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P70236

- MP2K6_MOUSE

UniProt

P70236 - MP2K6_MOUSE

Protein

Dual specificity mitogen-activated protein kinase kinase 6

Gene

Map2k6

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 119 (01 Oct 2014)
      Sequence version 1 (01 Feb 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. With MAP3K3/MKK3, catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in the MAP kinases p38 MAPK11, MAPK12, MAPK13 and MAPK14 and plays an important role in the regulation of cellular responses to cytokines and all kinds of stresses. Especially, MAP2K3/MKK3 and MAP2K6/MKK6 are both essential for the activation of MAPK11 and MAPK13 induced by environmental stress, whereas MAP2K6/MKK6 is the major MAPK11 activator in response to TNF. MAP2K6/MKK6 also phosphorylates and activates PAK6. The p38 MAP kinase signal transduction pathway leads to direct activation of transcription factors. Nuclear targets of p38 MAP kinase include the transcription factors ATF2 and ELK1. Within the p38 MAPK signal transduction pathway, MAP3K6/MKK6 mediates phosphorylation of STAT4 through MAPK14 activation, and is therefore required for STAT4 activation and STAT4-regulated gene expression in response to IL-12 stimulation. The pathway is also crucial for IL-6-induced SOCS3 expression and down-regulation of IL-6-mediated gene induction; and for IFNG-dependent gene transcription. Has a role in osteoclast differentiation through NF-kappa-B transactivation by TNFSF11, and in endochondral ossification and since SOX9 is another likely downstream target of the p38 MAPK pathway. MAP2K6/MKK6 mediates apoptotic cell death in thymocytes. Acts also as a regulator for melanocytes dendricity, through the modulation of Rho family GTPases.7 Publications

    Catalytic activityi

    ATP + a protein = ADP + a phosphoprotein.

    Enzyme regulationi

    Activated by dual phosphorylation on Ser-207 and Thr-211 in response to a variety of cellular stresses, including UV radiation, osmotic shock, hypoxia, inflammatory cytokines, interferon gamma (IFNG), and less often by growth factors. MAP2K6/MKK6 is activated by the majority of M3Ks, such as MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K2/MEKK2, MAP3K3/MEKK3, MAP3K4/MEKK4, MAP3K7/TAK1, MAP3K11/MLK3 and MAP3K17/TAOK2.1 Publication

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei82 – 821ATPPROSITE-ProRule annotation
    Active sitei179 – 1791Proton acceptorPROSITE-ProRule annotation

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi59 – 679ATPPROSITE-ProRule annotation

    GO - Molecular functioni

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

    GO - Biological processi

    1. activation of MAPK activity Source: MGI
    2. apoptotic process Source: UniProtKB-KW
    3. cardiac muscle contraction Source: MGI
    4. cellular response to sorbitol Source: Ensembl
    5. MAPK cascade Source: MGI
    6. positive regulation of apoptotic process Source: Ensembl
    7. protein phosphorylation Source: MGI
    8. regulation of transcription, DNA-templated Source: UniProtKB-KW
    9. response to drug Source: Ensembl
    10. response to ischemia Source: Ensembl
    11. transcription, DNA-templated Source: UniProtKB-KW

    Keywords - Molecular functioni

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

    Keywords - Biological processi

    Apoptosis, Stress response, Transcription, Transcription regulation

    Keywords - Ligandi

    ATP-binding, Nucleotide-binding

    Enzyme and pathway databases

    BRENDAi2.7.12.2. 3474.
    ReactomeiREACT_188970. Oxidative Stress Induced Senescence.
    REACT_211125. NOD1/2 Signaling Pathway.
    REACT_224208. Interleukin-1 signaling.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Dual specificity mitogen-activated protein kinase kinase 6 (EC:2.7.12.2)
    Short name:
    MAP kinase kinase 6
    Short name:
    MAPKK 6
    Alternative name(s):
    MAPK/ERK kinase 6
    Short name:
    MEK 6
    SAPKK3
    Gene namesi
    Name:Map2k6
    Synonyms:Prkmk6, Sapkk3
    OrganismiMus musculus (Mouse)
    Taxonomic identifieri10090 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
    ProteomesiUP000000589: Chromosome 11

    Organism-specific databases

    MGIiMGI:1346870. Map2k6.

