MAPK14 - Mitogen-activated protein kinase 14 - human protein (Function)
 
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MAPK14 »  Mitogen-activated protein kinase 14   [ EC 2.7.11.24 ]  (MAPK 14)
 
Protein also known as:  Cytokine suppressive anti-inflammatory drug-binding protein (CSBP).
Gene name:  MAPK14
Entry whose protein(s) existence is based on evidence at protein level
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GENE REF ISO

Function

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Overview 
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.  
17
  • CuratedUniProtKB
Isoform  Exip   May play a role in the early onset of apoptosis. Phosphorylates S100A9 at 'Thr-113'.  
17
  • CuratedUniProtKB
Isoform  Mxi2   Activation is stimulated by mitogens and oxidative stress and only poorly phosphorylates ELK1 and ATF2.  
17
  • CuratedUniProtKB
GO molecular function 
ATP bindingdefinition[GO:0005524]  
  • IEAUniProtKB KW
MAP kinase activitydefinition[GO:0004707]  
3
  • IDAUniProtKB
MAP kinase kinase activitydefinition[GO:0004708]  
1
  • TASPINC
NFAT protein bindingdefinition[GO:0051525]  
  • ISSOrtholog Curator
Protein bindingdefinition[GO:0005515]  
23
  • IPIIntAct
  • IPIBHF-UCL
GO biological process 
3'-UTR-mediated mRNA stabilizationdefinition[GO:0070935]  
1
  • TASUniProtKB
Angiogenesisdefinition[GO:0001525] silver  
  • IEAOrtholog Compara
Apoptotic processdefinition[GO:0006915]  
  • IEAUniProtKB KW
Cartilage condensationdefinition[GO:0001502] silver  
  • IEAOrtholog Compara
Cell morphogenesisdefinition[GO:0000902] silver  
  • IEAOrtholog Compara
Cell surface receptor signaling pathwaydefinition[GO:0007166]  
1
  • TASPINC
Cellular component movementdefinition[GO:0006928]  
1
  • TASPINC
Cellular response to ionizing radiationdefinition[GO:0071479]  
1
  • IMPBHF-UCL
Cellular response to lipopolysaccharidedefinition[GO:0071222]  
1
  • IDAMGI
Cellular response to vascular endothelial growth factor stimulusdefinition[GO:0035924]  
1
  • IMPBHF-UCL
Chemotaxisdefinition[GO:0006935]  
1
  • TASPINC
Chondrocyte differentiationdefinition[GO:0002062] silver  
  • IEAOrtholog Compara
DNA damage checkpointdefinition[GO:0000077] silver  
  • IEAOrtholog Compara
Fatty acid oxidationdefinition[GO:0019395] silver  
  • IEAOrtholog Compara
Glucose metabolic processdefinition[GO:0006006] silver  
  • IEAOrtholog Compara
Intracellular signal transductiondefinition[GO:0035556]  
1
  • IDAUniProtKB
Lipopolysaccharide-mediated signaling pathwaydefinition[GO:0031663] silver  
  • IEAOrtholog Compara
Negative regulation of canonical Wnt signaling pathwaydefinition[GO:0090090] silver  
  • IEAOrtholog Compara
Osteoclast differentiationdefinition[GO:0030316]  
  • ISSOrtholog Curator
p38MAPK cascadedefinition[GO:0038066]  
  • ISSOrtholog Curator
Peptidyl-serine phosphorylationdefinition[GO:0018105]  
  • ISSOrtholog Curator
Not  Positive regulation of blood vessel endothelial cell migrationdefinition[GO:0043536]  
1
  • IMPBHF-UCL
Positive regulation of erythrocyte differentiationdefinition[GO:0045648] silver  
  • IEAOrtholog Compara
Positive regulation of myoblast differentiationdefinition[GO:0045663]  
  • ISSOrtholog Curator
Positive regulation of myoblast fusiondefinition[GO:1901741]  
  • ISSOrtholog Curator
Positive regulation of myotube differentiationdefinition[GO:0010831]  
  • ISSOrtholog Curator
Positive regulation of protein import into nucleusdefinition[GO:0042307] silver  
  • IEAOrtholog Compara
Positive regulation of reactive oxygen species metabolic processdefinition[GO:2000379]  
1
  • IMPBHF-UCL
Positive regulation of transcription from RNA polymerase II promoterdefinition[GO:0045944] silver  
