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Q63538

- MK12_RAT

UniProt

Q63538 - MK12_RAT

Protein

Mitogen-activated protein kinase 12

Gene

Mapk12

Organism
Rattus norvegicus (Rat)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 127 (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. MAPK12 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors such as ELK1 and ATF2. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases such as MAPKAPK2, which are activated through phosphorylation and further phosphorylate additional targets. Plays a role in myoblast differentiation and also in the down-regulation of cyclin D1 in response to hypoxia in adrenal cells suggesting MAPK12 may inhibit cell proliferation while promoting differentiation. Phosphorylates DLG1. Following osmotic shock, MAPK12 in the cell nucleus increases its association with nuclear DLG1, thereby causing dissociation of DLG1-SFPQ complexes. This function is independent of its catalytic activity and could affect mRNA processing and/or gene transcription to aid cell adaptation to osmolarity changes in the environment. Regulates UV-induced checkpoint signaling and repair of UV-induced DNA damage and G2 arrest after gamma-radiation exposure. MAPK12 is involved in the regulation of SLC2A1 expression and basal glucose uptake in L6 myotubes; and negatively regulates SLC2A4 expression and contraction-mediated glucose uptake in adult skeletal muscle. C-Jun (JUN) phosphorylation is stimulated by MAPK14 and inhibited by MAPK12, leading to a distinct AP-1 regulation. MAPK12 is required for the normal kinetochore localization of PLK1, prevents chromosomal instability and supports mitotic cell viability. MAPK12-signaling is also positively regulating the expansion of transient amplifying myogenic precursor cells during muscle growth and regeneration.2 Publications

    Catalytic activityi

    ATP + a protein = ADP + a phosphoprotein.

    Cofactori

    Binds 2 magnesium ions.

    Enzyme regulationi

    Activated by phosphorylation on threonine and tyrosine. MAP2K3/MKK3 and MAP2K6/MKK6 are both essential for the activation of MAPK12 induced by environmental stress, whereas MAP2K6/MKK6 is the major MAPK12 activator in response to TNF-alpha.1 Publication

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei56 – 561ATPPROSITE-ProRule annotation
    Active sitei153 – 1531Proton acceptorPROSITE-ProRule annotation

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi33 – 419ATPPROSITE-ProRule annotation

    GO - Molecular functioni

    1. ATP binding Source: RGD
    2. magnesium ion binding Source: Ensembl
    3. MAP kinase activity Source: RGD
    4. protein binding Source: IntAct
    5. protein serine/threonine kinase activity Source: UniProtKB

    GO - Biological processi

    1. cell cycle Source: UniProtKB-KW
    2. MAPK cascade Source: GOC
    3. myoblast differentiation Source: Ensembl
    4. negative regulation of cell cycle Source: UniProtKB
    5. peptidyl-serine phosphorylation Source: Ensembl
    6. protein phosphorylation Source: RGD
    7. regulation of transcription, DNA-templated Source: UniProtKB-KW
    8. response to stress Source: UniProtKB-KW
    9. transcription, DNA-templated Source: UniProtKB-KW

    Keywords - Molecular functioni

    Kinase, Serine/threonine-protein kinase, Transferase

    Keywords - Biological processi

    Cell cycle, Stress response, Transcription, Transcription regulation

    Keywords - Ligandi

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

    Enzyme and pathway databases

    ReactomeiREACT_209077. Activation of PPARGC1A (PGC-1alpha) by phosphorylation.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Mitogen-activated protein kinase 12 (EC:2.7.11.24)
    Short name:
    MAP kinase 12
    Short name:
    MAPK 12
    Alternative name(s):
    Extracellular signal-regulated kinase 6
    Short name:
    ERK-6
    Mitogen-activated protein kinase p38 gamma
    Short name:
    MAP kinase p38 gamma
    Stress-activated protein kinase 3
    Gene namesi
    Name:Mapk12
    Synonyms:Sapk3
    OrganismiRattus norvegicus (Rat)
    Taxonomic identifieri10116 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
    ProteomesiUP000002494: Chromosome 7

    Organism-specific databases

    RGDi70975. Mapk12.

    Subcellular locationi

    Cytoplasm. Nucleus By similarity. Mitochondrion
    Note: Mitochondrial when associated with SH3BP5. In skeletal muscle colocalizes with SNTA1 at the neuromuscular junction and throughout the sarcolemma.

