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P47809

- MP2K4_MOUSE

UniProt

P47809 - MP2K4_MOUSE

Protein

Dual specificity mitogen-activated protein kinase kinase 4

Gene

Map2k4

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 124 (01 Oct 2014)
      Sequence version 2 (01 Nov 1997)
      Previous versions | rss
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    Functioni

    Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K7/MKK7, is the one of the only known kinase to directly activate the stress-activated protein kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they differ in their preference for the phosphorylation site in the Thr-Pro-Tyr motif. MAP2K4 shows preference for phosphorylation of the Tyr residue and MAP2K7/MKK7 for the Thr residue. The phosphorylation of the Thr residue by MAP2K7/MKK7 seems to be the prerequisite for JNK activation at least in response to proinflammatory cytokines, while other stimuli activate both MAP2K4/MKK4 and MAP2K7/MKK7 which synergistically phosphorylate JNKs. MAP2K4 is required for maintaining peripheral lymphoid homeostasis. The MKK/JNK signaling pathway is also involved in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis. Whereas MAP2K7/MKK7 exclusively activates JNKs, MAP2K4/MKK4 additionally activates the p38 MAPKs MAPK11, MAPK12, MAPK13 and MAPK14.5 Publications

    Catalytic activityi

    ATP + a protein = ADP + a phosphoprotein.

    Enzyme regulationi

    Activated in response to a variety of cellular stresses, including UV and gamma-irradiation, heat shock, hyperosmolarity, T-cell receptor stimulation, peroxide and inflammatory cytokines. Also activated by developmental cues. MAP2K4/MKK4 is activated by the majority of MKKKs, such as MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K7/TAK1, MAP3K10/MLK2, MAP3K11/MLK3, MAP3K12/DLK and MAP3K13/LZK.1 Publication

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei129 – 1291ATP
    Active sitei227 – 2271Proton acceptorPROSITE-ProRule annotation

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi106 – 1149ATPPROSITE-ProRule annotation

    GO - Molecular functioni

    1. ATP binding Source: UniProtKB-KW
    2. JUN kinase kinase activity Source: Ensembl
    3. protein binding Source: BHF-UCL
    4. protein serine/threonine kinase activity Source: UniProtKB-KW
    5. protein tyrosine kinase activity Source: UniProtKB-KW

    GO - Biological processi

    1. activation of JUN kinase activity Source: MGI
    2. apoptotic process Source: UniProtKB-KW
    3. cellular response to mechanical stimulus Source: Ensembl
    4. cellular response to sorbitol Source: Ensembl
    5. JNK cascade Source: MGI
    6. MAPK cascade Source: MGI
    7. positive regulation of DNA replication Source: Ensembl
    8. positive regulation of neuron apoptotic process Source: Ensembl

    Keywords - Molecular functioni

    Kinase, Serine/threonine-protein kinase, Transferase, Tyrosine-protein kinase

    Keywords - Biological processi

    Apoptosis, Stress response

    Keywords - Ligandi

    ATP-binding, Nucleotide-binding

    Enzyme and pathway databases

    BRENDAi2.7.12.2. 3474.
    ReactomeiREACT_188530. FCERI mediated MAPK activation.
    REACT_188970. Oxidative Stress Induced Senescence.
    REACT_204812. JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
    REACT_224208. Interleukin-1 signaling.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Dual specificity mitogen-activated protein kinase kinase 4 (EC:2.7.12.2)
    Short name:
    MAP kinase kinase 4
    Short name:
    MAPKK 4
    Alternative name(s):
    C-JUN N-terminal kinase kinase 1
    Short name:
    JNK kinase 1
    Short name:
    JNKK 1
    JNK-activating kinase 1
    MAPK/ERK kinase 4
    Short name:
    MEK 4
    SAPK/ERK kinase 1
    Short name:
    SEK1
    Gene namesi
    Name:Map2k4
    Synonyms:Jnkk1, Mek4, Mkk4, Prkmk4, Sek1, Serk1, Skk1
    OrganismiMus musculus (Mouse)
    Taxonomic identifieri10090 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
    ProteomesiUP000000589: Chromosome 11

    Organism-specific databases

    MGIiMGI:1346869. Map2k4.

