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Protein

Mitogen-activated protein kinase kinase kinase 8

Gene

MAP3K8

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 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. Isoform 1 shows some transforming activity, although it is much weaker than that of the activated oncogenic variant.8 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Cofactori

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei167ATPPROSITE-ProRule annotation1
Active sitei253Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi144 – 152ATPPROSITE-ProRule annotation9

GO - Molecular functioni

GO - Biological processi

  • apoptotic process Source: GO_Central
  • cell cycle Source: UniProtKB-KW
  • protein phosphorylation Source: ProtInc
  • stress-activated MAPK cascade Source: Reactome
  • T cell costimulation Source: Reactome
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

Enzyme and pathway databases

BioCyciZFISH:HS03052-MONOMER.
ReactomeiR-HSA-389357. CD28 dependent PI3K/Akt signaling.
R-HSA-5684264. MAP3K8 (TPL2)-dependent MAPK1/3 activation.
SignaLinkiP41279.
SIGNORiP41279.

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, ESTF
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 10

Organism-specific databases

HGNCiHGNC:6860. MAP3K8.

Subcellular locationi

  • Cytoplasm 2 Publications

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi62S → A: Decreased IL1-stimulated activity. Loss of IL1-stimulated phosphorylation of T-290 and MEK phosphorylation activity; when associated with A-400. 1 Publication1
Mutagenesisi167K → R: Loss of catalytic activity. 1 Publication1
Mutagenesisi270D → A: Loss of catalytic activity. 1 Publication1
Mutagenesisi290T → A: Loss of MEK phosphorylation activity and almost abolished autophosphorylation activity. Loss of IL1-stimulated MEK phosphorylation activity but not of IL1-stimulated autophosphorylation activity. No effect on KSR2 binding. 2 Publications1
Mutagenesisi290T → D: Impaired MEK phosphorylation and autophosphorylation activities. No effect on KSR2 binding. 2 Publications1
Mutagenesisi290T → E: Loss of MEK phosphorylation activity and almost abolished autophosphorylation activity. No effect on KSR2 binding. 2 Publications1
Mutagenesisi400S → A: Slightly decreased IL1-stimulated MEK phosphorylation activity. Loss of IL1-stimulated phosphorylation of T-290 and MEK phosphorylation activity; when associated with A-62. 1 Publication1

Keywords - Diseasei

Proto-oncogene

Organism-specific databases

DisGeNETi1326.
MalaCardsiMAP3K8.
OpenTargetsiENSG00000107968.
PharmGKBiPA30606.

Chemistry databases

ChEMBLiCHEMBL4899.
GuidetoPHARMACOLOGYi2083.

Polymorphism and mutation databases

BioMutaiMAP3K8.
DMDMi50403742.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000243501 – 467Mitogen-activated protein kinase kinase kinase 8Add BLAST467

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei62Phosphoserine; by autocatalysis1 Publication1
Modified residuei80Phosphothreonine1 Publication1
Modified residuei141PhosphoserineCombined sources1
Modified residuei290Phosphothreonine3 Publications1
Modified residuei400Phosphoserine3 Publications1
Modified residuei443Phosphoserine1 Publication1

Post-translational modificationi

Autophosphorylated. Isoform 1 undergoes phosphorylation mainly on Ser residues, and isoform 2 on both Ser and Thr residues. Thr-290 is autophosphorylated (PubMed:19754427) and/or transphosphorylated (PubMed:15466476); the phosphorylation is necessary but not sufficient for full kinase activity in vitro and for the dissociation of isoform 1 from NFKB1, leading to its degradation. Ser-400 is autophosphorylated (PubMed:19754427) and/or transphosphorylated by IKBKB (PubMed:22988300); the phosphorylation is required for LPS-stimulated activation of the MAPK/ERK pathway in macrophages.5 Publications

Keywords - PTMi

Phosphoprotein

Proteomic databases

MaxQBiP41279.
PaxDbiP41279.
PeptideAtlasiP41279.
PRIDEiP41279.

PTM databases

iPTMnetiP41279.
PhosphoSitePlusiP41279.

