Mitogen-activated protein kinase 14

Details

Name
Mitogen-activated protein kinase 14
Synonyms
  • 2.7.11.24
  • CSAID-binding protein
  • CSBP
  • CSBP1
  • CSBP2
  • CSPB1
  • Cytokine suppressive anti-inflammatory drug-binding protein
  • MAP kinase 14
  • MAP kinase MXI2
  • MAP kinase p38 alpha
  • MAX-interacting protein 2
  • Mitogen-activated protein kinase p38 alpha
  • MXI2
  • SAPK2A
  • Stress-activated protein kinase 2a
Gene Name
MAPK14
Organism
Humans
Amino acid sequence
>lcl|BSEQ0002029|Mitogen-activated protein kinase 14
MSQERPTFYRQELNKTIWEVPERYQNLSPVGSGAYGSVCAAFDTKTGLRVAVKKLSRPFQ
SIIHAKRTYRELRLLKHMKHENVIGLLDVFTPARSLEEFNDVYLVTHLMGADLNNIVKCQ
KLTDDHVQFLIYQILRGLKYIHSADIIHRDLKPSNLAVNEDCELKILDFGLARHTDDEMT
GYVATRWYRAPEIMLNWMHYNQTVDIWSVGCIMAELLTGRTLFPGTDHIDQLKLILRLVG
TPGAELLKKISSESARNYIQSLTQMPKMNFANVFIGANPLAVDLLEKMLVLDSDKRITAA
QALAHAYFAQYHDPDDEPVADPYDQSFESRDLLIDEWKSLTYDEVISFVPPPLDQEEMES
Number of residues
360
Molecular Weight
41292.885
Theoretical pI
5.58
GO Classification
Functions
ATP binding / enzyme binding / MAP kinase activity / MAP kinase kinase activity / NFAT protein binding / protein phosphatase binding / protein serine/threonine kinase activity
Processes
3'-UTR-mediated mRNA stabilization / activation of MAPK activity / apoptotic process / blood coagulation / cell surface receptor signaling pathway / cellular response to ionizing radiation / cellular response to lipopolysaccharide / cellular response to vascular endothelial growth factor stimulus / cellular response to virus / chemotaxis / gene expression / innate immune response / intracellular signal transduction / mitochondrion organization / movement of cell or subcellular component / muscle cell differentiation / MyD88-dependent toll-like receptor signaling pathway / MyD88-independent toll-like receptor signaling pathway / neurotrophin TRK receptor signaling pathway / organelle organization / osteoclast differentiation / p38MAPK cascade / peptidyl-serine phosphorylation / platelet activation / positive regulation of cyclase activity / positive regulation of erythrocyte differentiation / positive regulation of gene expression / positive regulation of interleukin-12 secretion / positive regulation of muscle cell differentiation / positive regulation of myoblast differentiation / positive regulation of myoblast fusion / positive regulation of myotube differentiation / positive regulation of reactive oxygen species metabolic process / Ras protein signal transduction / regulation of cytokine production involved in inflammatory response / regulation of mRNA stability / regulation of sequence-specific DNA binding transcription factor activity / regulation of transcription from RNA polymerase II promoter / signal transduction / signal transduction in response to DNA damage / stress-activated MAPK cascade / stress-induced premature senescence / toll-like receptor 10 signaling pathway / toll-like receptor 2 signaling pathway / toll-like receptor 3 signaling pathway / toll-like receptor 4 signaling pathway / toll-like receptor 5 signaling pathway / toll-like receptor 9 signaling pathway / toll-like receptor signaling pathway / toll-like receptor TLR1 / toll-like receptor TLR6 / transcription, DNA-templated / TRIF-dependent toll-like receptor signaling pathway / vascular endothelial growth factor receptor signaling pathway
Components
cytoplasm / cytosol / extracellular exosome / nucleoplasm / nucleus
General Function
Protein serine/threonine kinase activity
Specific Function
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. Isoform MXI2 activation is stimulated by mitogens and oxidative stress and only poorly phosphorylates ELK1 and ATF2. Isoform EXIP may play a role in the early onset of apoptosis. Phosphorylates S100A9 at 'Thr-113'.