    Subcellular locationi

    Cytoplasm 1 Publication. Nucleus 1 Publication

    GO - Cellular componenti

    1. cytosol Source: Reactome
    2. dendrite cytoplasm Source: Ensembl
    3. nucleus Source: UniProtKB-SubCell
    4. perikaryon Source: Ensembl

    Keywords - Cellular componenti

    Cytoplasm, Nucleus

    Pathology & Biotechi

    Disruption phenotypei

    Causes irregular alignment of Purkinje cells in the cerebellum and delayed radial migration in the cortex during brain development. The cardiac-specific deletion prevents pathological cardiac hypertrophy.2 Publications

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi129 – 1291K → R: Loss of ATP-binding. 1 Publication

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Initiator methioninei1 – 11RemovedBy similarity
    Chaini2 – 397396Dual specificity mitogen-activated protein kinase kinase 4PRO_0000086382Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei2 – 21N-acetylalanineBy similarity
    Modified residuei88 – 881PhosphoserineBy similarity
    Modified residuei255 – 2551Phosphoserine; by MAP3KBy similarity
    Modified residuei259 – 2591Phosphothreonine; by MAP3KBy similarity

    Post-translational modificationi

    Activated by phosphorylation on Ser-255 and Thr-259 by MAP kinase kinase kinases (MAP3Ks).By similarity

    Keywords - PTMi

    Acetylation, Phosphoprotein

    Proteomic databases

    MaxQBiP47809.
    PaxDbiP47809.
    PRIDEiP47809.

    PTM databases

    PhosphoSiteiP47809.

    Expressioni

    Tissue specificityi

    Strong expression is detected in most of the central nervous system and in liver and thymus during early stages of development. While expression in nervous system increases over time, expression in fetal liver and thymus gradually decreases as embryogenesis proceeds. High level of expression in the central nervous system persists throughout postnatal development and remained at a stable level in adult brain.1 Publication

    Gene expression databases

    ArrayExpressiP47809.
    BgeeiP47809.
    CleanExiMM_MAP2K4.
    GenevestigatoriP47809.

    Interactioni

    Subunit structurei

    Interacts with SPAG9. Interacts (via its D domain) with its substrates MAPK8/JNK1, MAPK9/JNK2, MAPK10/JNK3, MAPK11 and MAPK14 By similarity. Interacts (via its DVD domain) with MAP3Ks activators like MAP3K1/MEKK1 and MAP3K11/MLK3. Interacts with ARRB1, ARRB2 and MAPK8IP3/JIP3 By similarity.By similarity

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    Map3k1P533492EBI-447934,EBI-447913
    Mapk8ip3Q9ESN9-23EBI-447934,EBI-9549291

    Protein-protein interaction databases

    BioGridi204952. 7 interactions.
    DIPiDIP-869N.
    IntActiP47809. 3 interactions.
    MINTiMINT-4102306.
    STRINGi10090.ENSMUSP00000041282.

    Structurei

    3D structure databases

    ProteinModelPortaliP47809.
    SMRiP47809. Positions 93-386.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini100 – 366267Protein kinasePROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni35 – 5016D domainBy similarityAdd
    BLAST
    Regioni362 – 38524DVD domainBy similarityAdd
    BLAST

    Compositional bias

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Compositional biasi5 – 1713Gly/Ser-richAdd
    BLAST

    Domaini

    The DVD domain (residues 362-385) contains a conserved docking site and is found in the mammalian MAP kinase kinases (MAP2Ks). The DVD sites bind to their specific upstream MAP kinase kinase kinases (MAP3Ks) and are essential for activation By similarity.By similarity
    The D domain (residues 35-50) contains a conserved docking site and is required for the binding to MAPk substrates.

    Sequence similaritiesi

    Contains 1 protein kinase domain.PROSITE-ProRule annotation

    Phylogenomic databases

    eggNOGiCOG0515.
    HOGENOMiHOG000234206.
    HOVERGENiHBG108518.
    InParanoidiP47809.
    KOiK04430.
    OMAiVMKSNDC.
    OrthoDBiEOG7J9VPW.
    PhylomeDBiP47809.
    TreeFamiTF350701.

