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Q01986

- MP2K1_RAT

UniProt

Q01986 - MP2K1_RAT

Protein

Dual specificity mitogen-activated protein kinase kinase 1

Gene

Map2k1

Organism
Rattus norvegicus (Rat)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 134 (01 Oct 2014)
      Sequence version 2 (23 Jan 2007)
      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. Binding of extracellular ligands such as growth factors, cytokines and hormones to their cell-surface receptors activates RAS and this initiates RAF1 activation. RAF1 then further activates the dual-specificity protein kinases MAP2K1/MEK1 and MAP2K2/MEK2. Both MAP2K1/MEK1 and MAP2K2/MEK2 function specifically in the MAPK/ERK cascade, and catalyze the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in the extracellular signal-regulated kinases MAPK3/ERK1 and MAPK1/ERK2, leading to their activation and further transduction of the signal within the MAPK/ERK cascade. Depending on the cellular context, this pathway mediates diverse biological functions such as cell growth, adhesion, survival and differentiation, predominantly through the regulation of transcription, metabolism and cytoskeletal rearrangements. One target of the MAPK/ERK cascade is peroxisome proliferator-activated receptor gamma (PPARG), a nuclear receptor that promotes differentiation and apoptosis. MAP2K1/MEK1 has been shown to export PPARG from the nucleus. The MAPK/ERK cascade is also involved in the regulation of endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC), as well as in the fragmentation of the Golgi apparatus during mitosis.2 Publications

    Catalytic activityi

    ATP + a protein = ADP + a phosphoprotein.

    Enzyme regulationi

    Ras proteins such as HRAS mediate the activation of RAF proteins such as RAF1 or BRAF which in turn activate extracellular signal-regulated kinases (ERK) through MAPK (mitogen-activated protein kinases) and ERK kinases MAP2K1/MEK1 and MAP2K2/MEK2. Activation occurs through phosphorylation of Ser-218 and Ser-222. MAP2K1/MEK1 is also the target of negative feed-back regulation by its substrate kinases, such as MAPK1/ERK2. These phosphorylate MAP2K1/MEK1 on Thr-292, thereby facilitating dephosphorylation of the activating residues Ser-218 and Ser-222. Inhibited by serine/threonine phosphatase 2A.4 Publications

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sitei8 – 92Cleavage; by anthrax lethal factorBy similarity
    Binding sitei97 – 971ATPPROSITE-ProRule annotation
    Active sitei190 – 1901Proton acceptorPROSITE-ProRule annotation

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi74 – 829ATPPROSITE-ProRule annotation

    GO - Molecular functioni

    1. ATP binding Source: RGD
    2. MAP kinase kinase activity Source: RGD
    3. mitogen-activated protein kinase kinase kinase binding Source: RGD
    4. protein binding Source: RGD
    5. protein kinase binding Source: RGD
    6. protein serine/threonine/tyrosine kinase activity Source: UniProtKB
    7. protein serine/threonine kinase activator activity Source: Ensembl
    8. protein serine/threonine kinase activity Source: UniProtKB-KW
    9. protein tyrosine kinase activity Source: UniProtKB-KW
    10. Ras GTPase binding Source: RGD
    11. receptor signaling protein tyrosine phosphatase activity Source: Ensembl

    GO - Biological processi

    1. activation of MAPK activity Source: UniProtKB
    2. cell cycle arrest Source: Ensembl
    3. cell motility Source: Ensembl
    4. cell proliferation Source: RGD
    5. cellular senescence Source: Ensembl
    6. Golgi inheritance Source: RGD
    7. intracellular signal transduction Source: RGD
    8. keratinocyte differentiation Source: Ensembl
    9. labyrinthine layer development Source: Ensembl
    10. MAPK cascade Source: RGD
    11. melanosome transport Source: RGD
    12. mitotic nuclear division Source: RGD
    13. negative regulation of cell proliferation Source: Ensembl
    14. negative regulation of homotypic cell-cell adhesion Source: RGD
    15. neuron differentiation Source: RGD
    16. neuron projection morphogenesis Source: RGD
    17. placenta blood vessel development Source: Ensembl
    18. positive regulation of cell differentiation Source: Ensembl
    19. positive regulation of cell migration Source: RGD
    20. positive regulation of Ras GTPase activity Source: RGD
    21. positive regulation of Ras protein signal transduction Source: MGI
    22. positive regulation of transcription elongation from RNA polymerase II promoter Source: RGD
    23. protein heterooligomerization Source: RGD
    24. protein phosphorylation Source: RGD
    25. regulation of early endosome to late endosome transport Source: UniProtKB
    26. regulation of Golgi inheritance Source: UniProtKB
    27. regulation of stress-activated MAPK cascade Source: UniProtKB
    28. regulation of vascular smooth muscle contraction Source: RGD
    29. response to axon injury Source: RGD
    30. response to glucocorticoid Source: RGD
    31. response to oxidative stress Source: RGD
    32. vesicle transport along microtubule Source: RGD