Pfam Domain Function
Transmembrane Regions
Not Available
Cellular Location
Cytoplasm
Gene sequence
>lcl|BSEQ0021282|Mitogen-activated protein kinase 14 (MAPK14)
ATGTCTCAGGAGAGGCCCACGTTCTACCGGCAGGAGCTGAACAAGACAATCTGGGAGGTG
CCCGAGCGTTACCAGAACCTGTCTCCAGTGGGCTCTGGCGCCTATGGCTCTGTGTGTGCT
GCTTTTGACACAAAAACGGGGTTACGTGTGGCAGTGAAGAAGCTCTCCAGACCATTTCAG
TCCATCATTCATGCGAAAAGAACCTACAGAGAACTGCGGTTACTTAAACATATGAAACAT
GAAAATGTGATTGGTCTGTTGGACGTTTTTACACCTGCAAGGTCTCTGGAGGAATTCAAT
GATGTGTATCTGGTGACCCATCTCATGGGGGCAGATCTGAACAACATTGTGAAATGTCAG
AAGCTTACAGATGACCATGTTCAGTTCCTTATCTACCAAATTCTCCGAGGTCTAAAGTAT
ATACATTCAGCTGACATAATTCACAGGGACCTAAAACCTAGTAATCTAGCTGTGAATGAA
GACTGTGAGCTGAAGATTCTGGATTTTGGACTGGCTCGGCACACAGATGATGAAATGACA
GGCTACGTGGCCACTAGGTGGTACAGGGCTCCTGAGATCATGCTGAACTGGATGCATTAC
AACCAGACAGTTGATATTTGGTCAGTGGGATGCATAATGGCCGAGCTGTTGACTGGAAGA
ACATTGTTTCCTGGTACAGACCATATTAACCAGCTTCAGCAGATTATGCGTCTGACAGGA
ACACCCCCCGCTTATCTCATTAACAGGATGCCAAGCCATGAGGCAAGAAACTATATTCAG
TCTTTGACTCAGATGCCGAAGATGAACTTTGCGAATGTATTTATTGGTGCCAATCCCCTG
GCTGTCGACTTGCTGGAGAAGATGCTTGTATTGGACTCAGATAAGAGAATTACAGCGGCC
CAAGCCCTTGCACATGCCTACTTTGCTCAGTACCACGATCCTGATGATGAACCAGTGGCC
GATCCTTATGATCAGTCCTTTGAAAGCAGGGACCTCCTTATAGATGAGTGGAAAAGCCTG
ACCTATGATGAAGTCATCAGCTTTGTGCCACCACCCCTTGACCAAGAAGAGATGGAGTCC
TGA
Chromosome Location
6
Locus
6p21.3-p21.2
External Identifiers
ResourceLink
UniProtKB IDQ16539
UniProtKB Entry NameMK14_HUMAN
GenBank Protein ID603917
GenBank Gene IDL35263
GenAtlas IDMAPK14
HGNC IDHGNC:6876
General References
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Drug Relations

Drug Relations
DrugBank IDNameDrug groupPharmacological action?ActionsDetails
DB017614-[5-[2-(1-Phenyl-Ethylamino)-Pyrimidin-4-Yl]-1-Methyl-4-(3-Trifluoromethylphenyl)-1h-Imidazol-2-Yl]-PiperidineexperimentalunknownDetails
DB01807N-[(3z)-5-Tert-Butyl-2-Phenyl-1,2-Dihydro-3h-Pyrazol-3-Ylidene]-N'-(4-Chlorophenyl)UreaexperimentalunknownDetails
DB019481-(2,6-Dichlorophenyl)-5-(2,4-Difluorophenyl)-7-Piperidin-4-Yl-3,4-Dihydroquinolin-2(1h)-OneexperimentalunknownDetails
DB01953Inhibitor of P38 KinaseexperimentalunknownDetails
DB019886((S)-3-Benzylpiperazin-1-Yl)-3-(Naphthalen-2-Yl)-4-(Pyridin-4-Yl)PyrazineexperimentalunknownDetails
DB021953-(4-Fluorophenyl)-1-Hydroxy-2-(Pyridin-4-Yl)-1h-Pyrrolo[3,2-B]PyridineexperimentalunknownDetails
DB022771-(5-Tert-Butyl-2-Methyl-2h-Pyrazol-3-Yl)-3-(4-Chloro-Phenyl)-UreaexperimentalunknownDetails