    GO - Cellular componenti

    1. cytoplasm Source: UniProtKB
    2. mitochondrion Source: UniProtKB-SubCell
    3. nucleus Source: UniProtKB-SubCell

    Keywords - Cellular componenti

    Cytoplasm, Mitochondrion, Nucleus

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi183 – 1831T → A: Loss of kinase activity. 1 Publication
    Mutagenesisi185 – 1851Y → A: Loss of kinase activity. 1 Publication

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 367367Mitogen-activated protein kinase 12PRO_0000186284Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei183 – 1831Phosphothreonine; by MAP2K3 and MAP2K61 Publication
    Modified residuei185 – 1851Phosphotyrosine; by MAP2K3 and MAP2K61 Publication

    Post-translational modificationi

    Dually phosphorylated on Thr-183 and Tyr-185 by MAP2K3/MKK3 and MAP2K6/MKK6, which activates the enzyme.1 Publication
    Ubiquitinated. Ubiquitination leads to degradation by the proteasome pathway By similarity.By similarity

    Keywords - PTMi

    Phosphoprotein, Ubl conjugation

    Proteomic databases

    PRIDEiQ63538.

    PTM databases

    PhosphoSiteiQ63538.

    Expressioni

    Tissue specificityi

    Highly expressed in skeletal muscle, lung and testes and also in the heart and thymus of both adult and neonatal rats.1 Publication

    Gene expression databases

    GenevestigatoriQ63538.

    Interactioni

    Subunit structurei

    Monomer. Interacts with the PDZ domain of the syntrophin SNTA1. Interacts with LIN7C, SCRIB, SYNJ2BP and SH3BP5.3 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    SNTA1Q134245EBI-783937,EBI-717191From a different organism.

    Protein-protein interaction databases

    BioGridi248795. 1 interaction.
    IntActiQ63538. 1 interaction.
    STRINGi10116.ENSRNOP00000046455.

    Structurei

    3D structure databases

    ProteinModelPortaliQ63538.
    SMRiQ63538. Positions 8-353.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini27 – 311285Protein kinasePROSITE-ProRule annotationAdd
    BLAST

    Motif

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Motifi183 – 1853TXY

    Domaini

    The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.

    Sequence similaritiesi

    Contains 1 protein kinase domain.PROSITE-ProRule annotation

    Phylogenomic databases

    eggNOGiCOG0515.
    GeneTreeiENSGT00680000099969.
    HOGENOMiHOG000233024.
    HOVERGENiHBG014652.
    InParanoidiQ63538.
    KOiK04441.
    OMAiNFKPPQT.
    OrthoDBiEOG7PCJGV.
    PhylomeDBiQ63538.
    TreeFamiTF105100.

    Family and domain databases

    InterProiIPR011009. Kinase-like_dom.
    IPR003527. MAP_kinase_CS.
    IPR008352. MAPK_p38.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR002290. Ser/Thr_dual-sp_kinase_dom.
    [Graphical view]
    PfamiPF00069. Pkinase. 1 hit.
    [Graphical view]
    PRINTSiPR01773. P38MAPKINASE.
    SMARTiSM00220. S_TKc. 1 hit.
    [Graphical view]
    SUPFAMiSSF56112. SSF56112. 1 hit.
    PROSITEiPS01351. MAPK. 1 hit.
    PS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    Q63538-1 [UniParc]FASTAAdd to Basket

    « Hide

    MSSPPPARKG FYRQEVTKTA WEVRAVYQDL QPVGSGAYGA VCSAVDSRTG    50
    NKVAIKKLYR PFQSELFAKR AYRELRLLKH MRHENVIGLL DVFTPDETLD 100
    DFTDFYLVMP FMGTDLGKLM KHETLSEDRI QFLVYQMLKG LKYIHAAGVI 150
    HRDLKPGNLA VNEDCELKIL DFGLARQADS EMTGYVVTRW YRAPEVILNW 200
    MRYTQTVDIW SVGCIMAEMI TGKILFKGND HLDQLKEIMK VTGTPPPEFV 250
    QKLQSAEAKN YMEGLPELEK KDFASVLTNA SPQAVNLLEK MLVLDAEQRV 300
    TAAEALAHPY FESLRDTEDE PKAQKYDDSF DDVDRTLEEW KRVTYKEVLS 350
    FKPPRQLGAR VPKETAL 367
    Length:367
    Mass (Da):41,985
    Last modified:November 1, 1996 - v1
    Checksum:iB77193D9F45E1D4E
    GO

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    X96488 mRNA. Translation: CAA65342.1.
    PIRiS68680.
    RefSeqiNP_068514.1. NM_021746.1.
    UniGeneiRn.162968.

