InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: MAPK11

Summary

InnateDB Protein

IDBP-13125.6

Last Modified

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

Gene Symbol

MAPK11

Protein Name

mitogen-activated protein kinase 11

Synonyms

p38-2; P38B; p38Beta; P38BETA2; PRKM11; SAPK2; SAPK2B;

Species

Homo sapiens

Ensembl Protein

ENSP00000333685

InnateDB Gene

IDBG-13123 (MAPK11)

Protein Structure

UniProt Annotation

Function

Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK11 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. MAPK11 functions are mostly redundant with those of MAPK14. 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. 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. 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. Additional examples of p38 MAPK substrates are the 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. {ECO:0000269PubMed:10330143, ECO:0000269PubMed:11154262, ECO:0000269PubMed:15356147, ECO:0000269PubMed:9430721, ECO:0000269PubMed:9687510}.

Subcellular Localization

Cytoplasm {ECO:0000250}. Nucleus {ECO:0000250}.

Disease Associations

Tissue Specificity

Highest levels in the brain and heart. Also expressed in the placenta, lung, liver, skeletal muscle, kidney and pancreas.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 50 experimentally validated interaction(s) in this database.
They are also associated with 4 interaction(s) predicted by orthology.

Experimentally validated
Total	50 [view]
Protein-Protein	49 [view]
Protein-DNA	0
Protein-RNA	0
DNA-DNA	1 [view]
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	4 [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:0004713	protein tyrosine kinase activity
GO:0005515	protein binding
GO:0005524	ATP binding
GO:0016772	transferase activity, transferring phosphorus-containing groups
GO:0016773	phosphotransferase activity, alcohol group as acceptor

Biological Process

GO:0000187	activation of MAPK activity
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:0006351	transcription, DNA-templated
GO:0006468	protein phosphorylation
GO:0006950	response to stress
GO:0007165	signal transduction
GO:0007265	Ras protein signal transduction
GO:0009103	lipopolysaccharide biosynthetic process
GO:0010467	gene expression
GO:0016070	RNA metabolic process
GO:0016071	mRNA metabolic process
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:0038123	toll-like receptor TLR1:TLR2 signaling pathway
GO:0038124	toll-like receptor TLR6:TLR2 signaling pathway
GO:0042692	muscle cell differentiation
GO:0045087	innate immune response
GO:0048011	neurotrophin TRK receptor signaling pathway
GO:0051090	regulation of sequence-specific DNA binding transcription factor activity
GO:0051149	positive regulation of muscle cell differentiation
GO:0051403	stress-activated MAPK cascade

Cellular Component

GO:0005654	nucleoplasm
GO:0005829	cytosol
GO:0016020	membrane

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
IPR008351 Mitogen-activated protein (MAP) kinase, JNK
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
PR01772
PR01773

PIRSF

SMART

SM00220
SM00219

TIGRFAMs

Post-translational Modifications

Modification

Cross-References

SwissProt