    Family and domain databases

    InterProiIPR011009. Kinase-like_dom.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR002290. Ser/Thr_dual-sp_kinase_dom.
    IPR008271. Ser/Thr_kinase_AS.
    [Graphical view]
    PfamiPF00069. Pkinase. 1 hit.
    [Graphical view]
    SMARTiSM00220. S_TKc. 1 hit.
    [Graphical view]
    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.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    P47809-1 [UniParc]FASTAAdd to Basket

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    MAAPSPSGGG GSGGGGGTPG PIGPPASGHP AVSSMQGKRK ALKLNFANPP    50
    VKSTARFTLN PNTTGVQNPH IERLRTHSIE SSGKLKISPE QHWDFTAEDL 100
    KDLGEIGRGA YGSVNKMVHK PSGQIMAVKR IRSTVDEKEQ KQLLMDLDVV 150
    MRSSDCPYIV QFYGALFREG DCWICMELMS TSFDKFYKYV YSVLDDVIPE 200
    EILGKITLAT VKALNHLKEN LKIIHRDIKP SNILLDRSGN IKLCDFGISG 250
    QLVDSIAKTR DAGCRPYMAP ERIDPSASRQ GYDVRSDVWS LGITLYELAT 300
    GRFPYPKWNS VFDQLTQVVK GDPPQLSNSE EREFSPSFIN FVNLCLTKDE 350
    SKRPKYKELL KHPFILMYEE RTVEVACYVC KILDQMPATP SSPMYVD 397
    Length:397
    Mass (Da):44,114
    Last modified:November 1, 1997 - v2
    Checksum:iB99C6688184E5B3D
    GO

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U18310 mRNA. Translation: AAB81554.1.
    CCDSiCCDS24844.1.
    PIRiS52423.
    RefSeqiNP_033183.1. NM_009157.4.
    UniGeneiMm.412922.

    Genome annotation databases

    EnsembliENSMUST00000046963; ENSMUSP00000041282; ENSMUSG00000033352.
    GeneIDi26398.
    KEGGimmu:26398.
    UCSCiuc007jlb.1. mouse.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U18310 mRNA. Translation: AAB81554.1 .
    CCDSi CCDS24844.1.
    PIRi S52423.
    RefSeqi NP_033183.1. NM_009157.4.
    UniGenei Mm.412922.

    3D structure databases

    ProteinModelPortali P47809.
    SMRi P47809. Positions 93-386.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 204952. 7 interactions.
    DIPi DIP-869N.
    IntActi P47809. 3 interactions.
    MINTi MINT-4102306.
    STRINGi 10090.ENSMUSP00000041282.

    Chemistry

    BindingDBi P47809.
    ChEMBLi CHEMBL2201.

    PTM databases

    PhosphoSitei P47809.

    Proteomic databases

    MaxQBi P47809.
    PaxDbi P47809.
    PRIDEi P47809.

    Protocols and materials databases

    DNASUi 26398.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSMUST00000046963 ; ENSMUSP00000041282 ; ENSMUSG00000033352 .
    GeneIDi 26398.
    KEGGi mmu:26398.
    UCSCi uc007jlb.1. mouse.

    Organism-specific databases

    CTDi 6416.
    MGIi MGI:1346869. Map2k4.

    Phylogenomic databases

    eggNOGi COG0515.
    HOGENOMi HOG000234206.
    HOVERGENi HBG108518.
    InParanoidi P47809.
    KOi K04430.
    OMAi VMKSNDC.
    OrthoDBi EOG7J9VPW.
    PhylomeDBi P47809.
    TreeFami TF350701.

    Enzyme and pathway databases

    BRENDAi 2.7.12.2. 3474.
    Reactomei REACT_188530. FCERI mediated MAPK activation.
    REACT_188970. Oxidative Stress Induced Senescence.
    REACT_204812. JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
    REACT_224208. Interleukin-1 signaling.

    Miscellaneous databases

    NextBioi 304351.
    PROi P47809.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi P47809.
    Bgeei P47809.
    CleanExi MM_MAP2K4.
    Genevestigatori P47809.

