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P45985

- MP2K4_HUMAN

UniProt

P45985 - MP2K4_HUMAN

Protein

Dual specificity mitogen-activated protein kinase kinase 4

Gene

MAP2K4

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 150 (01 Oct 2014)
      Sequence version 1 (01 Nov 1995)
      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 MAPK14.1 Publication

    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
    Sitei45 – 462Cleavage; by anthrax lethal factor
    Sitei58 – 592Cleavage; by anthrax lethal factor
    Binding sitei131 – 1311ATPPROSITE-ProRule annotation
    Active sitei229 – 2291Proton acceptorPROSITE-ProRule annotation

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi108 – 1169ATPPROSITE-ProRule annotation

    GO - Molecular functioni

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

    GO - Biological processi

    1. apoptotic process Source: UniProtKB-KW
    2. cellular response to mechanical stimulus Source: UniProtKB
    3. cellular response to sorbitol Source: Ensembl
    4. Fc-epsilon receptor signaling pathway Source: Reactome
    5. innate immune response Source: Reactome
    6. JNK cascade Source: Reactome
    7. MyD88-dependent toll-like receptor signaling pathway Source: Reactome
    8. MyD88-independent toll-like receptor signaling pathway Source: Reactome
    9. positive regulation of DNA replication Source: Ensembl
    10. positive regulation of neuron apoptotic process Source: Ensembl
    11. signal transduction Source: ProtInc
    12. stress-activated MAPK cascade Source: Reactome
    13. toll-like receptor 10 signaling pathway Source: Reactome
    14. toll-like receptor 2 signaling pathway Source: Reactome
    15. toll-like receptor 3 signaling pathway Source: Reactome
    16. toll-like receptor 4 signaling pathway Source: Reactome
    17. toll-like receptor 5 signaling pathway Source: Reactome
    18. toll-like receptor 9 signaling pathway Source: Reactome
    19. toll-like receptor signaling pathway Source: Reactome
    20. toll-like receptor TLR1:TLR2 signaling pathway Source: Reactome
    21. toll-like receptor TLR6:TLR2 signaling pathway Source: Reactome
    22. TRIF-dependent toll-like receptor signaling pathway Source: Reactome

    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. 2681.
    ReactomeiREACT_163701. FCERI mediated MAPK activation.
    REACT_169436. Oxidative Stress Induced Senescence.
    REACT_21368. JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
    REACT_22442. Interleukin-1 signaling.
    SignaLinkiP45985.

    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):
    JNK-activating kinase 1
    MAPK/ERK kinase 4
    Short name:
    MEK 4
    SAPK/ERK kinase 1
    Short name:
    SEK1
    Stress-activated protein kinase kinase 1
    Short name:
    SAPK kinase 1
    Short name:
    SAPKK-1
    Short name:
    SAPKK1
    c-Jun N-terminal kinase kinase 1
    Short name:
    JNKK
    Gene namesi
    Name:MAP2K4
    Synonyms:JNKK1, MEK4, MKK4, PRKMK4, SEK1, SERK1, SKK1
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 17

    Organism-specific databases

    HGNCiHGNC:6844. MAP2K4.

    Subcellular locationi

    Cytoplasm By similarity. Nucleus By similarity

    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

    Organism-specific databases

    PharmGKBiPA30589.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Initiator methioninei1 – 11Removed1 Publication
    Chaini2 – 399398Dual specificity mitogen-activated protein kinase kinase 4PRO_0000086381Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei2 – 21N-acetylalanine1 Publication
    Modified residuei90 – 901Phosphoserine1 Publication
    Modified residuei257 – 2571Phosphoserine; by MAP3K1 Publication
    Modified residuei261 – 2611Phosphothreonine; by MAP3K1 Publication

    Post-translational modificationi

    Activated by phosphorylation on Ser-257 and Thr-261 by MAP kinase kinase kinases (MAP3Ks).3 Publications

    Keywords - PTMi

    Acetylation, Phosphoprotein

    Proteomic databases

    MaxQBiP45985.
    PaxDbiP45985.
    PRIDEiP45985.

    PTM databases

    PhosphoSiteiP45985.

    Miscellaneous databases

    PMAP-CutDBP45985.