    Subcellular locationi

    Nucleus By similarity. Cytoplasm By similarity. Cytoplasmcytoskeleton By similarity
    Note: Binds to microtubules.By similarity

    GO - Cellular componenti

    1. cytoskeleton Source: UniProtKB-SubCell
    2. cytosol Source: Reactome
    3. nucleus Source: UniProtKB-SubCell

    Keywords - Cellular componenti

    Cytoplasm, Cytoskeleton, Nucleus

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 334334Dual specificity mitogen-activated protein kinase kinase 6PRO_0000086387Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei207 – 2071Phosphoserine; by MAPK3Curated
    Modified residuei211 – 2111Phosphothreonine; by MAPK3Curated

    Post-translational modificationi

    Weakly autophosphorylated. Phosphorylated at Ser-207 and Thr-211 by the majority of M3Ks, such as MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K2/MEKK2, MAP3K3/MEKK3, MAP3K4/MEKK4, MAP3K7/TAK1, MAP3K11/MLK3 and MAP3K17/TAOK2.By similarity

    Keywords - PTMi

    Phosphoprotein

    Proteomic databases

    MaxQBiP70236.
    PaxDbiP70236.
    PRIDEiP70236.

    PTM databases

    PhosphoSiteiP70236.

    Expressioni

    Inductioni

    MSAPK14 can negatively regulate the stability of the MAP2K6/MKK6 mRNA and thus control the steady-state concentration of one of its upstream activator.1 Publication

    Gene expression databases

    ArrayExpressiP70236.
    BgeeiP70236.
    CleanExiMM_MAP2K6.
    GenevestigatoriP70236.

    Interactioni

    Subunit structurei

    Dimer. Interacts (via its D domain) with its substrates MAPK11, MAPK12, MAPK13 and MAPK14. Interacts (via its DVD domain) with MAP3Ks activators like MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K2/MEKK2, MAP3K3/MEKK3, MAP3K4/MEKK4, MAP3K7/TAK1, MAP3K11/MLK3 and MAP3K17/TAOK2. Interacts with DCTN1. Interacts with EIF2AK2/PKR.By similarity

    Protein-protein interaction databases

    BioGridi204953. 2 interactions.
    IntActiP70236. 1 interaction.
    MINTiMINT-4102323.

    Structurei

    3D structure databases

    ProteinModelPortaliP70236.
    SMRiP70236. Positions 44-334.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini53 – 314262Protein kinasePROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni4 – 1916D domainBy similarityAdd
    BLAST
    Regioni311 – 33424DVD domainBy similarityAdd
    BLAST

    Domaini

    The DVD domain (residues 311-334) 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 4-19) contains a conserved docking site and is required for the binding to MAPK substrates.By similarity

    Sequence similaritiesi

    Contains 1 protein kinase domain.PROSITE-ProRule annotation

    Phylogenomic databases

    eggNOGiCOG0515.
    HOGENOMiHOG000234206.
    HOVERGENiHBG108518.
    InParanoidiP70236.
    KOiK04433.
    OMAiDISMRAS.
    OrthoDBiEOG7J9VPW.
    PhylomeDBiP70236.
    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.

    P70236-1 [UniParc]FASTAAdd to Basket

    « Hide

    MSQSKGKKRN PGLKIPKEAF EQPQTSSTPP RDLDSKACIS IGNQNFEVKA    50
    DDLEPIVELG RGAYGVVEKM RHVPSGQIMA VKRIRATVNS QEQKRLLMDL 100
    DVSMRTVDCP FTVTFYGALF REGDVWICME LMDTSLDKFY KQVIDKGQTI 150
    PEDILGKIAV SIVKALEHLH SKLSVIHRDV KPSNVLINTL GQVKMCDFGI 200
    SGYLVDSVAK TIDAGCKPYM APERINPELN QKGYSVKSDI WSLGITMIEL 250
    AILRFPYDSW GTPFQQLKQV VEEPSPQLPA DKFSADFVDF TSQCLKKNSK 300
    ERPTYPELMQ HPFFTVHESK AADVASFVKL ILGD 334
    Length:334
    Mass (Da):37,432
    Last modified:February 1, 1997 - v1
    Checksum:i62CEF6C28AF50BAC
    GO

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    X97052 mRNA. Translation: CAA65764.1.
    BC075652 mRNA. Translation: AAH75652.1.
    CCDSiCCDS25592.1.
    PIRiS71632.
    RefSeqiNP_036073.1. NM_011943.2.
    UniGeneiMm.14487.

    Genome annotation databases

    EnsembliENSMUST00000020949; ENSMUSP00000020949; ENSMUSG00000020623.
    GeneIDi26399.
    KEGGimmu:26399.
    UCSCiuc007mdr.1. mouse.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    X97052 mRNA. Translation: CAA65764.1 .
    BC075652 mRNA. Translation: AAH75652.1 .
    CCDSi CCDS25592.1.
    PIRi S71632.
    RefSeqi NP_036073.1. NM_011943.2.
    UniGenei Mm.14487.

