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O02812

- MK14_CANFA

UniProt

O02812 - MK14_CANFA

Protein

Mitogen-activated protein kinase 14

Gene

MAPK14

Organism
Canis familiaris (Dog) (Canis lupus familiaris)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at transcript leveli
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    • History
      Entry version 123 (01 Oct 2014)
      Sequence version 3 (23 Jan 2007)
      Previous versions | rss
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    Functioni

    Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK14 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. 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 which are activated through phosphorylation and further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1. RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery. On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2. MAPK14 interacts also with casein kinase II, leading to its activation through autophosphorylation and further phosphorylation of TP53/p53. In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF-induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. In a similar way, MAPK14 phosphorylates the ubiquitin ligase SIAH2, regulating its activity towards EGLN3. MAPK14 may also inhibit the lysosomal degradation pathway of autophagy by interfering with the intracellular trafficking of the transmembrane protein ATG9. Another function of MAPK14 is to regulate the endocytosis of membrane receptors by different mechanisms that impinge on the small GTPase RAB5A. In addition, clathrin-mediated EGFR internalization induced by inflammatory cytokines and UV irradiation depends on MAPK14-mediated phosphorylation of EGFR itself as well as of RAB5A effectors. Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane-associated metalloprotease ADAM17. Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Another p38 MAPK substrate is FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A. The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers. The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF-kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment. Phosphorylates CDC25B and CDC25C which is required for binding to 14-3-3 proteins and leads to initiation of a G2 delay after ultraviolet radiation. Phosphorylates TIAR following DNA damage, releasing TIAR from GADD45A mRNA and preventing mRNA degradation. The p38 MAPKs may also have kinase-independent roles, which are thought to be due to the binding to targets in the absence of phosphorylation. Protein O-Glc-N-acylation catalyzed by the OGT is regulated by MAPK14, and, although OGT does not seem to be phosphorylated by MAPK14, their interaction increases upon MAPK14 activation induced by glucose deprivation. This interaction may regulate OGT activity by recruiting it to specific targets such as neurofilament H, stimulating its O-Glc-N-acylation. Required in mid-fetal development for the growth of embryo-derived blood vessels in the labyrinth layer of the placenta. Also plays an essential role in developmental and stress-induced erythropoiesis, through regulation of EPO gene expression By similarity. Phosphorylates S100A9 at 'Thr-113' By similarity.By similarity

    Catalytic activityi

    ATP + a protein = ADP + a phosphoprotein.

    Cofactori

    Magnesium.By similarity

    Enzyme regulationi

    Activated by cell stresses such as DNA damage, heat shock, osmotic shock, anisomycin and sodium arsenite, as well as pro-inflammatory stimuli such as bacterial lipopolysaccharide (LPS) and interleukin-1. Activation occurs through dual phosphorylation of Thr-180 and Tyr-182 by either of two dual specificity kinases, MAP2K3/MKK3 or MAP2K6/MKK6, and potentially also MAP2K4/MKK4, as well as by TAB1-mediated autophosphorylation. MAPK14 phosphorylated on both Thr-180 and Tyr-182 is 10-20-fold more active than MAPK14 phosphorylated only on Thr-180, whereas MAPK14 phosphorylated on Tyr-182 alone is inactive. whereas Thr-180 is necessary for catalysis, Tyr-182 may be required for auto-activation and substrate recognition. Phosphorylated at Tyr-323 by ZAP70 in an alternative activation pathway in response to TCR signaling in T-cells. This alternative pathway is inhibited by GADD45A. Inhibited by dual specificity phosphatases, such as DUSP1, DUSP10, and DUSP16. Specifically inhibited by the binding of pyridinyl-imidazole compounds, which are cytokine-suppressive anti-inflammatory drugs (CSAID). SB203580 is an inhibitor of MAPK14 By similarity.By similarity

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei53 – 531ATPPROSITE-ProRule annotation
    Active sitei150 – 1501Proton acceptorPROSITE-ProRule annotation

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi30 – 389ATPPROSITE-ProRule annotation

