Drug Target / Biomarker: MAPK14 (p38) (G1432)

NCBI ID: G1432

MAPK14

Drug Target / Biomarker: MAPK14 (p38)

p38 signaling pathway and apoptosis in T2DM and periodontitis patients: The p38 signaling pathway plays a role in upregulating apoptosis in neutrophils, leading to efficient reduction of neutrophils in individuals with type 2 diabetes mellitus (T2DM) and periodontitis.

p38's role in repair and recruitment to DNA damage: Inhibition of p38 signaling affects repair and recruitment to DNA damage caused by oxidative stress.

p38 MAPK pathway in response to oxidative stress: Under moderate oxidative stress, the p38 MAPK pathway is inactivated through ZNF32-dependent regulation, promoting cell survival. However, excessive oxidative stress activates the p38 MAPK pathway, leading to cell death.

Positive-feedback circuit involving p38 and GATA-2: Activation of p38 and ERK signaling by GATA-2 stimulates AML cell proliferation and upregulates the expression of cytokines such as IL1B and CXCL2, forming a positive-feedback circuit.

p38 activation in drug-tolerant breast cancer cells: under drug stress, sustained p38 activation is associated with a phenotype switch towards a drug-tolerant state in breast cancer cells. Inhibition of p38 can potentially reduce Bcl-2 expression and increase cell death.

Overall, p38 MAPK plays a significant role in various biological processes, including apoptosis, DNA damage response, oxidative stress, cell proliferation, and drug tolerance.
Based on the given context information, here are some key viewpoints regarding p38 MAPK (MAPK14):

Knockdown of KLF5 sensitizes cells to cisplatin, indicating that p38 MAPK may play a role in cisplatin resistance.
Activation of p38 MAPK is involved in the IL-1 signaling pathway, leading to the phosphorylation of JNK and p38.

CD40-CD40L interaction recruits TRAFs and activates multiple signaling pathways including p38 MAPK.

The p38 MAPK axis is implicated in regulating the expression of pro-angiogenic and anti-angiogenic factors in the retinal pigment epithelium of the diabetic retina.

LRRC8A triggers WNK activation, which in turn promotes regulatory volume increase (RVI) and cell survival under hypertonic conditions, potentially through p38 MAPK phosphorylation.

These viewpoints suggest that p38 MAPK is involved in various cellular processes, including drug resistance, IL-1 signaling, CD40-mediated signaling, angiogenesis, and cell survival under hypertonic conditions.

Protein Name: Mitogen-activated Protein Kinase 14

Functions: 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 (PubMed:9687510, PubMed:9792677). 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 (PubMed:9687510, PubMed:9792677). 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 (PubMed:11154262). MAPK14 interacts also with casein kinase II, leading to its activation through autophosphorylation and further phosphorylation of TP53/p53 (PubMed:10747897). 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 (PubMed:17003045). MAPK14 may also inhibit the lysosomal degradation pathway of autophagy by interfering with the intracellular trafficking of the transmembrane protein ATG9 (PubMed:19893488). 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 (PubMed:16932740). 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 (PubMed:20188673). 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 (PubMed:9430721, PubMed:9858528, PubMed:10330143). 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 (PubMed:11333986). Phosphorylates TIAR following DNA damage, releasing TIAR from GADD45A mRNA and preventing mRNA degradation (PubMed:20932473). 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

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