    3D structure databases

    ProteinModelPortali P70236.
    SMRi P70236. Positions 44-334.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 204953. 2 interactions.
    IntActi P70236. 1 interaction.
    MINTi MINT-4102323.

    PTM databases

    PhosphoSitei P70236.

    Proteomic databases

    MaxQBi P70236.
    PaxDbi P70236.
    PRIDEi P70236.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSMUST00000020949 ; ENSMUSP00000020949 ; ENSMUSG00000020623 .
    GeneIDi 26399.
    KEGGi mmu:26399.
    UCSCi uc007mdr.1. mouse.

    Organism-specific databases

    CTDi 5608.
    MGIi MGI:1346870. Map2k6.

    Phylogenomic databases

    eggNOGi COG0515.
    HOGENOMi HOG000234206.
    HOVERGENi HBG108518.
    InParanoidi P70236.
    KOi K04433.
    OMAi DISMRAS.
    OrthoDBi EOG7J9VPW.
    PhylomeDBi P70236.
    TreeFami TF350701.

    Enzyme and pathway databases

    BRENDAi 2.7.12.2. 3474.
    Reactomei REACT_188970. Oxidative Stress Induced Senescence.
    REACT_211125. NOD1/2 Signaling Pathway.
    REACT_224208. Interleukin-1 signaling.

    Miscellaneous databases

    NextBioi 304355.
    PROi P70236.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi P70236.
    Bgeei P70236.
    CleanExi MM_MAP2K6.
    Genevestigatori P70236.

    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. "Purification and cDNA cloning of SAPKK3, the major activator of RK/p38 in stress- and cytokine-stimulated monocytes and epithelial cells."
      Cuenda A., Alonso G., Morrice N., Jones M., Meier R., Cohen P., Nebreda A.R.
      EMBO J. 15:4156-4164(1996) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    2. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
      Strain: C57BL/6.
      Tissue: Eye.
    3. "Differential involvement of p38 mitogen-activated protein kinase kinases MKK3 and MKK6 in T-cell apoptosis."
      Tanaka N., Kamanaka M., Enslen H., Dong C., Wysk M., Davis R.J., Flavell R.A.
      EMBO Rep. 3:785-791(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN REGULATION OF T-CELL APOPTOSIS.
    4. "Involvement of MKK6 in TCRalphabeta(int)CD69lo: a target population for apoptotic cell death in thymocytes."
      Suzuki H., Wu J., Hossain K., Ohhata T., Du J., Akhand A.A., Hayakawa A., Kimura H., Hagiwara M., Nakashima I.
      FASEB J. 17:1538-1540(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN REGULATION OF T-CELL APOPTOSIS.
    5. Cited for: FUNCTION OF THE P38 MAP KINASE SIGNAL TRANSDUCTION PATHWAY.
    6. "Negative feedback regulation of MKK6 mRNA stability by p38alpha mitogen-activated protein kinase."
      Ambrosino C., Mace G., Galban S., Fritsch C., Vintersten K., Black E., Gorospe M., Nebreda A.R.
      Mol. Cell. Biol. 23:370-381(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: INDUCTION.
    7. "Activation of mitogen-activated protein kinase kinase (MKK) 3 and MKK6 by type I interferons."
      Li Y., Batra S., Sassano A., Majchrzak B., Levy D.E., Gaestel M., Fish E.N., Davis R.J., Platanias L.C.
      J. Biol. Chem. 280:10001-10010(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: ENZYME REGULATION, FUNCTION OF THE P38 MAP KINASE SIGNAL TRANSDUCTION PATHWAY.
    8. "Osteoclast differentiation requires TAK1 and MKK6 for NFATc1 induction and NF-kappaB transactivation by RANKL."
      Huang H., Ryu J., Ha J., Chang E.J., Kim H.J., Kim H.M., Kitamura T., Lee Z.H., Kim H.H.
      Cell Death Differ. 13:1879-1891(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION OF THE P38 MAP KINASE SIGNAL TRANSDUCTION PATHWAY.
    9. "Constitutive activation of MKK6 in chondrocytes of transgenic mice inhibits proliferation and delays endochondral bone formation."
      Zhang R., Murakami S., Coustry F., Wang Y., de Crombrugghe B.
      Proc. Natl. Acad. Sci. U.S.A. 103:365-370(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION OF THE P38 MAP KINASE SIGNAL TRANSDUCTION PATHWAY.
    10. Cited for: FUNCTION.
    11. Cited for: REVIEW ON ENZYME REGULATION, REVIEW ON FUNCTION.

    Entry informationi

    Entry nameiMP2K6_MOUSE
    AccessioniPrimary (citable) accession number: P70236
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: July 15, 1998
    Last sequence update: February 1, 1997
    Last modified: October 1, 2014
    This is version 119 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