    Expressioni

    Tissue specificityi

    Abundant expression is seen in the skeletal muscle. It is also widely expressed in other tissues.

    Gene expression databases

    ArrayExpressiP45985.
    BgeeiP45985.
    CleanExiHS_MAP2K4.
    GenevestigatoriP45985.

    Organism-specific databases

    HPAiCAB007751.

    Interactioni

    Subunit structurei

    Interacts with SPAG9 By similarity. Interacts (via its D domain) with its substrates MAPK8/JNK1, MAPK9/JNK2, MAPK10/JNK3, MAPK11 and MAPK14. Interacts (via its DVD domain) with MAP3Ks activators like MAP3K1/MEKK1 and MAP3K11/MLK3. Interacts with ARRB1, ARRB2 and MAPK8IP3/JIP3.By similarity5 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    MAP3K1Q132333EBI-447868,EBI-49776

    Protein-protein interaction databases

    BioGridi112315. 38 interactions.
    IntActiP45985. 11 interactions.
    MINTiMINT-151438.
    STRINGi9606.ENSP00000262445.

    Structurei

    Secondary structure

    1
    399
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Beta strandi85 – 884
    Beta strandi93 – 953
    Beta strandi101 – 1033
    Beta strandi107 – 1104
    Beta strandi112 – 12110
    Turni122 – 1243
    Beta strandi127 – 1348
    Helixi139 – 15315
    Beta strandi164 – 1696
    Beta strandi171 – 1788
    Beta strandi182 – 1843
    Helixi185 – 19410
    Helixi202 – 22322
    Helixi232 – 2343
    Beta strandi235 – 2373
    Beta strandi243 – 2453
    Beta strandi249 – 2513
    Beta strandi267 – 2704
    Helixi272 – 2743
    Helixi287 – 30216
    Beta strandi312 – 3143
    Beta strandi316 – 3216
    Helixi338 – 34710
    Helixi352 – 3543
    Helixi358 – 3614
    Helixi365 – 3728
    Helixi377 – 38711

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    3ALNX-ray2.30A/B/C80-399[»]
    3ALOX-ray2.60A80-399[»]
    3VUTX-ray3.50A/B80-399[»]
    ProteinModelPortaliP45985.
    SMRiP45985. Positions 95-388.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP45985.

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini102 – 367266Protein kinasePROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni37 – 5216D domainAdd
    BLAST
    Regioni364 – 38724DVD domainAdd
    BLAST

    Compositional bias

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Compositional biasi5 – 1915Gly/Ser-richAdd
    BLAST

    Domaini

    The DVD domain (residues 364-387) 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.
    The D domain (residues 34-52) 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.
    HOVERGENiHBG108518.
    InParanoidiP45985.
    KOiK04430.
    OMAiVMKSNDC.
    OrthoDBiEOG7J9VPW.
    PhylomeDBiP45985.
    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]

    Sequences (2)i

    Sequence statusi: Complete.

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

    This entry describes 2 isoformsi produced by alternative splicing. Align

    Isoform 1 (identifier: P45985-1) [UniParc]FASTAAdd to Basket

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide

    MAAPSPSGGG GSGGGSGSGT PGPVGSPAPG HPAVSSMQGK RKALKLNFAN    50
    PPFKSTARFT LNPNPTGVQN PHIERLRTHS IESSGKLKIS PEQHWDFTAE 100
    DLKDLGEIGR GAYGSVNKMV HKPSGQIMAV KRIRSTVDEK EQKQLLMDLD 150
    VVMRSSDCPY IVQFYGALFR EGDCWICMEL MSTSFDKFYK YVYSVLDDVI 200
    PEEILGKITL ATVKALNHLK ENLKIIHRDI KPSNILLDRS GNIKLCDFGI 250
    SGQLVDSIAK TRDAGCRPYM APERIDPSAS RQGYDVRSDV WSLGITLYEL 300
    ATGRFPYPKW NSVFDQLTQV VKGDPPQLSN SEEREFSPSF INFVNLCLTK 350
    DESKRPKYKE LLKHPFILMY EERAVEVACY VCKILDQMPA TPSSPMYVD 399
    Length:399
    Mass (Da):44,288
    Last modified:November 1, 1995 - v1
    Checksum:iA472537F2F26770B
    GO
    Isoform 2 (identifier: P45985-2) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         39-39: G → GFQINFCEKAQS

    Note: No experimental confirmation available.