  • IEAOrtholog Compara
Regulation of transcription from RNA polymerase II promoterdefinition[GO:0006357]  
  • ISSOrtholog Curator
Response to muramyl dipeptidedefinition[GO:0032495] silver  
  • IEAOrtholog Compara
Signal transductiondefinition[GO:0007165]  
1
  • TASPINC
Signal transduction in response to DNA damagedefinition[GO:0042770]  
1
  • IMPBHF-UCL
Skeletal muscle tissue developmentdefinition[GO:0007519] silver  
  • IEAOrtholog Compara
Stress-induced premature senescencedefinition[GO:0090400]  
1
  • IMPBHF-UCL
Striated muscle cell differentiationdefinition[GO:0051146] silver  
  • IEAOrtholog Compara
Transcription, DNA-templateddefinition[GO:0006351]  
  • IEAUniProtKB KW
Transmembrane receptor protein serine/threonine kinase signaling pathwaydefinition[GO:0007178] silver  
  • IEAOrtholog Compara
Vascular endothelial growth factor receptor signaling pathwaydefinition[GO:0048010]  
1
  • IMPBHF-UCL
Enzymatic activity 
This protein acts as an enzyme. It is known to catalyze the following reaction
EC 2.7.11.24: ATP + a protein ADP + a phosphoprotein.  
  • CuratedUniProtKB
It requires the following cofactor
Magnesium.  
1
  • CuratedUniProtKB
It is regulated in the following manners
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).  
18
  • CuratedUniProtKB
Isoform  Exip   Is not activated by MAP2K6. SB203580 is an inhibitor of MAPK14.  
18
  • CuratedUniProtKB
Isoform  Mxi2   Is 100-fold less sensitive to these agents than the other isoforms and is not inhibited by DUSP1.  
18
  • CuratedUniProtKB
Pathways 
According to KEGG, this protein belongs to the following pathways:
Amyotrophic lateral sclerosis (ALS)  hsa05014+1432  
Chagas disease (American trypanosomiasis)  hsa05142+1432  
Dopaminergic synapse  hsa04728+1432  
Epithelial cell signaling in Helicobacter pylori infection  hsa05120+1432  
Fc epsilon RI signaling pathway  hsa04664+1432  
GnRH signaling pathway  hsa04912+1432  
Hepatitis C  hsa05160+1432  
Influenza A  hsa05164+1432  
Leishmaniasis  hsa05140+1432  
Leukocyte transendothelial migration  hsa04670+1432  
MAPK signaling pathway  hsa04010+1432  
Neurotrophin signaling pathway  hsa04722+1432  
NOD-like receptor signaling pathway  hsa04621+1432  
Osteoclast differentiation  hsa04380+1432  
Pertussis  hsa05133+1432  
Progesterone-mediated oocyte maturation  hsa04914+1432  
RIG-I-like receptor signaling pathway  hsa04622+1432  
Salmonella infection  hsa05132+1432  
Shigellosis  hsa05131+1432  
T cell receptor signaling pathway  hsa04660+1432  
Toll-like receptor signaling pathway  hsa04620+1432  
Toxoplasmosis  hsa05145+1432  
Tuberculosis  hsa05152+1432  
VEGF signaling pathway  hsa04370+1432  
According to Reactome, this protein belongs to the following pathways:
Cell-Cell communication  REACT_111155  
Cellular responses to stress  REACT_120956  
Developmental Biology  REACT_111045  
Gene Expression  REACT_71  
Hemostasis  REACT_604  
Immune System  REACT_6900  
Metabolism of RNA  REACT_21257  
Organelle biogenesis and maintenance  REACT_200751  
Signal Transduction  REACT_111102  
TRAF6 Mediated Induction of proinflammatory cytokines  REACT_6782  
 

Keywords

Biological process 
Apoptosis  definition   [KW-0053]
Stress response  definition   [KW-0346]
Transcription  definition   [KW-0804]
Transcription regulation  definition   [KW-0805]
Molecular function 
Kinase  definition   [KW-0418]
Serine/threonine-protein kinase  definition   [KW-0723]
Transferase  definition   [KW-0808]
Technical term 
Reference proteome  definition   [KW-1185]
 

Further external links

Other
GeneWiki: MAPK14
GenomeRNAi: 1432
PRO: PR:Q16539
Chemistry
GuidetoPHARMACOLOGY: 1499