Expressioni

Tissue specificityi

Expressed in several normal tissues and human tumor-derived cell lines.

Developmental stagei

Isoform 1 is activated specifically during the S and G2/M phases of the cell cycle.

Inductioni

Up-regulated by IL12 in T-lymphocytes. Up-regulated in subcutaneous adipose tissue of obese individuals.2 Publications

Gene expression databases

BgeeiENSG00000107968.
CleanExiHS_MAP3K8.
ExpressionAtlasiP41279. baseline and differential.
GenevisibleiP41279. HS.

Organism-specific databases

HPAiCAB005120.
HPA017962.

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.5 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
HSP90AB1P082382EBI-354900,EBI-352572
NFKB1P1983813EBI-354900,EBI-300010
NFKB2Q006532EBI-354900,EBI-307326
PIN1Q135268EBI-354900,EBI-714158
TNIP2Q8NFZ510EBI-354900,EBI-359372

Protein-protein interaction databases

BioGridi107719. 21 interactors.
DIPiDIP-27534N.
IntActiP41279. 14 interactors.
MINTiMINT-1140505.
STRINGi9606.ENSP00000263056.

Chemistry databases

BindingDBiP41279.

Structurei

Secondary structure

1467
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi75 – 78Combined sources4
Helixi81 – 92Combined sources12
Beta strandi106 – 109Combined sources4
Beta strandi117 – 119Combined sources3
Turni124 – 126Combined sources3
Beta strandi127 – 130Combined sources4
Helixi135 – 137Combined sources3
Beta strandi138 – 145Combined sources8
Beta strandi148 – 157Combined sources10
Turni158 – 160Combined sources3
Beta strandi163 – 170Combined sources8
Helixi171 – 173Combined sources3
Helixi177 – 184Combined sources8
Beta strandi193 – 199Combined sources7
Beta strandi202 – 207Combined sources6
Helixi215 – 222Combined sources8
Helixi227 – 246Combined sources20
Helixi256 – 258Combined sources3
Beta strandi259 – 261Combined sources3
Beta strandi266 – 268Combined sources3
Beta strandi278 – 282Combined sources5
Helixi291 – 293Combined sources3
Helixi296 – 300Combined sources5
Helixi307 – 322Combined sources16
Turni326 – 330Combined sources5
Helixi340 – 346Combined sources7
Helixi350 – 352Combined sources3
Beta strandi355 – 357Combined sources3
Helixi359 – 368Combined sources10
Turni373 – 375Combined sources3
Helixi379 – 382Combined sources4
Helixi386 – 388Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4Y83X-ray2.89A/B/C66-395[»]
4Y85X-ray2.33A/B/C66-395[»]
5IU2X-ray2.70A/B66-395[»]
ProteinModelPortaliP41279.
SMRiP41279.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini138 – 388Protein kinasePROSITE-ProRule annotationAdd BLAST251

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG0201. Eukaryota.
ENOG410XP9G. LUCA.
GeneTreeiENSGT00800000124036.
HOGENOMiHOG000285978.
HOVERGENiHBG006306.
InParanoidiP41279.
KOiK04415.
OMAiIHLFMEA.
OrthoDBiEOG091G0682.
PhylomeDBiP41279.
TreeFamiTF105117.

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]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative initiation. AlignAdd to basket

Isoform 1 (identifier: P41279-1) [UniParc]FASTAAdd to basket
Also known as: 58 kDa