DB023523-(Benzyloxy)Pyridin-2-AmineexperimentalunknownDetails
DB028731-(2,6-Dichlorophenyl)-5-(2,4-Difluorophenyl)-7-Piperazin-1-Yl-3,4-Dihydroquinazolin-2(1h)-OneexperimentalunknownDetails
DB029844-[3-Methylsulfanylanilino]-6,7-DimethoxyquinazolineexperimentalunknownDetails
DB030441-(5-Tert-Butyl-2-P-Tolyl-2h-Pyrazol-3-Yl)-3-[4-(2-Morpholin-4-Yl-Ethoxy)-Naphthalen-1-Yl]-Ureaexperimental, investigationalunknownDetails
DB031102-ChlorophenolexperimentalunknownDetails
DB04338SB220025experimentalunknownDetails
DB046324-(2-HYDROXYBENZYLAMINO)-N-(3-(4-FLUOROPHENOXY)PHENYL)PIPERIDINE-1-SULFONAMIDEexperimentalunknownDetails
DB04797TriazolopyridineexperimentalunknownDetails
DB05412TalmapimodinvestigationalunknownDetails
DB05157KC706investigationalunknownDetails
DB05470VX-702investigationalunknownDetails
DB068821-[1-(3-aminophenyl)-3-tert-butyl-1H-pyrazol-5-yl]-3-naphthalen-1-ylureaexperimentalunknownDetails
DB06940N-ethyl-4-{[5-(methoxycarbamoyl)-2-methylphenyl]amino}-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamideexperimentalunknownDetails
DB06991N-[2-methyl-5-(methylcarbamoyl)phenyl]-2-{[(1R)-1-methylpropyl]amino}-1,3-thiazole-5-carboxamideexperimentalunknownDetails
DB07138NeflamapimodinvestigationalunknownDetails
DB07307N-cyclopropyl-4-methyl-3-[1-(2-methylphenyl)phthalazin-6-yl]benzamideexperimentalunknownDetails
DB074594-PHENOXY-N-(PYRIDIN-2-YLMETHYL)BENZAMIDEexperimentalunknownDetails
DB076074-[5-(3-IODO-PHENYL)-2-(4-METHANESULFINYL-PHENYL)-1H-IMIDAZOL-4-YL]-PYRIDINEexperimentalunknownDetails
DB07811N-cyclopropyl-2',6-dimethyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl-3-carboxamideexperimentalunknownDetails
DB078294-[3-(4-FLUOROPHENYL)-1H-PYRAZOL-4-YL]PYRIDINEexperimentalunknownDetails
DB078324-{4-[(5-hydroxy-2-methylphenyl)amino]quinolin-7-yl}-1,3-thiazole-2-carbaldehydeexperimentalunknownDetails
DB07833N-(3-cyanophenyl)-2'-methyl-5'-(5-methyl-1,3,4-oxadiazol-2-yl)-4-biphenylcarboxamideexperimentalunknownDetails
DB07834N-(cyclopropylmethyl)-2'-methyl-5'-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-carboxamideexperimentalunknownDetails
DB07835N~3~-cyclopropyl-N~4~'-(cyclopropylmethyl)-6-methylbiphenyl-3,4'-dicarboxamideexperimentalunknownDetails
DB07941PH-797804investigationalunknownDetails
DB079422-fluoro-4-[4-(4-fluorophenyl)-1H-pyrazol-3-yl]pyridineexperimentalunknownDetails
