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Q62073 (M3K7_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 133. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Mitogen-activated protein kinase kinase kinase 7

EC=2.7.11.25
Alternative name(s):
Transforming growth factor-beta-activated kinase 1
Short name=TGF-beta-activated kinase 1
Gene names
Name:Map3k7
Synonyms:Tak1
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length579 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.1 Ref.2 Ref.4

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Cofactor

Magnesium By similarity.

Enzyme regulation

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.

Subunit structure

Binds both upstream activators and downstream substrates in multimolecular complexes. Interacts with TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2 and TAB3/MAP3K7IP3 By similarity. Identified in the TRIKA2 complex composed of MAP3K7, TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2 By similarity. Interacts with PPM1L. 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 RBCK1 By similarity. Interacts with TGFBR1; induces MAP3K7 activation by TRAF6 By similarity. Interacts with CYLD. Interacts with MAPK8IP1, SMAD6 and VRK2. Interacts with TRIM5 By similarity. Ref.2 Ref.3 Ref.5 Ref.6

Subcellular location

Cytoplasm By similarity. Cell membrane; Peripheral membrane protein; Cytoplasmic side By similarity. Note: Although the majority of MAP3K7/TAK1 is found in the cytosol, when complexed with TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2, it is also localized at the cell membrane By similarity.

Post-translational modification

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.

'Lys-48'-linked polyubiquitination at Lys-72 is induced by TNFalpha, and leads to proteasomal degradation By similarity. '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.

Sequence similarities

Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily.

Contains 1 protein kinase domain.

Ontologies

Keywords
   Biological processApoptosis
Stress response
Transcription
Transcription regulation
   Cellular componentCell membrane
Cytoplasm
Membrane
   LigandATP-binding
Magnesium
Metal-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMIsopeptide bond
Phosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processI-kappaB phosphorylation

Inferred from sequence or structural similarity. Source: UniProtKB

MAPK cascade

Inferred from direct assay Ref.3. Source: MGI

activation of MAPK activity

Inferred from direct assay PubMed 12464436. Source: GOC

activation of MAPKK activity

Inferred from sequence or structural similarity. Source: GOC

angiogenesis

Inferred from mutant phenotype PubMed 16556914. Source: MGI

apoptotic process

Inferred from electronic annotation. Source: UniProtKB-KW

negative regulation of apoptotic signaling pathway

Inferred from mutant phenotype PubMed 16260493. Source: MGI

negative regulation of necroptotic process

Inferred from mutant phenotype PubMed 21052097. Source: UniProtKB

negative regulation of reactive oxygen species metabolic process

Inferred from mutant phenotype PubMed 21052097. Source: UniProtKB

negative regulation of ripoptosome assembly involved in necroptotic process

Inferred from genetic interaction PubMed 21052097. Source: MGI

neural tube formation

Inferred from mutant phenotype PubMed 16260493. Source: MGI

positive regulation of I-kappaB kinase/NF-kappaB signaling

Inferred from genetic interaction PubMed 16260493. Source: MGI

positive regulation of JNK cascade

Inferred from genetic interaction PubMed 16260493. Source: MGI

positive regulation of JUN kinase activity

Inferred from sequence or structural similarity. Source: UniProtKB

protein phosphorylation

Inferred from direct assay PubMed 12464436. Source: MGI

regulation of reactive oxygen species metabolic process

Inferred from mutant phenotype PubMed 21052097. Source: MGI

regulation of transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

response to stress

Inferred from electronic annotation. Source: UniProtKB-KW

transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

transforming growth factor beta receptor signaling pathway

Inferred from mutant phenotype PubMed 16145668. Source: MGI

   Cellular_componentcytoplasm

Inferred from electronic annotation. Source: UniProtKB-SubCell

plasma membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

MAP kinase kinase activity

Inferred from direct assay PubMed 12464436. Source: MGI

MAP kinase kinase kinase activity

Inferred from sequence or structural similarity. Source: UniProtKB

magnesium ion binding

Inferred from electronic annotation. Source: InterPro

Complete GO annotation...

Binary interactions

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 579579Mitogen-activated protein kinase kinase kinase 7
PRO_0000086253

Regions

Domain36 – 291256Protein kinase
Nucleotide binding42 – 509ATP By similarity
Region1 – 300300Interaction with MAPK8IP1
Compositional bias8 – 169Poly-Ser

Sites

Active site1561Proton acceptor By similarity
Binding site631ATP By similarity

Amino acid modifications

Modified residue1841Phosphothreonine; by autocatalysis By similarity
Modified residue1871Phosphothreonine; by autocatalysis By similarity
Modified residue1921Phosphoserine; by autocatalysis By similarity
Modified residue3891Phosphoserine Ref.9
Modified residue4121Phosphoserine Ref.8 Ref.9
Cross-link72Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-link158Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity

Sequences

Sequence LengthMass (Da)Tools
Q62073 [UniParc].