    Show »
    Length:410
    Mass (Da):45,584
    Checksum:i097F8966398DD6C0
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti118 – 1181K → R in CAG38801. 1 PublicationCurated
    Sequence conflicti179 – 1791E → G in BAG35884. (PubMed:14702039)Curated
    Sequence conflicti356 – 3561P → L in AAH60764. (PubMed:15489334)Curated

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti16 – 161S → R.1 Publication
    Corresponds to variant rs17855590 [ dbSNP | Ensembl ].
    VAR_062963
    Natural varianti142 – 1421Q → L in a lung squamous cell carcinoma sample; somatic mutation. 1 Publication
    VAR_040818
    Natural varianti154 – 1541R → W in a colorectal adenocarcinoma sample; somatic mutation. 1 Publication
    VAR_040819
    Natural varianti234 – 2341N → I in an ovarian serous carcinoma sample; somatic mutation. 1 Publication
    VAR_040820
    Natural varianti251 – 2511S → N in a metastatic melanoma sample; somatic mutation. 1 Publication
    VAR_040821
    Natural varianti279 – 2791A → T in a colorectal adenocarcinoma sample; somatic mutation. 1 Publication
    VAR_040822

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei39 – 391G → GFQINFCEKAQS in isoform 2. 1 PublicationVSP_038838

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    L36870 mRNA. Translation: AAC41719.1.
    U17743 mRNA. Translation: AAC50127.1.
    AF070090
    , AF070080, AF070081, AF070082, AF070083, AF070084, AF070085, AF070086, AF070087, AF070088, AF070089 Genomic DNA. Translation: AAC24130.1.
    CR536564 mRNA. Translation: CAG38801.1.
    BT019676 mRNA. Translation: AAV38482.1.
    AK131544 mRNA. Translation: BAG54774.1.
    AK313053 mRNA. Translation: BAG35884.1.
    DQ015703 Genomic DNA. Translation: AAY22176.1.
    AC005244 Genomic DNA. No translation available.
    AC005410 Genomic DNA. No translation available.
    CH471108 Genomic DNA. Translation: EAW89975.1.
    CH471108 Genomic DNA. Translation: EAW89974.1.
    CH471108 Genomic DNA. Translation: EAW89976.1.
    BC036032 mRNA. Translation: AAH36032.1.
    BC060764 mRNA. Translation: AAH60764.1.
    CCDSiCCDS11162.1. [P45985-1]
    CCDS62095.1. [P45985-2]
    PIRiI38901.
    RefSeqiNP_001268364.1. NM_001281435.1. [P45985-2]
    NP_003001.1. NM_003010.3. [P45985-1]
    UniGeneiHs.514681.

    Genome annotation databases

    EnsembliENST00000353533; ENSP00000262445; ENSG00000065559. [P45985-1]
    ENST00000415385; ENSP00000410402; ENSG00000065559. [P45985-2]
    GeneIDi6416.
    KEGGihsa:6416.
    UCSCiuc002gnj.3. human. [P45985-1]
    uc002gnk.3. human. [P45985-2]

    Polymorphism databases

    DMDMi1170596.

