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Q62073

- M3K7_MOUSE

UniProt

Q62073 - M3K7_MOUSE

Protein

Mitogen-activated protein kinase kinase kinase 7

Gene

Map3k7

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 138 (01 Oct 2014)
      Sequence version 1 (01 Nov 1996)
      Previous versions | rss
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    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 similarity

    Catalytic activityi

    ATP + a protein = ADP + a phosphoprotein.

    Cofactori

    Magnesium.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)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei63 – 631ATPPROSITE-ProRule annotation
    Active sitei156 – 1561Proton acceptorPROSITE-ProRule annotation

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi42 – 509ATPPROSITE-ProRule annotation

    GO - Molecular functioni

    1. ATP binding Source: UniProtKB-KW
    2. magnesium ion binding Source: InterPro
    3. MAP kinase kinase activity Source: MGI
    4. MAP kinase kinase kinase activity Source: UniProtKB
    5. protein binding Source: IntAct
    6. scaffold protein binding Source: MGI

    GO - Biological processi

    1. activation of MAPK activity Source: GOC
    2. activation of MAPKK activity Source: GOC
    3. angiogenesis Source: MGI
    4. apoptotic process Source: UniProtKB-KW
    5. I-kappaB phosphorylation Source: UniProtKB
    6. MAPK cascade Source: MGI
    7. negative regulation of apoptotic signaling pathway Source: MGI
    8. negative regulation of necroptotic process Source: UniProtKB
    9. negative regulation of reactive oxygen species metabolic process Source: UniProtKB
    10. negative regulation of ripoptosome assembly involved in necroptotic process Source: MGI
    11. neural tube formation Source: MGI
    12. positive regulation of I-kappaB kinase/NF-kappaB signaling Source: MGI
    13. positive regulation of JNK cascade Source: MGI
    14. positive regulation of JUN kinase activity Source: UniProtKB
    15. protein phosphorylation Source: MGI
    16. regulation of reactive oxygen species metabolic process Source: MGI
    17. regulation of transcription, DNA-templated Source: UniProtKB-KW
    18. response to stress Source: UniProtKB-KW
    19. transcription, DNA-templated Source: UniProtKB-KW
    20. transforming growth factor beta receptor signaling pathway Source: MGI

    Keywords - Molecular functioni

    Kinase, Serine/threonine-protein kinase, Transferase

    Keywords - Biological processi

    Apoptosis, Stress response, Transcription, Transcription regulation

    Keywords - Ligandi

    ATP-binding, Magnesium, Metal-binding, Nucleotide-binding

    Enzyme and pathway databases

    ReactomeiREACT_198536. IRAK2 mediated activation of TAK1 complex.
    REACT_198539. TRAF6 mediated induction of TAK1 complex.
    REACT_198690. IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation.
    REACT_199121. Activation of NF-kappaB in B cells.
    REACT_204812. JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
    REACT_205561. FCERI mediated NF-kB activation.
    REACT_211125. NOD1/2 Signaling Pathway.
    REACT_219800. TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
    REACT_221970. Ca2+ pathway.
    REACT_224208. Interleukin-1 signaling.
    REACT_225145. Downstream TCR signaling.

    Names & Taxonomyi

    Protein namesi
    Recommended 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 namesi
    Name:Map3k7
    Synonyms:Tak1
    OrganismiMus musculus (Mouse)
    Taxonomic identifieri10090 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
    ProteomesiUP000000589: Chromosome 4

    Organism-specific databases

    MGIiMGI:1346877. Map3k7.

    Subcellular locationi

    Cytoplasm By similarity. Cell membrane By similarity; Peripheral membrane protein By similarity; 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

    GO - Cellular componenti

    1. cytoplasm Source: UniProtKB-SubCell
    2. plasma membrane Source: UniProtKB-SubCell

    Keywords - Cellular componenti

    Cell membrane, Cytoplasm, Membrane

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 579579Mitogen-activated protein kinase kinase kinase 7PRO_0000086253Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Cross-linki72 – 72Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
    Cross-linki158 – 158Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
    Modified residuei184 – 1841Phosphothreonine; by autocatalysisBy similarity
    Modified residuei187 – 1871Phosphothreonine; by autocatalysisBy similarity
    Modified residuei192 – 1921Phosphoserine; by autocatalysisBy similarity
    Modified residuei389 – 3891Phosphoserine1 Publication
    Modified residuei412 – 4121Phosphoserine2 Publications

    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. '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 similarity4 Publications

    Keywords - PTMi

    Isopeptide bond, Phosphoprotein, Ubl conjugation

    Proteomic databases

    MaxQBiQ62073.
    PaxDbiQ62073.
    PRIDEiQ62073.

    PTM databases

    PhosphoSiteiQ62073.

    Expressioni

    Gene expression databases

    ArrayExpressiQ62073.
    BgeeiQ62073.
    CleanExiMM_MAP3K7.
    GenevestigatoriQ62073.

    Interactioni

    Subunit structurei

    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.By similarity

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    Mapk8ip1Q9WVI9-24EBI-1775345,EBI-288464
    Smad1P703403EBI-1775345,EBI-6992047
    Tab1Q8CF892EBI-1775345,EBI-1778503
    Tab2Q99K908EBI-1775345,EBI-1775124
    TAB3Q8N5C82EBI-1775345,EBI-359964From a different organism.
    Traf2P394292EBI-1775345,EBI-520016
    VRK2Q86Y07-13EBI-1775345,EBI-1207633From a different organism.

    Protein-protein interaction databases

    BioGridi204962. 36 interactions.
    DIPiDIP-40666N.
    IntActiQ62073. 18 interactions.

