MAPK14

The protein encoded by this gene is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. This kinase is activated by various environmental stresses and proinflammatory cytokines. The activation requires its phosphorylation by MAP kinase kinases (MKKs), or its autophosphorylation triggered by the interaction of MAP3K7IP1/TAB1 protein with this kinase. The substrates of this kinase include transcription regulator ATF2, MEF2C, and MAX, cell cycle regulator CDC25B, and tumor suppressor p53, which suggest the roles of this kinase in stress related transcription and cell cycle regulation, as well as in genotoxic stress response. Four alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

Mitogen-Activated Protein Kinase 14

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 pro-inflammatory 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'.
(Microbial infection) Activated by phosphorylation by M.tuberculosis EsxA in T-cells leading to inhibition of IFN-gamma production; phosphorylation is apparent within 15 minutes and is inhibited by kinase-specific inhibitors SB203580 and siRNA (PubMed:21586573).

3'-UTR-mediated mRNA stabilizationManual Assertion Based On ExperimentTAS:UniProtKB
AngiogenesisIEA:Ensembl
Apoptotic processIEA:UniProtKB-KW
Bone developmentIEA:Ensembl
Cartilage condensationIEA:Ensembl
Cell morphogenesisIEA:Ensembl
Cell surface receptor signaling pathwayManual Assertion Based On ExperimentTAS:ProtInc
Cellular response to ionizing radiationManual Assertion Based On ExperimentIMP:BHF-UCL
Cellular response to lipopolysaccharideManual Assertion Based On ExperimentIDA:MGI
Cellular response to lipoteichoic acidManual Assertion Based On ExperimentIMP:UniProtKB
Cellular response to tumor necrosis factorIEA:Ensembl
Cellular response to vascular endothelial growth factor stimulusManual Assertion Based On ExperimentIMP:BHF-UCL
Cellular response to virusManual Assertion Based On ExperimentIMP:UniProtKB
Cellular senescenceTAS:Reactome
ChemotaxisManual Assertion Based On ExperimentTAS:ProtInc
Chondrocyte differentiationIEA:Ensembl
DNA damage checkpoint signalingIEA:Ensembl
Fatty acid oxidationIEA:Ensembl
Glucose metabolic processIEA:Ensembl
Intracellular signal transductionManual Assertion Based On ExperimentIDA:UniProtKB
Lipopolysaccharide-mediated signaling pathwayIEA:Ensembl
Negative regulation of canonical Wnt signaling pathwayIEA:Ensembl
Negative regulation of hippo signalingManual Assertion Based On ExperimentIMP:FlyBase
Negative regulation of inflammatory response to antigenic stimulusTAS:Reactome
Osteoblast differentiationIEA:Ensembl
Osteoclast differentiationISS:BHF-UCL
p38MAPK cascadeISS:UniProtKB
Peptidyl-serine phosphorylationISS:BHF-UCL
Placenta developmentIEA:Ensembl
Platelet activationTAS:Reactome
Positive regulation of brown fat cell differentiationIEA:Ensembl
Positive regulation of cardiac muscle cell proliferationIEA:Ensembl
Positive regulation of cyclase activityManual Assertion Based On ExperimentIMP:CACAO
Positive regulation of erythrocyte differentiationManual Assertion Based On ExperimentIMP:BHF-UCL
Positive regulation of gene expressionManual Assertion Based On ExperimentIMP:UniProtKB
Positive regulation of glucose importIEA:Ensembl
Positive regulation of interleukin-12 productionManual Assertion Based On ExperimentIMP:UniProtKB
Positive regulation of muscle cell differentiationTAS:Reactome
Positive regulation of myoblast differentiationISS:UniProtKB
Positive regulation of myoblast fusionISS:UniProtKB
Positive regulation of myotube differentiationISS:UniProtKB
Positive regulation of protein import into nucleusIEA:Ensembl
Positive regulation of reactive oxygen species metabolic processManual Assertion Based On ExperimentIMP:BHF-UCL
Positive regulation of transcription by RNA polymerase IIIEA:Ensembl
Regulation of cytokine production involved in inflammatory responseManual Assertion Based On ExperimentIDA:CACAO
Regulation of ossificationIEA:Ensembl
Regulation of synaptic membrane adhesionIEA:Ensembl
Regulation of transcription by RNA polymerase IIISS:UniProtKB
Response to dietary excessIEA:Ensembl
Response to insulinIEA:Ensembl
Response to muramyl dipeptideIEA:Ensembl
Response to muscle stretchIEA:Ensembl
Signal transductionManual Assertion Based On ExperimentTAS:ProtInc
Signal transduction in response to DNA damageManual Assertion Based On ExperimentIMP:BHF-UCL
Skeletal muscle tissue developmentIEA:Ensembl
Stress-induced premature senescenceManual Assertion Based On ExperimentIMP:BHF-UCL
Striated muscle cell differentiationIEA:Ensembl
Transmembrane receptor protein serine/threonine kinase signaling pathwayIEA:Ensembl
Vascular endothelial growth factor receptor signaling pathwayManual Assertion Based On ExperimentIMP:BHF-UCL

Cytoplasm
Nucleus

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. PPM1D also mediates dephosphorylation and inactivation of MAPK14 (PubMed:21283629).
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.
Ubiquitinated. Ubiquitination leads to degradation by the proteasome pathway.