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Cross-referencesi

    Web resourcesi

    NIEHS-SNPs
    Atlas of Genetics and Cytogenetics in Oncology and Haematology

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    L36870 mRNA. Translation: AAC41719.1 .
    U17743 mRNA. Translation: AAC50127.1 .
    AF070090
    , AF070080 , AF070081 , AF070082 , AF070083 , AF070084 , AF070085 , AF070086 , AF070087 , AF070088 , AF070089 Genomic DNA. Translation: AAC24130.1 .
    CR536564 mRNA. Translation: CAG38801.1 .
    BT019676 mRNA. Translation: AAV38482.1 .
    AK131544 mRNA. Translation: BAG54774.1 .
    AK313053 mRNA. Translation: BAG35884.1 .
    DQ015703 Genomic DNA. Translation: AAY22176.1 .
    AC005244 Genomic DNA. No translation available.
    AC005410 Genomic DNA. No translation available.
    CH471108 Genomic DNA. Translation: EAW89975.1 .
    CH471108 Genomic DNA. Translation: EAW89974.1 .
    CH471108 Genomic DNA. Translation: EAW89976.1 .
    BC036032 mRNA. Translation: AAH36032.1 .
    BC060764 mRNA. Translation: AAH60764.1 .
    CCDSi CCDS11162.1. [P45985-1 ]
    CCDS62095.1. [P45985-2 ]
    PIRi I38901.
    RefSeqi NP_001268364.1. NM_001281435.1. [P45985-2 ]
    NP_003001.1. NM_003010.3. [P45985-1 ]
    UniGenei Hs.514681.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    3ALN X-ray 2.30 A/B/C 80-399 [» ]
    3ALO X-ray 2.60 A 80-399 [» ]
    3VUT X-ray 3.50 A/B 80-399 [» ]
    ProteinModelPortali P45985.
    SMRi P45985. Positions 95-388.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 112315. 38 interactions.
    IntActi P45985. 11 interactions.
    MINTi MINT-151438.
    STRINGi 9606.ENSP00000262445.

    Chemistry

    BindingDBi P45985.
    ChEMBLi CHEMBL2897.
    GuidetoPHARMACOLOGYi 2065.

    PTM databases

    PhosphoSitei P45985.

    Polymorphism databases

    DMDMi 1170596.

    Proteomic databases

    MaxQBi P45985.
    PaxDbi P45985.
    PRIDEi P45985.

    Protocols and materials databases

    DNASUi 6416.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000353533 ; ENSP00000262445 ; ENSG00000065559 . [P45985-1 ]
    ENST00000415385 ; ENSP00000410402 ; ENSG00000065559 . [P45985-2 ]
    GeneIDi 6416.
    KEGGi hsa:6416.
    UCSCi uc002gnj.3. human. [P45985-1 ]
    uc002gnk.3. human. [P45985-2 ]

    Organism-specific databases

    CTDi 6416.
    GeneCardsi GC17P011864.
    HGNCi HGNC:6844. MAP2K4.
    HPAi CAB007751.
    MIMi 601335. gene.
    neXtProti NX_P45985.
    PharmGKBi PA30589.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi COG0515.
    HOVERGENi HBG108518.
    InParanoidi P45985.
    KOi K04430.
    OMAi VMKSNDC.
    OrthoDBi EOG7J9VPW.
    PhylomeDBi P45985.
    TreeFami TF350701.

    Enzyme and pathway databases

    BRENDAi 2.7.12.2. 2681.
    Reactomei REACT_163701. FCERI mediated MAPK activation.
    REACT_169436. Oxidative Stress Induced Senescence.
    REACT_21368. JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
    REACT_22442. Interleukin-1 signaling.
    SignaLinki P45985.

    Miscellaneous databases

    ChiTaRSi MAP2K4. human.
    EvolutionaryTracei P45985.
    GeneWikii MAP2K4.
    GenomeRNAii 6416.
    NextBioi 24922.
    PMAP-CutDB P45985.
    PROi P45985.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi P45985.
    Bgeei P45985.
    CleanExi HS_MAP2K4.
    Genevestigatori P45985.