    GO - Molecular functioni

    1. ATP binding Source: UniProtKB-KW
    2. MAP kinase activity Source: UniProtKB

    GO - Biological processi

    1. angiogenesis Source: Ensembl
    2. apoptotic process Source: UniProtKB-KW
    3. cartilage condensation Source: Ensembl
    4. cell morphogenesis Source: Ensembl
    5. cellular response to ionizing radiation Source: Ensembl
    6. cellular response to vascular endothelial growth factor stimulus Source: Ensembl
    7. chondrocyte differentiation Source: Ensembl
    8. DNA damage checkpoint Source: Ensembl
    9. fatty acid oxidation Source: Ensembl
    10. glucose metabolic process Source: Ensembl
    11. intracellular signal transduction Source: UniProtKB
    12. lipopolysaccharide-mediated signaling pathway Source: Ensembl
    13. negative regulation of canonical Wnt signaling pathway Source: Ensembl
    14. osteoclast differentiation Source: Ensembl
    15. p38MAPK cascade Source: UniProtKB
    16. peptidyl-serine phosphorylation Source: Ensembl
    17. positive regulation of erythrocyte differentiation Source: Ensembl
    18. positive regulation of myoblast differentiation Source: UniProtKB
    19. positive regulation of myoblast fusion Source: UniProtKB
    20. positive regulation of myotube differentiation Source: UniProtKB
    21. positive regulation of protein import into nucleus Source: Ensembl
    22. positive regulation of reactive oxygen species metabolic process Source: Ensembl
    23. positive regulation of transcription from RNA polymerase II promoter Source: Ensembl
    24. regulation of transcription from RNA polymerase II promoter Source: UniProtKB
    25. response to muramyl dipeptide Source: Ensembl
    26. signal transduction in response to DNA damage Source: Ensembl
    27. skeletal muscle tissue development Source: Ensembl
    28. stress-induced premature senescence Source: Ensembl
    29. striated muscle cell differentiation Source: Ensembl
    30. transcription, DNA-templated Source: UniProtKB-KW
    31. transmembrane receptor protein serine/threonine kinase signaling pathway Source: Ensembl
    32. vascular endothelial growth factor receptor signaling pathway Source: Ensembl

    Keywords - Molecular functioni

    Kinase, Serine/threonine-protein kinase, Transferase

    Keywords - Biological processi

    Apoptosis, Stress response, Transcription, Transcription regulation

    Keywords - Ligandi

    ATP-binding, Nucleotide-binding

    Enzyme and pathway databases

    ReactomeiREACT_174808. Oxidative Stress Induced Senescence.
    REACT_182627. KSRP destabilizes mRNA.
    REACT_202307. Activation of PPARGC1A (PGC-1alpha) by phosphorylation.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Mitogen-activated protein kinase 14 (EC:2.7.11.24)
    Short name:
    MAP kinase 14
    Short name:
    MAPK 14
    Alternative name(s):
    Mitogen-activated protein kinase p38 alpha
    Short name:
    MAP kinase p38 alpha
    Gene namesi
    Name:MAPK14
    Synonyms:CSBP1, CSBP2
    OrganismiCanis familiaris (Dog) (Canis lupus familiaris)
    Taxonomic identifieri9615 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaCarnivoraCaniformiaCanidaeCanis
    ProteomesiUP000002254: Chromosome 12

    Subcellular locationi

    Cytoplasm By similarity. Nucleus By similarity

    GO - Cellular componenti

    1. cytoplasm Source: UniProtKB
    2. cytosol Source: Ensembl
    3. mitochondrion Source: Ensembl
    4. nucleus Source: UniProtKB
    5. spindle pole Source: Ensembl

    Keywords - Cellular componenti

    Cytoplasm, Nucleus

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Initiator methioninei1 – 11RemovedBy similarity
    Chaini2 – 360359Mitogen-activated protein kinase 14PRO_0000186290Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei2 – 21N-acetylserineBy similarity
    Modified residuei2 – 21PhosphoserineBy similarity
    Modified residuei16 – 161PhosphothreonineBy similarity
    Modified residuei53 – 531N6-acetyllysineBy similarity
    Modified residuei152 – 1521N6-acetyllysineBy similarity
    Modified residuei180 – 1801Phosphothreonine; by MAP2K3, MAP2K4, MAP2K6 and autocatalysisBy similarity
    Modified residuei182 – 1821Phosphotyrosine; by MAP2K3, MAP2K4, MAP2K6 and autocatalysisBy similarity
    Modified residuei263 – 2631PhosphothreonineBy similarity
    Modified residuei323 – 3231Phosphotyrosine; by ZAP70By similarity

    Post-translational modificationi

    Dually phosphorylated on Thr-180 and Tyr-182 by the MAP2Ks MAP2K3/MKK3, MAP2K4/MKK4 and MAP2K6/MKK6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme. Dual phosphorylation can also be mediated by TAB1-mediated autophosphorylation. TCR engagement in T-cells also leads to Tyr-323 phosphorylation by ZAP70. Dephosphorylated and inactivated by DUPS1, DUSP10 and DUSP16 By similarity.By similarity
    Acetylated at Lys-53 and Lys-152 by KAT2B and EP300. Acetylation at Lys-53 increases the affinity for ATP and enhances kinase activity. Lys-53 and Lys-152 are deacetylated by HDAC3 By similarity.By similarity
    Ubiquitinated. Ubiquitination leads to degradation by the proteasome pathway By similarity.By similarity

    Keywords - PTMi

    Acetylation, Phosphoprotein, Ubl conjugation

    Proteomic databases

    PRIDEiO02812.