    Genome annotation databases

    EnsembliENSRNOT00000044376; ENSRNOP00000046455; ENSRNOG00000031233.
    GeneIDi60352.
    KEGGirno:60352.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    X96488 mRNA. Translation: CAA65342.1 .
    PIRi S68680.
    RefSeqi NP_068514.1. NM_021746.1.
    UniGenei Rn.162968.

    3D structure databases

    ProteinModelPortali Q63538.
    SMRi Q63538. Positions 8-353.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 248795. 1 interaction.
    IntActi Q63538. 1 interaction.
    STRINGi 10116.ENSRNOP00000046455.

    PTM databases

    PhosphoSitei Q63538.

    Proteomic databases

    PRIDEi Q63538.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSRNOT00000044376 ; ENSRNOP00000046455 ; ENSRNOG00000031233 .
    GeneIDi 60352.
    KEGGi rno:60352.

    Organism-specific databases

    CTDi 6300.
    RGDi 70975. Mapk12.

    Phylogenomic databases

    eggNOGi COG0515.
    GeneTreei ENSGT00680000099969.
    HOGENOMi HOG000233024.
    HOVERGENi HBG014652.
    InParanoidi Q63538.
    KOi K04441.
    OMAi NFKPPQT.
    OrthoDBi EOG7PCJGV.
    PhylomeDBi Q63538.
    TreeFami TF105100.

    Enzyme and pathway databases

    Reactomei REACT_209077. Activation of PPARGC1A (PGC-1alpha) by phosphorylation.

    Miscellaneous databases

    NextBioi 612019.
    PROi Q63538.

    Gene expression databases

    Genevestigatori Q63538.

    Family and domain databases

    InterProi IPR011009. Kinase-like_dom.
    IPR003527. MAP_kinase_CS.
    IPR008352. MAPK_p38.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR002290. Ser/Thr_dual-sp_kinase_dom.
    [Graphical view ]
    Pfami PF00069. Pkinase. 1 hit.
    [Graphical view ]
    PRINTSi PR01773. P38MAPKINASE.
    SMARTi SM00220. S_TKc. 1 hit.
    [Graphical view ]
    SUPFAMi SSF56112. SSF56112. 1 hit.
    PROSITEi PS01351. MAPK. 1 hit.
    PS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "SAP kinase-3, a new member of the family of mammalian stress-activated protein kinases."
      Mertens S., Craxton M., Goedert M.
      FEBS Lett. 383:273-276(1996) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
      Tissue: Skeletal muscle.
    2. Cited for: INTERACTION WITH SNTA1, FUNCTION IN PHOSPHORYLATION OF SNTA1, SUBCELLULAR LOCATION.
    3. "Selective activation of p38alpha and p38gamma by hypoxia. Role in regulation of cyclin D1 by hypoxia in PC12 cells."
      Conrad P.W., Rust R.T., Han J., Millhorn D.E., Beitner-Johnson D.
      J. Biol. Chem. 274:23570-23576(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, PHOSPHORYLATION AT THR-183 AND TYR-185, MUTAGENESIS OF THR-183 AND TYR-185.
    4. "Cardiac expression and subcellular localization of the p38 mitogen-activated protein kinase member, stress-activated protein kinase-3 (SAPK3)."
      Court N.W., dos Remedios C.G., Cordell J., Bogoyevitch M.A.
      J. Mol. Cell. Cardiol. 34:413-426(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
    5. "Phosphorylation of the mitochondrial protein Sab by stress-activated protein kinase 3."
      Court N.W., Kuo I., Quigley O., Bogoyevitch M.A.
      Biochem. Biophys. Res. Commun. 319:130-137(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUBCELLULAR LOCATION, INTERACTION WITH SH3BP5.
    6. "Outer membrane protein 25-a mitochondrial anchor and inhibitor of stress-activated protein kinase-3."
      Court N.W., Ingley E., Klinken S.P., Bogoyevitch M.A.
      Biochim. Biophys. Acta 1744:68-75(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH LIN7C; SCRIB AND SYNJ2BP, ENZYME REGULATION.
    7. "Mechanisms and functions of p38 MAPK signalling."
      Cuadrado A., Nebreda A.R.
      Biochem. J. 429:403-417(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: REVIEW ON ENZYME REGULATION, REVIEW ON FUNCTION.

    Entry informationi

    Entry nameiMK12_RAT
    AccessioniPrimary (citable) accession number: Q63538
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: July 15, 1998
    Last sequence update: November 1, 1996
    Last modified: October 1, 2014
    This is version 127 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. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3