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Protein

Mitogen-activated protein kinase kinase kinase 7

Gene

Map3k7

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signal transduction of TRAF6, various cytokines including interleukin-1 (IL-1), transforming growth factor-beta (TGFB), TGFB-related factors like BMP2 and BMP4, toll-like receptors (TLR), tumor necrosis factor receptor CD40 and B-cell receptor (BCR). Ceramides are also able to activate MAP3K7/TAK1. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K1/MEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs, c-jun N-terminal kinases (JNKs) and I-kappa-B kinase complex (IKK). Both p38 MAPK and JNK pathways control the transcription factors activator protein-1 (AP-1), while nuclear factor-kappa B is activated by IKK. MAP3K7 activates also IKBKB and MAPK8/JNK1 in response to TRAF6 signaling and mediates BMP2-induced apoptosis. In osmotic stress signaling, plays a major role in the activation of MAPK8/JNK1, but not that of NF-kappa-B. Promotes TRIM5 capsid-specific restriction activity (By similarity).By similarity3 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.By similarity

Cofactori

Mg2+By similarity

Enzyme regulationi

Activated by proinflammatory cytokines and in response to physical and chemical stresses, including osmotic stress, oxidative stress, arsenic and ultraviolet light irradiation. Activated by 'Lys-63'-linked polyubiquitination and by autophosphorylation. Association with TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2 promotes activation through autophosphorylation, whereas PPM1B/PP2CB, PP2A and PPP6C dephosphorylation leads to inactivation.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei63ATPPROSITE-ProRule annotation1
Active sitei156Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi42 – 50ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • magnesium ion binding Source: InterPro
  • MAP kinase kinase activity Source: MGI
  • MAP kinase kinase kinase activity Source: UniProtKB
  • protein serine/threonine kinase activity Source: WormBase
  • receptor tyrosine kinase binding Source: WormBase
  • scaffold protein binding Source: MGI

GO - Biological processi

  • activation of MAPKK activity Source: GO_Central
  • angiogenesis Source: MGI
  • anoikis Source: ParkinsonsUK-UCL
  • I-kappaB phosphorylation Source: MGI
  • MAPK cascade Source: MGI
  • negative regulation of apoptotic signaling pathway Source: MGI
  • negative regulation of necroptotic process Source: UniProtKB
  • negative regulation of reactive oxygen species metabolic process Source: UniProtKB
  • negative regulation of ripoptosome assembly involved in necroptotic process Source: MGI
  • neural tube formation Source: MGI
  • peptidyl-threonine phosphorylation Source: WormBase
  • positive regulation of I-kappaB kinase/NF-kappaB signaling Source: MGI
  • positive regulation of JNK cascade Source: MGI
  • positive regulation of JUN kinase activity Source: UniProtKB
  • positive regulation of macroautophagy Source: ParkinsonsUK-UCL
  • protein phosphorylation Source: MGI
  • regulation of reactive oxygen species metabolic process Source: MGI
  • regulation of transcription, DNA-templated Source: UniProtKB-KW
  • transcription, DNA-templated Source: UniProtKB-KW
  • transforming growth factor beta receptor signaling pathway Source: MGI

Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase
Biological processApoptosis, Stress response, Transcription, Transcription regulation
LigandATP-binding, Magnesium, Metal-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.11.25 3474
ReactomeiR-MMU-168638 NOD1/2 Signaling Pathway
R-MMU-202424 Downstream TCR signaling
R-MMU-2871837 FCERI mediated NF-kB activation
R-MMU-4086398 Ca2+ pathway
R-MMU-445989 TAK1 activates NFkB by phosphorylation and activation of IKKs complex
R-MMU-450302 activated TAK1 mediates p38 MAPK activation
R-MMU-450321 JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1
R-MMU-5357956 TNFR1-induced NFkappaB signaling pathway
R-MMU-5607764 CLEC7A (Dectin-1) signaling
R-MMU-5689880 Ub-specific processing proteases
R-MMU-9020702 Interleukin-1 signaling
R-MMU-937042 IRAK2 mediated activation of TAK1 complex
R-MMU-937072 TRAF6-mediated induction of TAK1 complex within TLR4 complex
R-MMU-975163 IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation

Names & Taxonomyi

Protein namesi
Recommended name:
Mitogen-activated protein kinase kinase kinase 7 (EC:2.7.11.25By similarity)
Alternative name(s):
Transforming growth factor-beta-activated kinase 1
Short name:
TGF-beta-activated kinase 1
Gene namesi
Name:Map3k7
Synonyms:Tak1
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 4

Organism-specific databases

MGIiMGI:1346877 Map3k7

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000862531 – 579Mitogen-activated protein kinase kinase kinase 7Add BLAST579

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Cross-linki72Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei184Phosphothreonine; by autocatalysisBy similarity1
Modified residuei187Phosphothreonine; by autocatalysisBy similarity1
Modified residuei192Phosphoserine; by autocatalysisBy similarity1
Modified residuei367PhosphoserineBy similarity1
Modified residuei389PhosphoserineCombined sources1
Modified residuei412PhosphoserineCombined sources1
Modified residuei428PhosphoserineBy similarity1

Post-translational modificationi

Association with TAB1/MAP3K7IP1 promotes autophosphorylation and subsequent activation. Association with TAB2/MAP3K7IP2, itself associated with free unanchored Lys-63 polyubiquitin chain, promotes autophosphorylation and subsequent activation of MAP3K7. Dephosphorylation at Thr-187 by PP2A and PPP6C leads to inactivation (By similarity).By similarity
'Lys-48'-linked polyubiquitination at Lys-72 is induced by TNFalpha, and leads to proteasomal degradation (By similarity). Undergoes 'Lys-48'-linked polyubiquitination catalyzed by ITCH (PubMed:25632008). 'Lys-63'-linked polyubiquitination at Lys-158 by TRIM8 does not lead to proteasomal degradation but contributes to autophosphorylation and activation. Deubiquitinated by CYLD, a protease that selectively cleaves 'Lys-63'-linked ubiquitin chains.By similarity3 Publications

Keywords - PTMi

Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ62073
MaxQBiQ62073
PaxDbiQ62073
PRIDEiQ62073

PTM databases

iPTMnetiQ62073
PhosphoSitePlusiQ62073

Expressioni

Gene expression databases

BgeeiENSMUSG00000028284
CleanExiMM_MAP3K7
ExpressionAtlasiQ62073 baseline and differential
GenevisibleiQ62073 MM

Interactioni

Subunit structurei

Can form homodimer (By similarity). Binds both upstream activators and downstream substrates in multimolecular complexes (By similarity). Interacts with TAB1/MAP3K7IP1, TAB2/MAP3K7IP2 and TAB3/MAP3K7IP3 (By similarity). Identified in the TRIKA2 complex composed of MAP3K7/TAK1, TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2 (By similarity). Interacts with PPM1L and PPM1B/PP2CB (PubMed:12556533). Interaction with PP2A and PPP6C leads to its repressed activity (By similarity). Interacts with TRAF6 and TAB1/MAP3K7IP1; during IL-1 signaling (By similarity). Interacts with TAOK1 and TAOK2; interaction with TAOK2 interferes with MAP3K7 interaction with IKKA, thus preventing NF-kappa-B activation (By similarity). Interacts with WDR34 (via WD domains) (By similarity). Interacts with CYLD and RBCK1 (PubMed:17548520). Interacts with TGFBR1; induces MAP3K7/TAK1 activation by TRAF6 (By similarity). Interacts with MAPK8IP1 and SMAD6 (PubMed:10748100, PubMed:17709393). Interacts with isoform 1 of VRK2 (PubMed:17709393). Interacts with DAB2; the interaction is induced by TGF-beta stimulation and may mediate TGF-beta stimulated JNK activation (By similarity). Interacts with TRIM5 (By similarity). Part of a complex containing ITCH, NDFIP1 and MAP3K7 (PubMed:25632008). Interacts with PLEKHM1 (via N- and C-terminus) (PubMed:27777970). Interacts with TRIM8 (By similarity).By similarity6 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • receptor tyrosine kinase binding Source: WormBase
  • scaffold protein binding Source: MGI