DB079432-{4-[5-(4-chlorophenyl)-4-pyrimidin-4-yl-1H-pyrazol-3-yl]piperidin-1-yl}-2-oxoethanolexperimentalunknownDetails
DB08064N-(3-TERT-BUTYL-1H-PYRAZOL-5-YL)-N'-{4-CHLORO-3-[(PYRIDIN-3-YLOXY)METHYL]PHENYL}UREAexperimentalunknownDetails
DB08068N-[4-CHLORO-3-(PYRIDIN-3-YLOXYMETHYL)-PHENYL]-3-FLUORO-experimentalunknownDetails
DB080913-FLUORO-5-MORPHOLIN-4-YL-N-[3-(2-PYRIDIN-4-YLETHYL)-1H-INDOL-5-YL]BENZAMIDEexperimentalunknownDetails
DB080923-fluoro-N-1H-indol-5-yl-5-morpholin-4-ylbenzamideexperimentalunknownDetails
DB080933-(1-NAPHTHYLMETHOXY)PYRIDIN-2-AMINEexperimentalunknownDetails
DB080953-(2-CHLOROPHENYL)-1-(2-{[(1S)-2-HYDROXY-1,2-DIMETHYLPROPYL]AMINO}PYRIMIDIN-4-YL)-1-(4-METHOXYPHENYL)UREAexperimentalunknownDetails
DB080968-(2-CHLOROPHENYLAMINO)-2-(2,6-DIFLUOROPHENYLAMINO)-9-ETHYL-9H-PURINE-1,7-DIIUMexperimentalunknownDetails
DB080972-(2,6-DIFLUOROPHENOXY)-N-(2-FLUOROPHENYL)-9-ISOPROPYL-9H-PURIN-8-AMINEexperimentalunknownDetails
DB08242N,4-dimethyl-3-[(1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]benzamideexperimentalunknownDetails
DB08349N-cyclopropyl-3-{[1-(2,4-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-4-yl]amino}-4-methylbenzamideexperimentalunknownDetails
DB08351N-cyclopropyl-4-methyl-3-{2-[(2-morpholin-4-ylethyl)amino]quinazolin-6-yl}benzamideexperimentalunknownDetails
DB083526-[4-(2-fluorophenyl)-1,3-oxazol-5-yl]-N-(1-methylethyl)-1,3-benzothiazol-2-amineexperimentalunknownDetails
DB083952-(ETHOXYMETHYL)-4-(4-FLUOROPHENYL)-3-[2-(2-HYDROXYPHENOXY)PYRIMIDIN-4-YL]ISOXAZOL-5(2H)-ONEexperimentalunknownDetails
DB08423[5-AMINO-1-(4-FLUOROPHENYL)-1H-PYRAZOL-4-YL][3-(PIPERIDIN-4-YLOXY)PHENYL]METHANONEexperimentalunknownDetails
DB08424[5-AMINO-1-(4-FLUOROPHENYL)-1H-PYRAZOL-4-YL](3-{[(2R)-2,3-DIHYDROXYPROPYL]OXY}PHENYL)METHANONEexperimentalunknownDetails
DB085214-[5-(4-FLUORO-PHENYL)-2-(4-METHANESULFINYL-PHENYL)-3H-IMIDAZOL-4-YL]-PYRIDINEexperimentalunknownDetails
DB039804-(Fluorophenyl)-1-Cyclopropylmethyl-5-(2-Amino-4-Pyrimidinyl)ImidazoleexperimentalunknownDetails
DB085224-(4-FLUOROPHENYL)-1-CYCLOROPROPYLMETHYL-5-(4-PYRIDYL)-IMIDAZOLEexperimentalunknownDetails
DB087303-FLUORO-5-MORPHOLIN-4-YL-N-[1-(2-PYRIDIN-4-YLETHYL)-1H-INDOL-6-YL]BENZAMIDEexperimentalunknownDetails
DB01254Dasatinibapproved, investigationalunknownDetails
DB12010Fostamatinibapproved, investigationalunknowninhibitorDetails
DB06518R-1487investigationalunknownDetails