    Keywords - Molecular functioni

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

    Keywords - Ligandi

    ATP-binding, Nucleotide-binding

    Enzyme and pathway databases

    BRENDAi2.7.12.2. 5301.
    ReactomeiREACT_222166. Signaling by FGFR.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Dual specificity mitogen-activated protein kinase kinase 1 (EC:2.7.12.2)
    Short name:
    MAP kinase kinase 1
    Short name:
    MAPKK 1
    Alternative name(s):
    ERK activator kinase 1
    MAPK/ERK kinase 1
    Short name:
    MEK 1
    Gene namesi
    Name:Map2k1
    Synonyms:Mek1, Prkmk1
    OrganismiRattus norvegicus (Rat)
    Taxonomic identifieri10116 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
    ProteomesiUP000002494: Chromosome 8

    Organism-specific databases

    RGDi70495. Map2k1.

    Subcellular locationi

    Cytoplasmcytoskeletonmicrotubule organizing centercentrosome. Cytoplasmcytoskeletonmicrotubule organizing centerspindle pole body. Cytoplasm. Nucleus
    Note: Localizes at centrosomes during prometaphase, midzone during anaphase and midbody during telophase/cytokinesis.

    GO - Cellular componenti

    1. axon Source: RGD
    2. cell cortex Source: RGD
    3. cytosol Source: UniProtKB
    4. dendrite Source: RGD
    5. dendrite cytoplasm Source: RGD
    6. early endosome Source: UniProtKB
    7. focal adhesion Source: UniProtKB
    8. Golgi apparatus Source: UniProtKB
    9. late endosome Source: UniProtKB
    10. microtubule organizing center Source: UniProtKB-SubCell
    11. mitochondrion Source: UniProtKB
    12. nucleus Source: UniProtKB
    13. perikaryon Source: RGD
    14. perinuclear region of cytoplasm Source: RGD
    15. plasma membrane Source: RGD

    Keywords - Cellular componenti

    Cytoplasm, Cytoskeleton, Nucleus

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Initiator methioninei1 – 11RemovedBy similarity
    Chaini2 – 393392Dual specificity mitogen-activated protein kinase kinase 1PRO_0000086369Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei218 – 2181Phosphoserine; by RAFBy similarity
    Modified residuei222 – 2221Phosphoserine; by RAFBy similarity
    Modified residuei286 – 2861PhosphothreonineBy similarity
    Modified residuei292 – 2921Phosphothreonine; by MAPK12 Publications
    Modified residuei298 – 2981Phosphoserine; by PAK3 Publications

    Post-translational modificationi

    Phosphorylation at Ser-218 and Ser-222 by MAP kinase kinase kinases (RAF or MEKK1) positively regulates kinase activity. Also phosphorylated at Thr-292 by MAPK1/ERK2 and at Ser-298 by PAK. MAPK1/ERK2 phosphorylation of Thr-292 occurs in response to cellular adhesion and leads to inhibition of Ser-298 phosphorylation by PAK.3 Publications

    Keywords - PTMi

    Phosphoprotein

    Proteomic databases

    PaxDbiQ01986.
    PRIDEiQ01986.

    PTM databases

    PhosphoSiteiQ01986.

    Expressioni

    Gene expression databases

    GenevestigatoriQ01986.

    Interactioni

    Subunit structurei

    Forms a heterodimer with MAP2K2/MEK2 By similarity. Forms heterodimers with KSR2 which further dimerize to form tetramers By similarity. Interacts with MORG1 and VRK2 By similarity. Found in a complex with at least BRAF, HRAS, MAP2K1, MAPK3/ERK1 and RGS14. Interacts with ARRB2, LAMTOR3, MAPK1/ERK2, and RAF1 (via the proline-rich domain). Interacts with SGK1 By similarity. Interacts with BIRC6/bruce By similarity.By similarity

    Protein-protein interaction databases

    BioGridi251005. 5 interactions.
    STRINGi10116.ENSRNOP00000013933.

