Target name

P47811: Mitogen-activated protein kinase 14


  Protein 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. Phosphorylates S100A9 at 'Thr-113' (By similarity).

  Database links

Uniprot primary ID P47811
PDB ID 3P7A 3P7B 3P7C 2PUU 3P5K 2EWA 4LOQ 4LOP 1YW2 3PY3 4LOO 4KA3 2GTM 2GTN 3P4K 2OZA 1YWR 3P78 1P38 3TG1 1LEZ 3P79 1LEW 4TYH 2GHM 2GHL
DrugBank ID
BioGrid ID 204969
GuidetoPHARMACOLOGY ID
PharmGKB ID
KEGG ID mmu:26416
DIP ID DIP-31073N
STRING ID 10090.ENSMUSP00000004990
IntAct ID P47811
DMDM
BRENDA 2.7.11.24
Reactome R-MMU-418592 R-MMU-376172 R-MMU-2151209 R-MMU-168638 R-MMU-2559580 R-MMU-171007 R-MMU-432142 R-MMU-375170 R-MMU-450302 R-MMU-198753 R-MMU-450604 R-MMU-450341 R-MMU-4420097
SignaLink
BioCyc
Entrez Gene (Gene ID) 26416
BindingDB P47811

  Model Performance Metrics

Fingerprint type Sensitivity SEN_std Specificity SPE_std Accuracy ACC_std F1-score F1-score_std AUC AUC_std MCC MCC_std Download model
FP2 fingerprints 0.968 0.004 0.902 0.005 0.935 0.005 0.938 0.004 0.970 0.000 0.873 0.008 Download
Estate fingerprints 0.770 0.009 0.768 0.008 0.769 0.007 0.771 0.007 0.842 0.004 0.539 0.015 Download
MACCS fingerprints 0.930 0.007 0.810 0.003 0.870 0.000 0.879 0.003 0.940 0.000 0.747 0.005 Download
Daylight fingerprints 0.908 0.004 0.804 0.008 0.856 0.005 0.860 0.000 0.880 0.000 0.712 0.006 Download
ECFP2 fingerprints 1.000 0.000 0.890 0.011 0.945 0.005 0.947 0.005 0.990 0.000 0.894 0.007 Download
ECFP4 fingerprints 1.000 0.000 0.960 0.007 0.980 0.000 0.981 0.003 1.000 0.000 0.961 0.003 Download
ECFP6 fingerprints 0.997 0.005 0.983 0.004 0.990 0.005 0.990 0.005 1.000 0.000 0.982 0.008 Download

  Download datasets

Positive dataset Negative dataset


Copyright @ 2012-2014 Computational Biology & Drug Design Group,
School of Pharmaceutical Sciences, Central South University. All rights reserved.

The recommended browsers: Safari, Firefox, Chrome, IE(Ver.>8).
 E-mail: biomed@csu.edu.cn