Last modified November 1, 1996. Version 1.
Checksum: 97C8F6F3C8E283EE

FASTA57964,228
        10         20         30         40         50         60 
MSTASAASSS SSSSASEMIE APSQVLNFEE IDYKEIEVEE VVGRGAFGVV CKAKWRAKDV 

        70         80         90        100        110        120 
AIKQIESESE RKAFIVELRQ LSRVNHPNIV KLYGACLNPV CLVMEYAEGG SLYNVLHGAE 

       130        140        150        160        170        180 
PLPYYTAAHA MSWCLQCSQG VAYLHSMQPK ALIHRDLKPP NLLLVAGGTV LKICDFGTAC 

       190        200        210        220        230        240 
DIQTHMTNNK GSAAWMAPEV FEGSNYSEKC DVFSWGIILW EVITRRKPFD EIGGPAFRIM 

       250        260        270        280        290        300 
WAVHNGTRPP LIKNLPKPIE SLMTRCWSKD PSQRPSMEEI VKIMTHLMRY FPGADEPLQY 

       310        320        330        340        350        360 
PCQYSDEGQS NSATSTGSFM DIASTNTSNK SDTNMEQVPA TNDTIKRLES KLLKNQAKQQ 

       370        380        390        400        410        420 
SESGRLSLGA SRGSSVESLP PTSEGKRMSA DMSEIEARIV ATAGNGQPRR RSIQDLTVTG 

       430        440        450        460        470        480 
TEPGQVSSRS SSPSVRMITT SGPTSEKPAR SHPWTPDDST DTNGSDNSIP MAYLTLDHQL 

       490        500        510        520        530        540 
QPLAPCPNSK ESMAVFEQHC KMAQEYMKVQ TEIALLLQRK QELVAELDQD EKDQQNTSRL 

       550        560        570 
VQEHKKLLDE NKSLSTYYQQ CKKQLEVIRS QQQKRQGTS 

« Hide

References

« Hide 'large scale' references
[1]"Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction."
Yamaguchi K., Shirakabe K., Shibuya H., Irie K., Ohishi I., Ueno N., Taniguchi T., Nishida E., Matsumoto K.
Science 270:2008-2011(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION.
[2]"BMP2-induced apoptosis is mediated by activation of the TAK1-p38 kinase pathway that is negatively regulated by Smad6."
Kimura N., Matsuo R., Shibuya H., Nakashima K., Taga T.
J. Biol. Chem. 275:17647-17652(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH SMAD6.
[3]"Regulation of the interleukin-1-induced signaling pathways by a novel member of the protein phosphatase 2C family (PP2Cepsilon)."
Li M.G., Katsura K., Nomiyama H., Komaki K., Ninomiya-Tsuji J., Matsumoto K., Kobayashi T., Tamura S.
J. Biol. Chem. 278:12013-12021(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PPM1L.
[4]"X-linked inhibitor of apoptosis (XIAP) inhibits c-Jun N-terminal kinase 1 (JNK1) activation by transforming growth factor beta1 (TGF-beta1) through ubiquitin-mediated proteosomal degradation of the TGF-beta1-activated kinase 1 (TAK1)."
Kaur S., Wang F., Venkatraman M., Arsura M.
J. Biol. Chem. 280:38599-38608(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, UBIQUITINATION, PROTEASOMAL DEGRADATION.
[5]"Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses."
Reiley W.W., Jin W., Lee A.J., Wright A., Wu X., Tewalt E.F., Leonard T.O., Norbury C.C., Fitzpatrick L., Zhang M., Sun S.C.
J. Exp. Med. 204:1475-1485(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: UBIQUITINATION, INTERACTION WITH CYLD, DEUBIQUITINATION BY CYLD.
[6]"Vaccinia-related kinase 2 modulates the stress response to hypoxia mediated by TAK1."
Blanco S., Santos C., Lazo P.A.
Mol. Cell. Biol. 27:7273-7283(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH VRK2 AND MAPK8IP1.
[7]"Ubiquitin-mediated activation of TAK1 and IKK."
Adhikari A., Xu M., Chen Z.J.
Oncogene 26:3214-3226(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON ENZYME REGULATION.
[8]"Large-scale phosphorylation analysis of mouse liver."
Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-412, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Liver.
[9]"The phagosomal proteome in interferon-gamma-activated macrophages."
Trost M., English L., Lemieux S., Courcelles M., Desjardins M., Thibault P.
Immunity 30:143-154(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-389 AND SER-412, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[10]"The TAK1-TRAF6 signalling pathway."
Landstrom M.
Int. J. Biochem. Cell Biol. 42:585-589(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON ENZYME REGULATION, REVIEW ON FUNCTION.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
D76446 mRNA. Translation: BAA11184.1.
RefSeqNP_766276.1. NM_172688.3.
UniGeneMm.258589.

3D structure databases

ProteinModelPortalQ62073.
SMRQ62073. Positions 2-305.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid204962. 35 interactions.
DIPDIP-40666N.
IntActQ62073. 18 interactions.

PTM databases

PhosphoSiteQ62073.

Proteomic databases

PaxDbQ62073.
PRIDEQ62073.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000080933; ENSMUSP00000079734; ENSMUSG00000028284.
GeneID26409.
KEGGmmu:26409.
UCSCuc008sep.2. mouse.

Organism-specific databases

CTD6885.
MGIMGI:1346877. Map3k7.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00750000117464.
HOGENOMHOG000231735.
HOVERGENHBG003485.
KOK04427.

Gene expression databases

ArrayExpressQ62073.
BgeeQ62073.
CleanExMM_MAP3K7.
GenevestigatorQ62073.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR017421. MAPKKK7.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF07714. Pkinase_Tyr. 1 hit.
[Graphical view]
PIRSFPIRSF038168. MAPKKK7. 1 hit.
PRINTSPR00109. TYRKINASE.
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSMAP3K7. mouse.
NextBio304393.
PROQ62073.
SOURCESearch...

Entry information

Entry nameM3K7_MOUSE
AccessionPrimary (citable) accession number: Q62073
Entry history
Integrated into UniProtKB/Swiss-Prot: December 1, 2000
Last sequence update: November 1, 1996
Last modified: April 16, 2014
This is version 133 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot