. Translation: AAA42185.1.
PIRiA47388.
RefSeqiNP_446299.1. NM_053847.1.
UniGeneiRn.9939.

3D structure databases

ProteinModelPortaliQ63562.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi10116.ENSRNOP00000022190.

PTM databases

PhosphoSiteiQ63562.

Proteomic databases

PaxDbiQ63562.
PRIDEiQ63562.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi116596.
KEGGirno:116596.
UCSCiRGD:620969. rat.

Organism-specific databases

CTDi1326.
RGDi620969. Map3k8.

Phylogenomic databases

eggNOGiKOG0201. Eukaryota.
ENOG410XP9G. LUCA.
HOGENOMiHOG000285978.
HOVERGENiHBG006306.
InParanoidiQ63562.
KOiK04415.
PhylomeDBiQ63562.

Miscellaneous databases

NextBioi619291.
PROiQ63562.

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.
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "Tumor progression locus 2 (Tpl-2) encodes a protein kinase involved in the progression of rodent T-cell lymphomas and in T-cell activation."
    Patriotis C., Makris A., Bear S.E., Tsichlis P.N.
    Proc. Natl. Acad. Sci. U.S.A. 90:2251-2255(1993) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TISSUE SPECIFICITY.
    Strain: Long Evans.
    Tissue: Liver.
  2. "TPL-2 kinase regulates the proteolysis of the NF-kappaB-inhibitory protein NF-kappaB1 p105."
    Belich M.P., Salmeron A., Johnston L.H., Ley S.C.
    Nature 397:363-368(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH NFKB1.
  3. "Quantitative maps of protein phosphorylation sites across 14 different rat organs and tissues."
    Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C., Olsen J.V.
    Nat. Commun. 3:876-876(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-138 AND SER-141, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].

Entry informationi

Entry nameiM3K8_RAT
AccessioniPrimary (citable) accession number: Q63562
Entry historyi
Integrated into UniProtKB/Swiss-Prot: September 26, 2001
Last sequence update: November 1, 1996
Last modified: May 11, 2016
This is version 118 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. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.