    Interactioni

    Subunit structurei

    Binds to a kinase interaction motif within the protein tyrosine phosphatase, PTPRR. This interaction retains MAPK14 in the cytoplasm and prevents nuclear accumulation. Interacts with SPAG9 and GADD45A, CDC25B, CDC25C, DUSP1, DUSP10, DUSP16, NP60, SUPT20H and TAB1. Interacts with casein kinase II subunits CSNK2A1 and CSNK2B.By similarity

    Protein-protein interaction databases

    STRINGi9615.ENSCAFP00000031957.

    Structurei

    3D structure databases

    ProteinModelPortaliO02812.
    SMRiO02812. Positions 1-352.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini24 – 308285Protein kinasePROSITE-ProRule annotationAdd
    BLAST

    Motif

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Motifi180 – 1823TXY

    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.
    GeneTreeiENSGT00550000074271.
    HOGENOMiHOG000233024.
    HOVERGENiHBG014652.
    InParanoidiO02812.
    KOiK04441.
    OMAiMNFENVF.
    OrthoDBiEOG7PCJGV.
    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.

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

    O02812-1 [UniParc]FASTAAdd to Basket

    « Hide

    MSQERPTFYR QELNKTIWEV PERYQNLSPV GSGAYGSVCA AFDTKTGLRV    50
    AVKKLSRPFQ SIIHAKRTYR ELRLLKHMKH ENVIGLLDVF TPARSLEEFN 100
    DVYLVTHLMG ADLNNIVKCQ KLTDDHVQFL IYQILRGLKY IHSADIIHRD 150
    LKPSNLAVNE DCELKILDFG LARHTDDEMT GYVATRWYRA PEIMLNWMHY 200
    NQTVDIWSVG CIMAELLTGR TLFPGTDHID QLKLILRLVG TPGADLLKKI 250
    SSESARNYIQ SLTQMPKMNF ANVFIGANPL AVDLLEKMLV LDSDKRITAA 300
    QALAHAYFAQ YHDPDDEPVA DPYDQSFESR DLLIDEWKSL TYDEVVSFVP 350
    PPLDQEEMES 360
    Length:360
    Mass (Da):41,265
    Last modified:January 23, 2007 - v3
    Checksum:i786D81D08F6BB6CB
    GO

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AF003597 mRNA. Translation: AAC36131.1.
    RefSeqiNP_001003206.1. NM_001003206.1.
    UniGeneiCfa.2823.

    Genome annotation databases

    EnsembliENSCAFT00000002127; ENSCAFP00000001968; ENSCAFG00000001378.
    GeneIDi403856.
    KEGGicfa:403856.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AF003597 mRNA. Translation: AAC36131.1 .
    RefSeqi NP_001003206.1. NM_001003206.1.
    UniGenei Cfa.2823.

    3D structure databases

    ProteinModelPortali O02812.
    SMRi O02812. Positions 1-352.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    STRINGi 9615.ENSCAFP00000031957.

    Proteomic databases

    PRIDEi O02812.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSCAFT00000002127 ; ENSCAFP00000001968 ; ENSCAFG00000001378 .
    GeneIDi 403856.
    KEGGi cfa:403856.

    Organism-specific databases

    CTDi 1432.

    Phylogenomic databases

    eggNOGi COG0515.
    GeneTreei ENSGT00550000074271.
    HOGENOMi HOG000233024.
    HOVERGENi HBG014652.
    InParanoidi O02812.
    KOi K04441.
    OMAi MNFENVF.
    OrthoDBi EOG7PCJGV.
    TreeFami TF105100.

    Enzyme and pathway databases

    Reactomei REACT_174808. Oxidative Stress Induced Senescence.
    REACT_182627. KSRP destabilizes mRNA.
    REACT_202307. Activation of PPARGC1A (PGC-1alpha) by phosphorylation.

    Miscellaneous databases

    NextBioi 20817349.

    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. "p38 mitogen-activated protein kinase expression and activation in smooth muscle."
      Hedges J.C., Yamboliev I.A., Ngo M., Horowitz B., Adam L.P., Gerthoffer W.T.
      Am. J. Physiol. 275:C527-C534(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
      Tissue: Smooth muscle.

    Entry informationi

    Entry nameiMK14_CANFA
    AccessioniPrimary (citable) accession number: O02812
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: July 15, 1998
    Last sequence update: January 23, 2007
    Last modified: October 1, 2014
    This is version 123 of the entry and version 3 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