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MEYMSTGSDN KEEIDLLIKH LNVSDVIDIM ENLYASEEPA VYEPSLMTMC
60 70 80 90 100
QDSNQNDERS KSLLLSGQEV PWLSSVRYGT VEDLLAFANH ISNTAKHFYG
110 120 130 140 150
QRPQESGILL NMVITPQNGR YQIDSDVLLI PWKLTYRNIG SDFIPRGAFG
160 170 180 190 200
KVYLAQDIKT KKRMACKLIP VDQFKPSDVE IQACFRHENI AELYGAVLWG
210 220 230 240 250
ETVHLFMEAG EGGSVLEKLE SCGPMREFEI IWVTKHVLKG LDFLHSKKVI
260 270 280 290 300
HHDIKPSNIV FMSTKAVLVD FGLSVQMTED VYFPKDLRGT EIYMSPEVIL
310 320 330 340 350
CRGHSTKADI YSLGATLIHM QTGTPPWVKR YPRSAYPSYL YIIHKQAPPL
360 370 380 390 400
EDIADDCSPG MRELIEASLE RNPNHRPRAA DLLKHEALNP PREDQPRCQS
410 420 430 440 450
LDSALLERKR LLSRKELELP ENIADSSCTG STEESEMLKR QRSLYIDLGA
460
LAGYFNLVRG PPTLEYG
Length:467
Mass (Da):52,925
Last modified:July 19, 2004 - v2
Checksum:i7728969EA3E4E8EC
GO
Isoform 2 (identifier: P41279-2) [UniParc]FASTAAdd to basket
Also known as: 52 kDa

The sequence of this isoform differs from the canonical sequence as follows:
     1-29: Missing.

Show »
Length:438
Mass (Da):49,620
Checksum:i2121FEF4658882FD
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti399Q → T in BAA03387 (PubMed:2072910).Curated1
Sequence conflicti399Q → T no nucleotide entry (PubMed:8226782).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_051638214S → F.Corresponds to variant rs3087944dbSNPEnsembl.1
Natural variantiVAR_006198398 – 415CQSLD…LLSRK → GHQVIHEGSSTNDPNNSC in oncogenic form. Add BLAST18
Natural variantiVAR_006199416 – 467Missing in oncogenic form. Add BLAST52

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0188431 – 29Missing in isoform 2. 1 PublicationAdd BLAST29

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
D14497 mRNA. Translation: BAA03387.1.
Z14138 mRNA. Translation: CAA78512.1.
AK290320 mRNA. Translation: BAF83009.1.
AY309013 Genomic DNA. Translation: AAP45053.1.
AL161651 Genomic DNA. Translation: CAI14227.1.
CH471072 Genomic DNA. Translation: EAW86004.1.
CH471072 Genomic DNA. Translation: EAW86005.1.
CH471072 Genomic DNA. Translation: EAW86006.1.
CH471072 Genomic DNA. Translation: EAW86007.1.
BC104833 mRNA. Translation: AAI04834.1.
BC113566 mRNA. Translation: AAI13567.1.
AF133211 Genomic DNA. Translation: AAG13454.1.
CCDSiCCDS7166.1. [P41279-1]
PIRiA48713.
RefSeqiNP_001231063.1. NM_001244134.1. [P41279-1]
NP_001307890.1. NM_001320961.1. [P41279-1]
NP_005195.2. NM_005204.3. [P41279-1]
XP_016871196.1. XM_017015707.1. [P41279-1]
XP_016871197.1. XM_017015708.1. [P41279-1]
XP_016871198.1. XM_017015709.1. [P41279-1]
XP_016871199.1. XM_017015710.1. [P41279-1]
UniGeneiHs.432453.
Hs.663033.
Hs.731448.

Genome annotation databases

EnsembliENST00000263056; ENSP00000263056; ENSG00000107968. [P41279-1]
ENST00000375321; ENSP00000364470; ENSG00000107968. [P41279-1]
ENST00000542547; ENSP00000443610; ENSG00000107968. [P41279-1]
GeneIDi1326.
KEGGihsa:1326.
UCSCiuc001ivi.3. human. [P41279-1]