Protein-protein interaction databases

BioGridi204962, 44 interactors
DIPiDIP-40666N
IntActiQ62073, 21 interactors
MINTiQ62073
STRINGi10090.ENSMUSP00000040307

Structurei

3D structure databases

ProteinModelPortaliQ62073
SMRiQ62073
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini36 – 291Protein kinasePROSITE-ProRule annotationAdd BLAST256

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 300Interaction with MAPK8IP11 PublicationAdd BLAST300

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi8 – 16Poly-Ser9

Sequence similaritiesi

Phylogenomic databases

eggNOGiKOG0192 Eukaryota
COG0515 LUCA
GeneTreeiENSGT00900000140790
HOGENOMiHOG000231735
HOVERGENiHBG003485
InParanoidiQ62073
KOiK04427

Family and domain databases

InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR017421 MAPKKK7
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR001245 Ser-Thr/Tyr_kinase_cat_dom
IPR008271 Ser/Thr_kinase_AS
PANTHERiPTHR26392:SF74 PTHR26392:SF74, 1 hit
PfamiView protein in Pfam
PF07714 Pkinase_Tyr, 1 hit
PIRSFiPIRSF038168 MAPKKK7, 1 hit
PRINTSiPR00109 TYRKINASE
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit

Sequencei

Sequence statusi: Complete.

Q62073-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSTASAASSS SSSSASEMIE APSQVLNFEE IDYKEIEVEE VVGRGAFGVV
60 70 80 90 100
CKAKWRAKDV AIKQIESESE RKAFIVELRQ LSRVNHPNIV KLYGACLNPV
110 120 130 140 150
CLVMEYAEGG SLYNVLHGAE PLPYYTAAHA MSWCLQCSQG VAYLHSMQPK
160 170 180 190 200
ALIHRDLKPP NLLLVAGGTV LKICDFGTAC DIQTHMTNNK GSAAWMAPEV
210 220 230 240 250
FEGSNYSEKC DVFSWGIILW EVITRRKPFD EIGGPAFRIM WAVHNGTRPP
260 270 280 290 300
LIKNLPKPIE SLMTRCWSKD PSQRPSMEEI VKIMTHLMRY FPGADEPLQY
310 320 330 340 350
PCQYSDEGQS NSATSTGSFM DIASTNTSNK SDTNMEQVPA TNDTIKRLES
360 370 380 390 400
KLLKNQAKQQ SESGRLSLGA SRGSSVESLP PTSEGKRMSA DMSEIEARIV
410 420 430 440 450
ATAGNGQPRR RSIQDLTVTG TEPGQVSSRS SSPSVRMITT SGPTSEKPAR
460 470 480 490 500
SHPWTPDDST DTNGSDNSIP MAYLTLDHQL QPLAPCPNSK ESMAVFEQHC
510 520 530 540 550
KMAQEYMKVQ TEIALLLQRK QELVAELDQD EKDQQNTSRL VQEHKKLLDE
560 570
NKSLSTYYQQ CKKQLEVIRS QQQKRQGTS
Length:579
Mass (Da):64,228
Last modified:November 1, 1996 - v1
Checksum:i97C8F6F3C8E283EE
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
D76446 mRNA Translation: BAA11184.1
CCDSiCCDS18014.1
RefSeqiNP_766276.1, NM_172688.3
UniGeneiMm.258589

Genome annotation databases

EnsembliENSMUST00000080933; ENSMUSP00000079734; ENSMUSG00000028284
GeneIDi26409
KEGGimmu:26409
UCSCiuc008sep.2 mouse

Similar proteinsi

Entry informationi

Entry nameiM3K7_MOUSE
AccessioniPrimary (citable) accession number: Q62073
Entry historyiIntegrated into UniProtKB/Swiss-Prot: December 1, 2000
Last sequence update: November 1, 1996
Last modified: May 23, 2018
This is version 174 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families
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Main funding by: National Institutes of Health