Q62073 (M3K7_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified April 16, 2014. Version 133. History...
Names and origin
|Protein names||Recommended name:|
Mitogen-activated protein kinase kinase kinase 7
Transforming growth factor-beta-activated kinase 1
Short name=TGF-beta-activated kinase 1
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||579 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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
ATP + a protein = ADP + a phosphoprotein.
Magnesium By similarity.
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.
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
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.
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.
Contains 1 protein kinase domain.
|TAB3||Q8N5C8||2||EBI-1775345,EBI-359964||From a different organism.|
|VRK2||Q86Y07-1||3||EBI-1775345,EBI-1207633||From a different organism.|
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 579||579||Mitogen-activated protein kinase kinase kinase 7||PRO_0000086253|
|Domain||36 – 291||256||Protein kinase|
|Nucleotide binding||42 – 50||9||ATP By similarity|
|Region||1 – 300||300||Interaction with MAPK8IP1|
|Compositional bias||8 – 16||9||Poly-Ser|
|Active site||156||1||Proton acceptor By similarity|
|Binding site||63||1||ATP By similarity|
Amino acid modifications
|Modified residue||184||1||Phosphothreonine; by autocatalysis By similarity|
|Modified residue||187||1||Phosphothreonine; by autocatalysis By similarity|
|Modified residue||192||1||Phosphoserine; by autocatalysis By similarity|
|Modified residue||389||1||Phosphoserine Ref.9|
|Modified residue||412||1||Phosphoserine Ref.8 Ref.9|
|Cross-link||72||Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity|
|Cross-link||158||Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity|
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.
|||"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].
|||"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].
|||"The TAK1-TRAF6 signalling pathway."|
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.|
|D76446 mRNA. Translation: BAA11184.1.|
|RefSeq||NP_766276.1. NM_172688.3. |
3D structure databases
|SMR||Q62073. Positions 2-305. |
Protein-protein interaction databases
|BioGrid||204962. 35 interactions.|
|IntAct||Q62073. 18 interactions.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSMUST00000080933; ENSMUSP00000079734; ENSMUSG00000028284. |
|UCSC||uc008sep.2. mouse. |
|MGI||MGI:1346877. Map3k7. |
Gene expression databases
Family and domain databases
|InterPro||IPR011009. Kinase-like_dom. |
|Pfam||PF07714. Pkinase_Tyr. 1 hit. |
|PIRSF||PIRSF038168. MAPKKK7. 1 hit. |
|PRINTS||PR00109. TYRKINASE. |
|SUPFAM||SSF56112. SSF56112. 1 hit. |
|PROSITE||PS00107. PROTEIN_KINASE_ATP. 1 hit. |
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
|ChiTaRS||MAP3K7. mouse. |
|Accession||Primary (citable) accession number: Q62073|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|