Reactome | UniProt:P41279 MAP3K8

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UniProt:P41279 MAP3K8 Show undefined attributes

chain	chain:1-467
checksum	7728969EA3E4E8EC
comment	FUNCTION Required for lipopolysaccharide (LPS)-induced, TLR4-mediated activation of the MAPK/ERK pathway in macrophages, thus being critical for production of the pro-inflammatory cytokine TNF (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.CATALYTIC ACTIVITY L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+)CATALYTIC ACTIVITY L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+)COFACTOR 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.INTERACTION Expressed in several normal tissues and human tumor-derived cell lines.DEVELOPMENTAL STAGE Isoform 1 is activated specifically during the S and G2/M phases of the cell cycle.INDUCTION Up-regulated by IL12 in T-lymphocytes. Up-regulated in subcutaneous adipose tissue of obese individuals.PTM Autophosphorylated (PubMed:1833717, PubMed:8226782). Isoform 1 undergoes phosphorylation mainly on Ser residues, and isoform 2 on both Ser and Thr residues (PubMed:8226782). Phosphorylated on Thr-290; 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 (PubMed:15466476, PubMed:15699325). Phosphorylated on Ser-400 by IKBKB; the phosphorylation is required for LPS-stimulated activation of the MAPK/ERK pathway in macrophages (PubMed:17472361, PubMed:22988300).MISCELLANEOUS Can be converted to an oncogenic protein by proviral activation, leading to a C-terminally truncated protein with transforming activity.SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily.CAUTION A paper describing a role for this protein in IRAK1-independent activation of the MAPK/ERK pathway in response to IL1 has been retracted, because some of the experimental data could not be reproduced.
crossReference	[DatabaseIdentifier:12400811] RefSeq:XP_047280579.1 [DatabaseIdentifier:12818175] ZINC - World Drugs:M3K8_HUMAN [DatabaseIdentifier:12815397] ZINC target:P41279 [DatabaseIdentifier:12812049] ZINC - Substances:M3K8_HUMAN [DatabaseIdentifier:12810099] ZINC - Predictions - Purchasable:M3K8_HUMAN [DatabaseIdentifier:12807948] ZINC - Metabolites:M3K8_HUMAN [DatabaseIdentifier:12804456] ZINC - Biogenic:M3K8_HUMAN [DatabaseIdentifier:12400807] RefSeq:XP_054220808.1 [DatabaseIdentifier:11486776] ENSEMBL:ENSG00000107968 [DatabaseIdentifier:11591051] ENSEMBL:ENSP00000263056 [DatabaseIdentifier:11591052] ENSEMBL:ENSP00000443610 [DatabaseIdentifier:11591053] ENSEMBL:ENSP00000364470 [DatabaseIdentifier:11713751] ENSEMBL:ENST00000263056 [DatabaseIdentifier:11713750] ENSEMBL:ENST00000375321 [DatabaseIdentifier:11713752] ENSEMBL:ENST00000542547 [DatabaseIdentifier:11780510] Guide to Pharmacology - Targets:2083 [DatabaseIdentifier:11783485] GeneCards:MAP3K8 [DatabaseIdentifier:11830976] HMDB Protein:HMDBP08753 [DatabaseIdentifier:11836594] HPA:ENSG00000107968-MAP3K8 [DatabaseIdentifier:12121070] OpenTargets:ENSG00000107968 [DatabaseIdentifier:12152248] PDB:5IU2 [DatabaseIdentifier:12152249] PDB:4Y85 [DatabaseIdentifier:12152247] PDB:4Y83 [DatabaseIdentifier:12238847] PRO:P41279 [DatabaseIdentifier:12281402] Pharos - Targets:P41279 [DatabaseIdentifier:12400809] RefSeq:XP_054220806.1 [DatabaseIdentifier:12400805] RefSeq:XP_047280580.1 [DatabaseIdentifier:12400808] RefSeq:XP_054220805.1 [DatabaseIdentifier:12400810] RefSeq:XP_047280578.1 [DatabaseIdentifier:12400802] RefSeq:NP_001231063.1 [DatabaseIdentifier:12400812] RefSeq:XP_016871199.1 [DatabaseIdentifier:12400804] RefSeq:XP_016871198.1 [DatabaseIdentifier:12400806] RefSeq:XP_054220807.1 [DatabaseIdentifier:12400813] RefSeq:NP_001307890.1 [DatabaseIdentifier:12400803] RefSeq:NP_005195.2
databaseName	UniProt
dbId	58899
description	recommendedName: Mitogen-activated protein kinase kinase kinase 8 ecNumber: 2.7.11.25 alternativeName: Cancer Osaka thyroid oncogene alternativeName: Proto-oncogene c-Cot alternativeName: Serine/threonine-protein kinase cot alternativeName: Tumor progression locus 2 shortName: TPL-2
displayName	UniProt:P41279 MAP3K8
geneName	MAP3K8 COT ESTF
identifier	P41279
isSequenceChanged	false
keyword	3D-structure Alternative initiation ATP-binding Cell cycle Cytoplasm Immunity Kinase Magnesium Metal-binding Nucleotide-binding Phosphoprotein Proteomics identification Proto-oncogene Reference proteome Serine/threonine-protein kinase Transferase
modified	[InstanceEdit:9983091] Weiser, Joel, 2026-02-20
moleculeType	Protein
name	MAP3K8
otherIdentifier	11736217_at 11747602_a_at 1326 16703642 16703659 1891_at 205027_PM_s_at 205027_s_at 235421_PM_at 235421_at 3240988 3240989 3240990 3240991 3240992 3240994 3240995 3240996 3240997 3240998 3240999 3241005 3241008 3241009 3241010 3241013 3241015 3241017 3241018 3241019 3241020 3241023 34770_at 69820_at 76490_at 7926900 A_14_P133193 A_14_P201691 A_23_P23947 A_24_P696924 A_33_P3246505 D14497_at GE537493 GE57079 GE85389 GO:0000165 GO:0000166 GO:0000287 GO:0002376 GO:0003824 GO:0004672 GO:0004674 GO:0004709 GO:0005515 GO:0005524 GO:0005737 GO:0005829 GO:0006468 GO:0007165 GO:0016301 GO:0016740 GO:0031295 GO:0035556 GO:0046872 GO:0050729 GO:0106310 GO:0140096 HMNXSV003008993 HMNXSV003014689 Hs.122431.0.A1_3p_at ILMN_1741159 PH_hs_0025239 TC10000211.hg TC10000212.hg g4885146_3p_a_at
physicalEntity	[EntityWithAccessionedSequence:R-HSA-5684259] p-S400,T290-MAP3K8 [cytosol] - Homo sapiens [EntityWithAccessionedSequence:R-HSA-389388] MAP3K8 [cytosol] - Homo sapiens [EntityWithAccessionedSequence:R-HSA-389738] p-S400-MAP3K8 [cytosol] - Homo sapiens
referenceDatabase	[ReferenceDatabase:2] UniProt
referenceGene	[ReferenceDNASequence:ensembl:ENSG00000107968] ENSEMBL:ENSG00000107968 MAP3K8 [ReferenceDNASequence:12745956] UCSC:P41279 MAP3K8 [ReferenceDNASequence:11352043] BioGPS Gene:1326 MAP3K8 [ReferenceDNASequence:11400855] COSMIC - genes:MAP3K8 MAP3K8 [ReferenceDNASequence:11407157] CTD Gene:1326 MAP3K8 [ReferenceDNASequence:11438087] dbSNP Gene:1326 MAP3K8 [ReferenceDNASequence:11815102] HGNC:6860 MAP3K8 [ReferenceDNASequence:11891773] KEGG:hsa:1326 MAP3K8 [ReferenceDNASequence:11981832] Monarch:1326 MAP3K8 [ReferenceDNASequence:12065925] NCBI Gene:1326 MAP3K8 [ReferenceDNASequence:12106818] OMIM:191195 MAP3K8
referenceTranscript	[ReferenceRNASequence:12582534] RefSeq:XM_047424622.1 MAP3K8 [ReferenceRNASequence:12582541] RefSeq:XM_054364832.1 MAP3K8 [ReferenceRNASequence:12582543] RefSeq:XM_017015710.1 MAP3K8 [ReferenceRNASequence:12582540] RefSeq:XM_047424624.1 MAP3K8 [ReferenceRNASequence:12582539] RefSeq:XM_054364831.1 MAP3K8 [ReferenceRNASequence:12582538] RefSeq:XM_047424623.1 MAP3K8 [ReferenceRNASequence:12582535] RefSeq:XM_054364830.1 MAP3K8 [ReferenceRNASequence:12582533] RefSeq:XM_017015709.3 MAP3K8 [ReferenceRNASequence:12582532] RefSeq:NM_005204.3 MAP3K8 [ReferenceRNASequence:12582542] RefSeq:XM_054364833.1 MAP3K8 [ReferenceRNASequence:12582536] RefSeq:NM_001244134.1 MAP3K8 [ReferenceRNASequence:12582537] RefSeq:NM_001320961.2 MAP3K8
schemaClass	ReferenceGeneProduct
secondaryIdentifier	M3K8_HUMAN A8K2Q5 D3DRX1 Q14275 Q5T855 Q9HC81
sequenceLength	467
species	[Species:48887] Homo sapiens
stId	uniprot:P41279
url	http://purl.uniprot.org/uniprot/P41279

Referrals

(referenceEntity)	[EntityWithAccessionedSequence:R-HSA-5684259] p-S400,T290-MAP3K8 [cytosol] [EntityWithAccessionedSequence:R-HSA-389388] MAP3K8 [cytosol] [EntityWithAccessionedSequence:R-HSA-389738] p-S400-MAP3K8 [cytosol]
(referenceSequence)	[ModifiedResidue:5684253] O-phospho-L-threonine at 290 [ModifiedResidue:389739] O-phospho-L-serine at 400
(interactor)	[UndirectedInteraction:11170085] UniProt:P41279 <-> UniProt:P19838 (IntAct) [UndirectedInteraction:11170087] UniProt:P41279 <-> UniProt:Q8NFZ5 (IntAct) [UndirectedInteraction:11170089] UniProt:P41279 <-> UniProt:Q13526 (IntAct) [UndirectedInteraction:11170091] UniProt:P41279 <-> UniProt:P08238 (IntAct) [UndirectedInteraction:11170093] UniProt:P41279 <-> UniProt:Q00653 (IntAct)