MAPK14

MAPK14 contains 1 protein kinase domain and belongs to 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. MAPK14 can be detected in brain, heart, placenta, pancreas and skeletal muscle and it is expressed to a lesser extent in lung, liver and kidney. MAPK14 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 MAPK14. The substrates of p38 alpha include transcription regulator ATF2, MEF2C, and MAX, cell cycle regulator CDC25B, and tumor suppressor p53, which suggest the roles of p38 alpha in stress related transcription and cell cycle regulation, as well as in genotoxic stress response. In respond to activation by environmental stress, pro-inflammatory cytokines and lipopolysaccharide, MAPK14 phosphorylates a number of transcription factors, such as ELK1 and ATF2 and several downstream kinases, such as MAPKAPK2 and MAPKAPK5. MAPK14 plays a critical role in the production of some cytokines, for example IL-6. It may play a role in stabilization of EPO mRNA during hypoxic stress. Isoform Mxi2 activation is stimulated by mitogens and oxidative stress and only poorly phosphorylates ELK1 and ATF2.

MAPK14 Related Areas

Enzyme>>Protein Kinase>>Intracellular Kinase>>Mitogen-Activated Protein Kinase (MAPK)>>p38 alpha/MAPK14

Signal Transduction>>Protein Kinase>>Intracellular Kinase>>Mitogen-Activated Protein Kinase (MAPK)>>p38 alpha/MAPK14

MAPK14 Related Pathways

• VEGF Signaling
• Cytokine Receptor Signaling

MAPK14 Alternative Names

p38ALPHA, MAPK14, p38, CSBP1, CSBP2, Mxi2, PRKM14, PRKM15, RK, CSPB1, SAPK2A, EXIP, RP1-179N16.5 [Homo sapiens]

p38-alpha, Mapk14, p38, p38MAPK, p38a, p38alpha, Csbp1, CSBP2, Mxi2, PRKM14, PRKM15, Crk1, MGC102436, RP24-137E7.1 [Mus musculus]

Summaries for MAPK14

Entrez Gene summary for MAPK14:

The protein encoded by MAPK14 gene is a member of the MAP kinase family. MAPK14 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 MAPK14 gene encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

Wikipedia summary for MAPK14:

Mitogen-activated protein kinase 14, also called p38-α, is an enzyme that in humans is encoded by the MAPK14 gene.

The protein encoded by MAPK14 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 MAPK14 gene encoding distinct isoforms have been reported.

Human MAPK14 Protein General Information

 

• Protein names: Mitogen-activated protein kinase 14, Short name=MAPK 14
• Sequence length: 360 AA.
• Domain: The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.
• Sequence similarities: Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily. Contains 1 protein kinase domain.
• Post-translational modification: 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 a ctivates 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.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.
• Cofactor: Magnesium.
• Subunit structure: Binds to a kinase interaction motif within the protein tyrosine phosphatase, PTPRR By similarity. This interaction retains MAPK14 in the cytoplasm and prevents nuclear accumulation By similarity. Interacts with SPAG9 and GADD45A By similarity. Interacts with CDC25B, CDC25C, DUSP1, DUSP10, DUSP16, NP60, FAM48A and TAB1. Interacts with casein kinase II subunits CSNK2A1 and CSNK2B.
• Subcellular location: Cytoplasm. Nucleus
• Tissue specificity: Brain, heart, placenta, pancreas and skeletal muscle. Expressed to a lesser extent in lung, liver and kidney.
• Catalytic activity: ATP + a protein = ADP + a phosphoprotein.
• 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.

General information above from UniProt

Function for MAPK14 Protein

UniProtKB:

Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK14 is one of the four MAPK14s 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, MAPK14s 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 additionnal 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 MAPK14s, 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 MAPK14 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 MAPK14 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 MAPK14s as well. In response to inflammatory stimuli, MAPK14s 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 MAPK14 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 MAPK14 activation. In the nucleus, many transcription factors are phosphorylated and activated by MAPK14s in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A. The MAPK14s 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 MAPK14-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 MAPK14s 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.

Genatlas:

• serine/threonine kinase, MAPK14 may be playing a role in the early onset of apoptosis
• MAPK14 is involved in hypertrophic differentiation of chondrocytes
• MAPK14 is involved in cardiomyocyte proliferation and angiogenesis during development
• MAPK14 is involved in Sp1 phosphorylation
• MAPK14 mediates IL1A-induced down-regulation of aggrecan gene expression in chondrocytes
• MAPK14 may be regulating the early secretory pathway
• MAPK14 substrates of this kinase include ATF2, MEF2C, MAX, CDC25B, p53, suggesting a role in stress related transcription and cell cycle regulation
• MAPK14 controls myogenesis by antagonizing the activation of the JNK proliferation-promoting pathway, before its direct effect on muscle differentiation-specific gene transcription (fundamental role in muscle formation)
• recruited to muscle-specific gene promoters during muscle development suggesting that indeed MAPK14 might play an important role at the chromatin
• MAPK14 roles in activating CREB1 metabolic pathway in the events leading to erythroid differentiation)
• MAPK14's activity promotes timely checkpoint satisfaction by indirectly influencing the motor proteins (e.g., Klp10, Klp67A) involved in regulating the dynamics of kinetochore microtubule ends
• in intestinal epithelial cells MAPK14 contributes to the host immune responses against enteric bacteria by the recruitment of immune cells
• MAPK14 recruitment to target genes appears to be a broad mechanism to regulate transcription
• MAPK14's activity is not just necessary for gene promoter activation but might also be necessary for the nascent mRNA elongation of MAPK14-dependent genes
• MAPK14 regulates expression of osteoblast-specific genes by phosphorylation of osterix (SP7)
• MAPK14 maintains CDH1 expression by suppressing MAP3K7-NFKB signaling, thus impeding the induction of EMT in human primary mesothelial cells
• MAPK14 plays an important role in the regulation of hematopoietic stem cellself-renewal in vitro and inhibition of MAPK14 activation with a small molecule inhibitor may represent a novel approach to promote ex vivo expansion of hematopoietic stem cell
• MAPK14 controls prothrombin expression by regulated RNA 3prime end processing
• MAPK14 regulates G1-S transition in hypoxic cardiac fibroblasts
• MAPK14-signaling is a central pathway for the integration of instructive signals in dendritic cells for T(H)17 differentiation and inflammation

Homology for human MAPK14

• homolog to rattus Mapk14 (99,17 pc)
• homolog to murine Mapk14 (95,56 pc)

Drugs for MAPK14

Target	Drug Name	Disease	Drug Status
MAPK14	Dilmapimod	Acute lung injury & acute respiratory distress syndrome	Phase I
MAPK14	GSK610677	COPD	Phase I
MAPK14	Losmapimod	Cardiovascular disease, COPD and depression	Phase II

Drugs for MAPK14 from TTD (Therapeutic Targets Database)