Keywords - Coding sequence diversityi

Alternative initiation, Polymorphism

Cross-referencesi

Web resourcesi

SeattleSNPs

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
D14497 mRNA. Translation: BAA03387.1.
Z14138 mRNA. Translation: CAA78512.1.
AK290320 mRNA. Translation: BAF83009.1.
AY309013 Genomic DNA. Translation: AAP45053.1.
AL161651 Genomic DNA. Translation: CAI14227.1.
CH471072 Genomic DNA. Translation: EAW86004.1.
CH471072 Genomic DNA. Translation: EAW86005.1.
CH471072 Genomic DNA. Translation: EAW86006.1.
CH471072 Genomic DNA. Translation: EAW86007.1.
BC104833 mRNA. Translation: AAI04834.1.
BC113566 mRNA. Translation: AAI13567.1.
AF133211 Genomic DNA. Translation: AAG13454.1.
CCDSiCCDS7166.1. [P41279-1]
PIRiA48713.
RefSeqiNP_001231063.1. NM_001244134.1. [P41279-1]
NP_001307890.1. NM_001320961.1. [P41279-1]
NP_005195.2. NM_005204.3. [P41279-1]
XP_016871196.1. XM_017015707.1. [P41279-1]
XP_016871197.1. XM_017015708.1. [P41279-1]
XP_016871198.1. XM_017015709.1. [P41279-1]
XP_016871199.1. XM_017015710.1. [P41279-1]
UniGeneiHs.432453.
Hs.663033.
Hs.731448.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4Y83X-ray2.89A/B/C66-395[»]
4Y85X-ray2.33A/B/C66-395[»]
5IU2X-ray2.70A/B66-395[»]
ProteinModelPortaliP41279.
SMRiP41279.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi107719. 21 interactors.
DIPiDIP-27534N.
IntActiP41279. 14 interactors.
MINTiMINT-1140505.
STRINGi9606.ENSP00000263056.

Chemistry databases

BindingDBiP41279.
ChEMBLiCHEMBL4899.
GuidetoPHARMACOLOGYi2083.

PTM databases

iPTMnetiP41279.
PhosphoSitePlusiP41279.

Polymorphism and mutation databases

BioMutaiMAP3K8.
DMDMi50403742.

Proteomic databases

MaxQBiP41279.
PaxDbiP41279.
PeptideAtlasiP41279.
PRIDEiP41279.

Protocols and materials databases

DNASUi1326.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000263056; ENSP00000263056; ENSG00000107968. [P41279-1]
ENST00000375321; ENSP00000364470; ENSG00000107968. [P41279-1]
ENST00000542547; ENSP00000443610; ENSG00000107968. [P41279-1]
GeneIDi1326.
KEGGihsa:1326.
UCSCiuc001ivi.3. human. [P41279-1]

Organism-specific databases

CTDi1326.
DisGeNETi1326.
GeneCardsiMAP3K8.
HGNCiHGNC:6860. MAP3K8.
HPAiCAB005120.
HPA017962.
MalaCardsiMAP3K8.
MIMi191195. gene.
neXtProtiNX_P41279.
OpenTargetsiENSG00000107968.
PharmGKBiPA30606.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0201. Eukaryota.
ENOG410XP9G. LUCA.
GeneTreeiENSGT00800000124036.
HOGENOMiHOG000285978.
HOVERGENiHBG006306.
InParanoidiP41279.
KOiK04415.
OMAiIHLFMEA.
OrthoDBiEOG091G0682.
PhylomeDBiP41279.
TreeFamiTF105117.

Enzyme and pathway databases

BioCyciZFISH:HS03052-MONOMER.
ReactomeiR-HSA-389357. CD28 dependent PI3K/Akt signaling.
R-HSA-5684264. MAP3K8 (TPL2)-dependent MAPK1/3 activation.
SignaLinkiP41279.
SIGNORiP41279.

Miscellaneous databases

ChiTaRSiMAP3K8. human.
GeneWikiiMAP3K8.
GenomeRNAii1326.
PROiP41279.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000107968.
CleanExiHS_MAP3K8.
ExpressionAtlasiP41279. baseline and differential.
GenevisibleiP41279. HS.

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...

Entry informationi

Entry nameiM3K8_HUMAN
AccessioniPrimary (citable) accession number: P41279
Secondary accession number(s): A8K2Q5
, D3DRX1, Q14275, Q5T855, Q9HC81
Entry historyi
Integrated into UniProtKB/Swiss-Prot: February 1, 1995
Last sequence update: July 19, 2004
Last modified: November 30, 2016
This is version 166 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Miscellaneous

Can be converted to an oncogenic protein by proviral activation, leading to a C-terminally truncated protein with transforming activity.

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 10
    Human chromosome 10: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  7. 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.