    Structurei

    3D structure databases

    ProteinModelPortaliQ01986.
    SMRiQ01986. Positions 62-382.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini68 – 361294Protein kinasePROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni270 – 30738RAF1-bindingAdd
    BLAST

    Compositional bias

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Compositional biasi262 – 30746Pro-richAdd
    BLAST

    Domaini

    The proline-rich region localized between residues 270 and 307 is important for binding to RAF1 and activation of MAP2K1/MEK1.1 Publication

    Sequence similaritiesi

    Contains 1 protein kinase domain.PROSITE-ProRule annotation

    Phylogenomic databases

    eggNOGiCOG0515.
    GeneTreeiENSGT00690000101918.
    HOGENOMiHOG000234206.
    HOVERGENiHBG108518.
    InParanoidiQ01986.
    KOiK04368.
    OMAiSICMESM.
    OrthoDBiEOG7HF1KZ.
    PhylomeDBiQ01986.
    TreeFamiTF105137.

    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.

    Q01986-1 [UniParc]FASTAAdd to Basket

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    MPKKKPTPIQ LNPAPDGSAV NGTSSAETNL EALQKKLEEL ELDEQQRKRL    50
    EAFLTQKQKV GELKDDDFEK ISELGAGNGG VVFKVSHKPS GLVMARKLIH 100
    LEIKPAIRNQ IIRELQVLHE CNSPYIVGFY GAFYSDGEIS ICMEHMDGGS 150
    LDQVLKKAGR IPEQILGKVS IAVIKGLTYL REKHKIMHRD VKPSNILVNS 200
    RGEIKLCDFG VSGQLIDSMA NSFVGTRSYM SPERLQGTHY SVQSDIWSMG 250
    LSLVEMAVGR YPIPPPDAKE LELLFGCQVE GDAAETPPRP RTPGRPLSSY 300
    GMDSRPPMAI FELLDYIVNE PPPKLPSGVF SLEFQDFVNK CLIKNPAERA 350
    DLKQLMVHAF IKRSDAEEVD FAGWLCSTIG LNQPSTPTHA ASI 393
    Length:393
    Mass (Da):43,465
    Last modified:January 23, 2007 - v2
    Checksum:iA1C8D18FFC852D51
    GO

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    Z16415 mRNA. Translation: CAA78905.1.
    D13341 mRNA. Translation: BAA02603.1.
    D14591 mRNA. Translation: BAA03441.1.
    X62313 mRNA. Translation: CAA44192.1.
    BC089772 mRNA. Translation: AAH89772.1.
    PIRiJN0840.
    RefSeqiNP_113831.1. NM_031643.4.
    UniGeneiRn.5850.

    Genome annotation databases

    EnsembliENSRNOT00000013933; ENSRNOP00000013933; ENSRNOG00000010176.
    GeneIDi170851.
    KEGGirno:170851.
    UCSCiRGD:70495. rat.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    Z16415 mRNA. Translation: CAA78905.1 .
    D13341 mRNA. Translation: BAA02603.1 .
    D14591 mRNA. Translation: BAA03441.1 .
    X62313 mRNA. Translation: CAA44192.1 .
    BC089772 mRNA. Translation: AAH89772.1 .
    PIRi JN0840.
    RefSeqi NP_113831.1. NM_031643.4.
    UniGenei Rn.5850.

    3D structure databases

    ProteinModelPortali Q01986.
    SMRi Q01986. Positions 62-382.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 251005. 5 interactions.
    STRINGi 10116.ENSRNOP00000013933.

    PTM databases

    PhosphoSitei Q01986.

    Proteomic databases

    PaxDbi Q01986.
    PRIDEi Q01986.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSRNOT00000013933 ; ENSRNOP00000013933 ; ENSRNOG00000010176 .
    GeneIDi 170851.
    KEGGi rno:170851.
    UCSCi RGD:70495. rat.

    Organism-specific databases

    CTDi 5604.
    RGDi 70495. Map2k1.

    Phylogenomic databases

    eggNOGi COG0515.
    GeneTreei ENSGT00690000101918.
    HOGENOMi HOG000234206.
    HOVERGENi HBG108518.
    InParanoidi Q01986.
    KOi K04368.
    OMAi SICMESM.
    OrthoDBi EOG7HF1KZ.
    PhylomeDBi Q01986.
    TreeFami TF105137.

    Enzyme and pathway databases

    BRENDAi 2.7.12.2. 5301.
    Reactomei REACT_222166. Signaling by FGFR.

