InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: MAPK14

Summary

InnateDB Protein

IDBP-84617.7

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

MAPK14

Protein Name

mitogen-activated protein kinase 14

Synonyms

CSBP; CSBP1; CSBP2; CSPB1; EXIP; Mxi2; p38; p38ALPHA; PRKM14; PRKM15; RK; SAPK2A;

Species

Homo sapiens

Ensembl Protein

ENSP00000229795

InnateDB Gene

IDBG-84613 (MAPK14)

Protein Structure

UniProt Annotation

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'. {ECO:0000269PubMed:10330143, ECO:0000269PubMed:10747897, ECO:0000269PubMed:10943842, ECO:0000269PubMed:11154262, ECO:0000269PubMed:11333986, ECO:0000269PubMed:15905572, ECO:0000269PubMed:16932740, ECO:0000269PubMed:17003045, ECO:0000269PubMed:17724032, ECO:0000269PubMed:19893488, ECO:0000269PubMed:20188673, ECO:0000269PubMed:20932473, ECO:0000269PubMed:9430721, ECO:0000269PubMed:9687510, ECO:0000269PubMed:9792677, ECO:0000269PubMed:9858528}.

Subcellular Localization

Cytoplasm. Nucleus.

Disease Associations

Tissue Specificity

Brain, heart, placenta, pancreas and skeletal muscle. Expressed to a lesser extent in lung, liver and kidney.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 255 experimentally validated interaction(s) in this database.
They are also associated with 31 interaction(s) predicted by orthology.

Experimentally validated
Total	255 [view]
Protein-Protein	253 [view]
Protein-DNA	1 [view]
Protein-RNA	0
DNA-DNA	1 [view]
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	31 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0004672	protein kinase activity
GO:0004674	protein serine/threonine kinase activity
GO:0004707	MAP kinase activity
GO:0004708	MAP kinase kinase activity
GO:0004713	protein tyrosine kinase activity
GO:0005515	protein binding
GO:0005524	ATP binding
GO:0016301	kinase activity
GO:0016772	transferase activity, transferring phosphorus-containing groups
GO:0016773	phosphotransferase activity, alcohol group as acceptor
GO:0051525	NFAT protein binding

Biological Process

GO:0000077	DNA damage checkpoint
GO:0000187	activation of MAPK activity
GO:0000902	cell morphogenesis
GO:0001502	cartilage condensation
GO:0001525	angiogenesis
GO:0002062	chondrocyte differentiation
GO:0002224	toll-like receptor signaling pathway
GO:0002755	MyD88-dependent toll-like receptor signaling pathway
GO:0002756	MyD88-independent toll-like receptor signaling pathway
GO:0006006	glucose metabolic process
GO:0006351	transcription, DNA-templated
GO:0006355	regulation of transcription, DNA-templated
GO:0006357	regulation of transcription from RNA polymerase II promoter
GO:0006468	protein phosphorylation
GO:0006915	apoptotic process
GO:0006928	cellular component movement
GO:0006935	chemotaxis
GO:0006974	cellular response to DNA damage stimulus
GO:0007165	signal transduction
GO:0007166	cell surface receptor signaling pathway
GO:0007178	transmembrane receptor protein serine/threonine kinase signaling pathway
GO:0007265	Ras protein signal transduction
GO:0007519	skeletal muscle tissue development
GO:0007596	blood coagulation
GO:0009103	lipopolysaccharide biosynthetic process
GO:0010467	gene expression
GO:0010831	positive regulation of myotube differentiation
GO:0014835	myoblast differentiation involved in skeletal muscle regeneration
GO:0016070	RNA metabolic process
GO:0016071	mRNA metabolic process
GO:0018105	peptidyl-serine phosphorylation
GO:0019395	fatty acid oxidation
GO:0030168	platelet activation
GO:0030316	osteoclast differentiation
GO:0031663	lipopolysaccharide-mediated signaling pathway
GO:0032495	response to muramyl dipeptide
GO:0032496	response to lipopolysaccharide
GO:0034134	toll-like receptor 2 signaling pathway
GO:0034138	toll-like receptor 3 signaling pathway
GO:0034142	toll-like receptor 4 signaling pathway
GO:0034146	toll-like receptor 5 signaling pathway
GO:0034162	toll-like receptor 9 signaling pathway
GO:0034166	toll-like receptor 10 signaling pathway
GO:0035556	intracellular signal transduction
GO:0035666	TRIF-dependent toll-like receptor signaling pathway
GO:0035924	cellular response to vascular endothelial growth factor stimulus
GO:0038066	p38MAPK cascade
GO:0038123	toll-like receptor TLR1:TLR2 signaling pathway
GO:0038124	toll-like receptor TLR6:TLR2 signaling pathway
GO:0042307	positive regulation of protein import into nucleus
GO:0042692	muscle cell differentiation
GO:0042770	signal transduction in response to DNA damage
GO:0045087	innate immune response (InnateDB)
GO:0045648	positive regulation of erythrocyte differentiation
GO:0045663	positive regulation of myoblast differentiation
GO:0045944	positive regulation of transcription from RNA polymerase II promoter
GO:0048010	vascular endothelial growth factor receptor signaling pathway
GO:0048011	neurotrophin TRK receptor signaling pathway
GO:0051090	regulation of sequence-specific DNA binding transcription factor activity
GO:0051146	striated muscle cell differentiation
GO:0051149	positive regulation of muscle cell differentiation
GO:0051403	stress-activated MAPK cascade
GO:0070935	3'-UTR-mediated mRNA stabilization
GO:0071222	cellular response to lipopolysaccharide
GO:0071479	cellular response to ionizing radiation
GO:0090090	negative regulation of canonical Wnt signaling pathway
GO:0090400	stress-induced premature senescence
GO:1901741	positive regulation of myoblast fusion
GO:2000379	positive regulation of reactive oxygen species metabolic process

Cellular Component

GO:0000922	spindle pole
GO:0005623	cell
GO:0005634	nucleus
GO:0005654	nucleoplasm
GO:0005737	cytoplasm
GO:0005739	mitochondrion
GO:0005829	cytosol
GO:0016020	membrane
GO:0070062	extracellular vesicular exosome

Protein Structure and Domains

PDB ID

InterPro

IPR000719 Protein kinase domain
IPR001245 Serine-threonine/tyrosine-protein kinase catalytic domain
IPR002290 Serine/threonine/dual specificity protein kinase, catalytic domain
IPR008352 Mitogen-activated protein (MAP) kinase, p38
IPR010440 Lipopolysaccharide kinase
IPR011009 Protein kinase-like domain
IPR020635 Tyrosine-protein kinase, catalytic domain

PFAM

PF00069
PF07714
PF06293

PRINTS

PR00109
PR01773

PIRSF

SMART

SM00220
SM00219

TIGRFAMs

Post-translational Modifications

Modification

Cross-References

SwissProt