    Structurei

    3D structure databases

    ProteinModelPortaliQ62073.
    SMRiQ62073. Positions 2-305.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini36 – 291256Protein kinasePROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni1 – 300300Interaction with MAPK8IP1Add
    BLAST

    Compositional bias

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Compositional biasi8 – 169Poly-Ser

    Sequence similaritiesi

    Contains 1 protein kinase domain.PROSITE-ProRule annotation

    Phylogenomic databases

    eggNOGiCOG0515.
    GeneTreeiENSGT00750000117464.
    HOGENOMiHOG000231735.
    HOVERGENiHBG003485.
    KOiK04427.

    Family and domain databases

    InterProiIPR011009. 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]
    PfamiPF07714. Pkinase_Tyr. 1 hit.
    [Graphical view]
    PIRSFiPIRSF038168. MAPKKK7. 1 hit.
    PRINTSiPR00109. TYRKINASE.
    SUPFAMiSSF56112. SSF56112. 1 hit.
    PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS00108. PROTEIN_KINASE_ST. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    Q62073-1 [UniParc]FASTAAdd to Basket

    « Hide

    MSTASAASSS SSSSASEMIE APSQVLNFEE IDYKEIEVEE VVGRGAFGVV    50
    CKAKWRAKDV AIKQIESESE RKAFIVELRQ LSRVNHPNIV KLYGACLNPV 100
    CLVMEYAEGG SLYNVLHGAE PLPYYTAAHA MSWCLQCSQG VAYLHSMQPK 150
    ALIHRDLKPP NLLLVAGGTV LKICDFGTAC DIQTHMTNNK GSAAWMAPEV 200
    FEGSNYSEKC DVFSWGIILW EVITRRKPFD EIGGPAFRIM WAVHNGTRPP 250
    LIKNLPKPIE SLMTRCWSKD PSQRPSMEEI VKIMTHLMRY FPGADEPLQY 300
    PCQYSDEGQS NSATSTGSFM DIASTNTSNK SDTNMEQVPA TNDTIKRLES 350
    KLLKNQAKQQ SESGRLSLGA SRGSSVESLP PTSEGKRMSA DMSEIEARIV 400
    ATAGNGQPRR RSIQDLTVTG TEPGQVSSRS SSPSVRMITT SGPTSEKPAR 450
    SHPWTPDDST DTNGSDNSIP MAYLTLDHQL QPLAPCPNSK ESMAVFEQHC 500
    KMAQEYMKVQ TEIALLLQRK QELVAELDQD EKDQQNTSRL VQEHKKLLDE 550
    NKSLSTYYQQ CKKQLEVIRS QQQKRQGTS 579
    Length:579
    Mass (Da):64,228
    Last modified:November 1, 1996 - v1
    Checksum:i97C8F6F3C8E283EE
    GO

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    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.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    D76446 mRNA. Translation: BAA11184.1 .
    CCDSi CCDS18014.1.
    RefSeqi NP_766276.1. NM_172688.3.
    UniGenei Mm.258589.

    3D structure databases

    ProteinModelPortali Q62073.
    SMRi Q62073. Positions 2-305.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 204962. 36 interactions.
    DIPi DIP-40666N.
    IntActi Q62073. 18 interactions.

    PTM databases

    PhosphoSitei Q62073.

    Proteomic databases

    MaxQBi Q62073.
    PaxDbi Q62073.
    PRIDEi Q62073.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSMUST00000080933 ; ENSMUSP00000079734 ; ENSMUSG00000028284 .
    GeneIDi 26409.
    KEGGi mmu:26409.
    UCSCi uc008sep.2. mouse.

    Organism-specific databases

    CTDi 6885.
    MGIi MGI:1346877. Map3k7.

    Phylogenomic databases

    eggNOGi COG0515.
    GeneTreei ENSGT00750000117464.
    HOGENOMi HOG000231735.
    HOVERGENi HBG003485.
    KOi K04427.

    Enzyme and pathway databases

    Reactomei REACT_198536. IRAK2 mediated activation of TAK1 complex.
    REACT_198539. TRAF6 mediated induction of TAK1 complex.
    REACT_198690. IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation.
    REACT_199121. Activation of NF-kappaB in B cells.
    REACT_204812. JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
    REACT_205561. FCERI mediated NF-kB activation.
    REACT_211125. NOD1/2 Signaling Pathway.
    REACT_219800. TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
    REACT_221970. Ca2+ pathway.
    REACT_224208. Interleukin-1 signaling.
    REACT_225145. Downstream TCR signaling.

    Miscellaneous databases

    ChiTaRSi MAP3K7. mouse.
    NextBioi 304393.
    PROi Q62073.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi Q62073.
    Bgeei Q62073.
    CleanExi MM_MAP3K7.
    Genevestigatori Q62073.

    Family and domain databases

    InterProi IPR011009. 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 ]
    Pfami PF07714. Pkinase_Tyr. 1 hit.
    [Graphical view ]
    PIRSFi PIRSF038168. MAPKKK7. 1 hit.
    PRINTSi PR00109. TYRKINASE.
    SUPFAMi SSF56112. SSF56112. 1 hit.
    PROSITEi PS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS00108. PROTEIN_KINASE_ST. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    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. 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. Cited for: REVIEW ON ENZYME REGULATION, REVIEW ON FUNCTION.

    Entry informationi

    Entry nameiM3K7_MOUSE
    AccessioniPrimary (citable) accession number: Q62073
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: December 1, 2000
    Last sequence update: November 1, 1996
    Last modified: October 1, 2014
    This is version 138 of the entry and version 1 of the sequence. [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

    External Data

    Dasty 3