Names & Taxonomy

Uniprot ID:
Q16539
Entry Name:
MK14_HUMAN
Status:
reviewed
Protein Names:
Mitogen-activated protein kinase 14 (MAP kinase 14) (MAPK 14) (EC 2.7.11.24) (Cytokine suppressive anti-inflammatory drug-binding protein) (CSAID-binding protein) (CSBP) (MAP kinase MXI2) (MAX-interacting protein 2) (Mitogen-activated protein kinase p38 alpha) (MAP kinase p38 alpha) (Stress-activated protein kinase 2a) (SAPK2a)
Gene Names:
MAPK14 CSBP CSBP1 CSBP2 CSPB1 MXI2 SAPK2A
Gene Names Primary:
MAPK14
Organism:
Homo sapiens (Human)

Structure

Length:
360
Sequence:
MSQERPTFYRQELNKTIWEVPERYQNLSPVGSGAYGSVCAAFDTKTGLRVAVKKLSRPFQSIIHAKRTYRELRLLKHMKHENVIGLLDVFTPARSLEEFNDVYLVTHLMGADLNNIVKCQKLTDDHVQFLIYQILRGLKYIHSADIIHRDLKPSNLAVNEDCELKILDFGLARHTDDEMTGYVATRWYRAPEIMLNWMHYNQTVDIWSVGCIMAELLTGRTLFPGTDHIDQLKLILRLVGTPGAELLKKISSESARNYIQSLTQMPKMNFANVFIGANPLAVDLLEKMLVLDSDKRITAAQALAHAYFAQYHDPDDEPVADPYDQSFESRDLLIDEWKSLTYDEVISFVPPPLDQEEMES
Proteomes:
UP000005640

Subcellular location

Subcellular Location:
Cytoplasm

Function

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'.
Catalytic Activity:
ATP + a protein = ADP + a phosphoprotein.
Cofactor:
COFACTOR: Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
Enzyme Regulation:
ENZYME REGULATION: 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). Isoform Mxi2 is 100-fold less sensitive to these agents than the other isoforms and is not inhibited by DUSP1. Isoform Exip is not activated by MAP2K6. SB203580 is an inhibitor of MAPK14.
Active Site:
ACT_SITE 168 168 Proton acceptor.
Gene Ontology Go:
cytoplasm
cytosol
extracellular exosome
mitochondrion
nucleoplasm
nucleus
spindle pole
ATP binding
enzyme binding
MAP kinase activity
MAP kinase kinase activity
NFAT protein binding
protein phosphatase binding
protein serine/threonine kinase activity
3'-UTR-mediated mRNA stabilization
activation of MAPK activity
angiogenesis
apoptotic process
blood coagulation
cartilage condensation
cell morphogenesis
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
chondrocyte differentiation
DNA damage checkpoint
fatty acid oxidation
gene expression
glucose metabolic process
innate immune response
intracellular signal transduction
lipopolysaccharide-mediated signaling pathway
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
myoblast differentiation involved in skeletal muscle regeneration
negative regulation of canonical Wnt signaling pathway
neurotrophin TRK receptor signaling pathway
organelle organization
osteoclast differentiation
p38MAPK cascade
peptidyl-serine phosphorylation
placenta development
platelet activation
positive regulation of brown fat cell differentiation
positive regulation of cardiac muscle cell proliferation
positive regulation of cyclase activity
positive regulation of erythrocyte differentiation
positive regulation of gene expression
positive regulation of glucose import
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 protein import into nucleus
positive regulation of reactive oxygen species metabolic process
positive regulation of transcription from RNA polymerase II promoter
protein autophosphorylation
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
response to glucose
response to muramyl dipeptide
response to muscle stretch
signal transduction
signal transduction in response to DNA damage
skeletal muscle tissue development
stress-activated MAPK cascade
stress-induced premature senescence
striated muscle cell differentiation
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:TLR2 signaling pathway
toll-like receptor TLR6:TLR2 signaling pathway
transcription, DNA-templated
transmembrane receptor protein serine/threonine kinase signaling pathway
TRIF-dependent toll-like receptor signaling pathway
vascular endothelial growth factor receptor signaling pathway
Gene Ontology Biological Process:
3'-UTR-mediated mRNA stabilization
activation of MAPK activity
angiogenesis
apoptotic process
blood coagulation
cartilage condensation
cell morphogenesis
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
chondrocyte differentiation
DNA damage checkpoint
fatty acid oxidation
gene expression
glucose metabolic process
innate immune response
intracellular signal transduction
lipopolysaccharide-mediated signaling pathway
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
myoblast differentiation involved in skeletal muscle regeneration
negative regulation of canonical Wnt signaling pathway
neurotrophin TRK receptor signaling pathway
organelle organization
osteoclast differentiation
p38MAPK cascade
peptidyl-serine phosphorylation
placenta development
platelet activation
positive regulation of brown fat cell differentiation
positive regulation of cardiac muscle cell proliferation
positive regulation of cyclase activity
positive regulation of erythrocyte differentiation
positive regulation of gene expression
positive regulation of glucose import
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 protein import into nucleus
positive regulation of reactive oxygen species metabolic process
positive regulation of transcription from RNA polymerase II promoter
protein autophosphorylation
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
response to glucose
response to muramyl dipeptide
response to muscle stretch
signal transduction
signal transduction in response to DNA damage
skeletal muscle tissue development
stress-activated MAPK cascade
stress-induced premature senescence
striated muscle cell differentiation
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:TLR2 signaling pathway
toll-like receptor TLR6:TLR2 signaling pathway
transcription, DNA-templated
transmembrane receptor protein serine/threonine kinase signaling pathway
TRIF-dependent toll-like receptor signaling pathway
vascular endothelial growth factor receptor signaling pathway
Gene Ontology Molecular Function:
ATP binding
enzyme binding
MAP kinase activity
MAP kinase kinase activity
NFAT protein binding
protein phosphatase binding
protein serine/threonine kinase activity
Gene Ontology Cellular Component:
cytoplasm
cytosol
extracellular exosome
mitochondrion
nucleoplasm
nucleus
spindle pole
Keywords:
3D-structure
ATP-binding
Acetylation
Alternative splicing
Apoptosis
Complete proteome
Cytoplasm
Direct protein sequencing
Kinase
Nucleotide-binding
Nucleus
Phosphoprotein
Polymorphism
Reference proteome
Serine/threonine-protein kinase
Stress response
Transcription
Transcription regulation
Transferase
Ubl conjugation
Interacts With:
P31749; P28562; Q99956; P46734; P28482; P27361; P49137; Q16644; Q9BUB5; Q9HBH9; P49790; P35813; P35236; Q15256; P06400; O75676; Q8NEM7; Q15750; Q92574; Q07352; O43257

Publication

PubMed ID:
7997261 7696354 7479834 10727080 11866441 19906316 14702039 14574404 15489334 12665801 7923354 7535770 7493921 8622669 9687510 9430721 9792677 10391943 9858528 10330143 10943842 10838079 10747897 11010976 11278799 11359773 11154262 11333986 11847341 15284239 15905572 15592455 15735648 15735649 16751104 16932740 17003045 16352664 17724032 17525332 18088087 18691976 18669648 19369195 19690332 19893488 20932473 20188673 20068231 21269460 21224381 21444723 21283629 12452429 20626350 24275569 25944712 8910361 9095200 9753691 10633045 11896401 12482439 14561090 12897767 14726206 16342939 15837335 16169718 15658854 17255097 17344846