    Family and domain databases

    InterProi IPR011009. Kinase-like_dom.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR002290. Ser/Thr_dual-sp_kinase_dom.
    IPR008271. Ser/Thr_kinase_AS.
    [Graphical view ]
    Pfami PF00069. Pkinase. 1 hit.
    [Graphical view ]
    SMARTi SM00220. S_TKc. 1 hit.
    [Graphical view ]
    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. "Role of SAPK/ERK kinase-1 in the stress-activated pathway regulating transcription factor c-Jun."
      Sanchez I., Hughes R.T., Mayer B.J., Yee K., Woodgett J.R., Avruch J., Kyriakis J.M., Zon L.I.
      Nature 372:794-798(1994) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, MUTAGENESIS OF LYS-129.
      Tissue: Embryo.
    2. Zon L.I.
      Submitted (DEC-1996) to the EMBL/GenBank/DDBJ databases
      Cited for: SEQUENCE REVISION.
    3. "SEK1/MKK4 is required for maintenance of a normal peripheral lymphoid compartment but not for lymphocyte development."
      Swat W., Fujikawa K., Ganiatsas S., Yang D., Xavier R.J., Harris N.L., Davidson L., Ferrini R., Davis R.J., Labow M.A., Flavell R.A., Zon L.I., Alt F.W.
      Immunity 8:625-634(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION.
    4. "The MKK7 gene encodes a group of c-Jun NH2-terminal kinase kinases."
      Tournier C., Whitmarsh A.J., Cavanagh J., Barrett T., Davis R.J.
      Mol. Cell. Biol. 19:1569-1581(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: ENZYME REGULATION, SUBCELLULAR LOCATION, FUNCTION OF THE MKK/JNK PATHWAY.
    5. "Dynamic expression of SEK1 suggests multiple roles of the gene during embryogenesis and in adult brain of mice."
      Lee J.K., Hwang W.S., Lee Y.D., Han P.L.
      Brain Res. Mol. Brain Res. 66:133-140(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: TISSUE SPECIFICITY.
    6. "MKK7 is an essential component of the JNK signal transduction pathway activated by proinflammatory cytokines."
      Tournier C., Dong C., Turner T.K., Jones S.N., Flavell R.A., Davis R.J.
      Genes Dev. 15:1419-1426(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION.
    7. "A subdomain of MEKK1 that is critical for binding to MKK4."
      Tu Z., Mooney S.M., Lee F.S.
      Cell. Signal. 15:65-77(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION, INTERACTION WITH MAP3K1/MEKK1.
    8. "Different properties of SEK1 and MKK7 in dual phosphorylation of stress-induced activated protein kinase SAPK/JNK in embryonic stem cells."
      Kishimoto H., Nakagawa K., Watanabe T., Kitagawa D., Momose H., Seo J., Nishitai G., Shimizu N., Ohata S., Tanemura S., Asaka S., Goto T., Fukushi H., Yoshida H., Suzuki A., Sasaki T., Wada T., Penninger J.M., Nishina H., Katada T.
      J. Biol. Chem. 278:16595-16601(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION.
    9. "Targeted deletion of the mitogen-activated protein kinase kinase 4 gene in the nervous system causes severe brain developmental defects and premature death."
      Wang X., Nadarajah B., Robinson A.C., McColl B.W., Jin J.W., Dajas-Bailador F., Boot-Handford R.P., Tournier C.
      Mol. Cell. Biol. 27:7935-7946(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: DISRUPTION PHENOTYPE.
    10. "Cardiac-specific deletion of mkk4 reveals its role in pathological hypertrophic remodeling but not in physiological cardiac growth."
      Liu W., Zi M., Jin J., Prehar S., Oceandy D., Kimura T.E., Lei M., Neyses L., Weston A.H., Cartwright E.J., Wang X.
      Circ. Res. 104:905-914(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: DISRUPTION PHENOTYPE.
    11. "Differential regulation and properties of MAPKs."
      Raman M., Chen W., Cobb M.H.
      Oncogene 26:3100-3112(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: REVIEW ON ENZYME REGULATION.
    12. "Diverse physiological functions of MKK4 and MKK7 during early embryogenesis."
      Asaoka Y., Nishina H.
      J. Biochem. 148:393-401(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: REVIEW ON FUNCTION.
    13. "The bottleneck of JNK signaling: molecular and functional characteristics of MKK4 and MKK7."
      Haeusgen W., Herdegen T., Waetzig V.
      Eur. J. Cell Biol. 90:536-544(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: REVIEW ON REGULATION, REVIEW ON FUNCTION.
    14. "JLP: a scaffolding protein that tethers JNK/p38MAPK signaling modules and transcription factors."
      Lee C.M., Onesime D., Reddy C.D., Dhanasekaran N., Reddy E.P.
      Proc. Natl. Acad. Sci. U.S.A. 99:14189-14194(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH SPAG9.

    Entry informationi

    Entry nameiMP2K4_MOUSE
    AccessioniPrimary (citable) accession number: P47809
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: February 1, 1996
    Last sequence update: November 1, 1997
    Last modified: October 1, 2014
    This is version 124 of the entry and version 2 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