    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. "Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms."
      Derijard B., Raingeaud J., Barrett T., Wu I.-H., Han J., Ulevitch R.J., Davis R.J.
      Science 267:682-685(1995) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
      Tissue: Brain.
    2. "Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2."
      Lin A., Minden A., Martinetto H., Claret F.-X., Lange-Carter C., Mercurio F., Johnson G.L., Karin M.
      Science 268:286-290(1995) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION.
    3. "Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as a genetically targeted tumor suppressor gene."
      Su G.H., Hilgers W., Shekher M.C., Tang D.J., Yeo C.J., Hruban R.H., Kern S.E.
      Cancer Res. 58:2339-2342(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
    4. "Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)."
      Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.
      Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
    5. "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."
      Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A.
      Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
    6. "Complete sequencing and characterization of 21,243 full-length human cDNAs."
      Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.
      , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
      Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
      Tissue: Brain and Thalamus.
    7. NIEHS SNPs program
      Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
    8. "DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage."
      Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R., Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A., Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J., Chang J.L.
      , Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J., DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D., Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A., Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.
      Nature 440:1045-1049(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    9. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    10. "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] (ISOFORM 1), VARIANT ARG-16.
      Tissue: Brain and Testis.
    11. "MLK-3 activates the SAPK/JNK and p38/RK pathways via SEK1 and MKK3/6."
      Tibbles L.A., Ing Y.L., Kiefer F., Chan J., Iscove N., Woodgett J.R., Lassam N.J.
      EMBO J. 15:7026-7035(1996) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT THR-261, ENZYME REGULATION, INTERACTION WITH MAP3K11/MLK3.
    12. "Susceptibility of mitogen-activated protein kinase kinase family members to proteolysis by anthrax lethal factor."
      Vitale G., Bernardi L., Napolitani G., Mock M., Montecucco C.
      Biochem. J. 352:739-745(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: CLEAVAGE BY ANTHRAX LETHAL FACTOR.
    13. "Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3."
      McDonald P.H., Chow C.W., Miller W.E., Laporte S.A., Field M.E., Lin F.-T., Davis R.J., Lefkowitz R.J.
      Science 290:1574-1577(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH ARRB2.
    14. "Phosphorylation-dependent scaffolding role of JSAP1/JIP3 in the ASK1-JNK signaling pathway. A new mode of regulation of the MAP kinase cascade."
      Matsuura H., Nishitoh H., Takeda K., Matsuzawa A., Amagasa T., Ito M., Yoshioka K., Ichijo H.
      J. Biol. Chem. 277:40703-40709(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH MAPK8IP3/JIP3.
    15. "A docking site in MKK4 mediates high affinity binding to JNK MAPKs and competes with similar docking sites in JNK substrates."
      Ho D.T., Bardwell A.J., Abdollahi M., Bardwell L.
      J. Biol. Chem. 278:32662-32672(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: DOMAIN, INTERACTION WITH MAPK8/JNK1; MAPK9/JNK2; MAPK10/JNK3; MAPK11 AND MAPK14.
    16. "Conserved docking site is essential for activation of mammalian MAP kinase kinases by specific MAP kinase kinase kinases."
      Takekawa M., Tatebayashi K., Saito H.
      Mol. Cell 18:295-306(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: DOMAIN.
    17. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-90, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Cervix carcinoma.
    18. "Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach."
      Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.
      Anal. Chem. 81:4493-4501(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS], CLEAVAGE OF INITIATOR METHIONINE [LARGE SCALE ANALYSIS].
    19. "A scanning peptide array approach uncovers association sites within the JNK/beta arrestin signalling complex."
      Li X., MacLeod R., Dunlop A.J., Edwards H.V., Advant N., Gibson L.C., Devine N.M., Brown K.M., Adams D.R., Houslay M.D., Baillie G.S.
      FEBS Lett. 583:3310-3316(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH ARRB1 AND ARRB2.
    20. "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.
    21. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-257, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    22. "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.
    23. "Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis."
      Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.
      Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Cervix carcinoma.
    24. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    25. "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.
    26. "Crystal structures of MKK4 kinase domain reveal that substrate peptide binds to an allosteric site and induces an auto-inhibition state."
      Matsumoto T., Kinoshita T., Kirii Y., Yokota K., Hamada K., Tada T.
      Biochem. Biophys. Res. Commun. 400:369-373(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 80-399.
    27. "Patterns of somatic mutation in human cancer genomes."
      Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.
      , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.
      Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS [LARGE SCALE ANALYSIS] LEU-142; TRP-154; ILE-234; ASN-251 AND THR-279.

    Entry informationi

    Entry nameiMP2K4_HUMAN
    AccessioniPrimary (citable) accession number: P45985
    Secondary accession number(s): B2R7N7
    , B3KYB2, D3DTS5, Q5U0B8, Q6FHX4, Q6P9H2, Q6PIE6
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: November 1, 1995
    Last sequence update: November 1, 1995
    Last modified: October 1, 2014
    This is version 150 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. Human chromosome 17
      Human chromosome 17: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    6. Human and mouse protein kinases
      Human and mouse protein kinases: classification and index
    7. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3