    Miscellaneous databases

    NextBioi 621291.
    PROi Q01986.

    Gene expression databases

    Genevestigatori Q01986.

    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. "Molecular structure of a protein-tyrosine/threonine kinase activating p42 mitogen-activated protein (MAP) kinase: MAP kinase kinase."
      Wu J., Harrison J.K., Vincent L.A., Haystead C., Haystead T.A.J., Michel H., Hunt D.F., Lynch K.R., Sturgill T.W.
      Proc. Natl. Acad. Sci. U.S.A. 90:173-177(1993) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
      Strain: Sprague-Dawley.
      Tissue: Kidney.
    2. "Isolation of two members of the rat MAP kinase kinase gene family."
      Otsu M., Terada Y., Okayama H.
      FEBS Lett. 320:246-250(1993) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    3. "Cloning and sequencing of a cDNA encoding rat brain mitogen-activated protein (MAP) kinase activator."
      Doering F., Drewes G., Berling B., Mandelkow E.M.
      Gene 131:303-304(1993) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE.
      Strain: Sprague-Dawley.
    4. "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].
      Tissue: Thymus.
    5. Lubec G., Chen W.-Q.
      Submitted (APR-2007) to UniProtKB
      Cited for: PROTEIN SEQUENCE OF 206-227; 270-291 AND 325-340, IDENTIFICATION BY MASS SPECTROMETRY.
      Strain: Sprague-Dawley.
      Tissue: Hippocampus.
    6. "A proline-rich sequence unique to MEK1 and MEK2 is required for raf binding and regulates MEK function."
      Catling A.D., Schaeffer H.J., Reuter C.W., Reddy G.R., Weber M.J.
      Mol. Cell. Biol. 15:5214-5225(1995) [PubMed] [Europe PMC] [Abstract]
      Cited for: DOMAIN, INTERACTION WITH RAF1, ENZYME REGULATION.
    7. "MP1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade."
      Schaeffer H.J., Catling A.D., Eblen S.T., Collier L.S., Krauss A., Weber M.J.
      Science 281:1668-1671(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH LAMTOR3, ENZYME REGULATION.
    8. "A specific activation of the mitogen-activated protein kinase kinase 1 (MEK1) is required for Golgi fragmentation during mitosis."
      Colanzi A., Deerinck T.J., Ellisman M.H., Malhotra V.
      J. Cell Biol. 149:331-339(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION, FUNCTION.
    9. "Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds."
      Luttrell L.M., Roudabush F.L., Choy E.W., Miller W.E., Field M.E., Pierce K.L., Lefkowitz R.J.
      Proc. Natl. Acad. Sci. U.S.A. 98:2449-2454(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH ARRB2.
    10. Cited for: PHOSPHORYLATION AT SER-298, ENZYME REGULATION.
    11. "Mitogen-activated protein kinase feedback phosphorylation regulates MEK1 complex formation and activation during cellular adhesion."
      Eblen S.T., Slack-Davis J.K., Tarcsafalvi A., Parsons J.T., Weber M.J., Catling A.D.
      Mol. Cell. Biol. 24:2308-2317(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT THR-292 AND SER-298, INTERACTION WITH MAPK1/ERK2, ENZYME REGULATION.
    12. "The novel lipid raft adaptor p18 controls endosome dynamics by anchoring the MEK-ERK pathway to late endosomes."
      Nada S., Hondo A., Kasai A., Koike M., Saito K., Uchiyama Y., Okada M.
      EMBO J. 28:477-489(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION OF THE MAPK/ERK PATHWAY.
    13. Cited for: IDENTIFICATION IN A COMPLEX WITH BRAF; HRAS; MAPK3 AND RGS14.
    14. Cited for: REVIEW ON FUNCTION.
    15. Cited for: REVIEW ON ENZYME REGULATION.
    16. "The ERK signaling cascade--views from different subcellular compartments."
      Yao Z., Seger R.
      BioFactors 35:407-416(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: REVIEW ON FUNCTION.
    17. "The ERK cascade: distinct functions within various subcellular organelles."
      Wortzel I., Seger R.
      Genes Cancer 2:195-209(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: REVIEW ON FUNCTION.

    Entry informationi

    Entry nameiMP2K1_RAT
    AccessioniPrimary (citable) accession number: Q01986
    Secondary accession number(s): Q5EBD5
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: April 1, 1993
    Last sequence update: January 23, 2007
    Last modified: October 1, 2014
    This is version 134 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, Direct protein sequencing, Reference proteome

    Documents

    1. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3