MAPK14

Description

The MAPK14 (mitogen-activated protein kinase 14) is a protein-coding gene located on chromosome 6.

Mitogen-activated protein kinase 14, also called p38-α, is an enzyme that in humans is encoded by the MAPK14 gene. MAPK14 encodes p38α mitogen-activated protein kinase (MAPK) which is the prototypic member of the p38 MAPK family. p38 MAPKs are also known as stress-activated serine/threonine-specific kinases (SAPKs). In addition to MAPK14 for p38α MAPK, the p38 MAPK family has three additional members, including MAPK11, MAPK12 and MAPK13 which encodes p38β MAPK, p38γ MAPK and p38δ MAPK isoforms, respectively. p38α MAPK was originally identified as a tyrosine phosphorylated protein detected in activated immune cell macrophages with an essential role in inflammatory cytokine induction, such as Tumor Necrotic Factor α (TNFα). However, p38α MAPK mediated kinase activity has been implicated in many tissues beyond immune systems. p38α MAPK is mainly activated through MAPK kinase kinase cascades and exerts its biological function via downstream substrate phosphorylation. p38α MAPK is implicated in diverse cellular functions, from gene expression to programmed cell death through a network of signaling molecules and transcription factors. Pharmacological and genetic inhibition of p38α MAPK not only revealed its biological significance in physiological function but also the potential of targeting p38α MAPK in human disease such as immune disorders and heart failure.

== Structure == MAPK14 is a 41 kDa protein composed of 360 amino acids.

MAPK14 is a serine/threonine kinase involved in the MAP kinase signal transduction pathway. It is one of the four p38 MAPKs, which are activated by extracellular stimuli, such as pro-inflammatory cytokines or physical stress, and directly activate transcription factors. p38 MAPKs have a broad range of substrates, estimated to be 200-300. Some substrates are downstream kinases, which are activated by phosphorylation, further phosphorylating additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 directly phosphorylate and activate transcription factors, including CREB1, ATF1, RELA/NFKB3, STAT1, and STAT3, and can also phosphorylate histone H3 and HMGN1. RPS6KA5/MSK1 and RPS6KA4/MSK2 play key roles in rapid induction of immediate-early genes by chromatin remodeling or recruiting the transcription machinery. MAPKAPK2/MK2 and MAPKAPK3/MK3 control gene expression at the post-transcriptional level by phosphorylating ZFP36, ELAVL1, and EEF2K, important for mRNA elongation. MKNK1/MNK1 and MKNK2/MNK2 regulate protein synthesis by phosphorylating EIF4E2. MAPK14 interacts with casein kinase II, leading to activation through autophosphorylation and TP53/p53 phosphorylation. In the cytoplasm, the p38 MAPK pathway regulates protein turnover. For example, CFLAR, an inhibitor of TNF-induced apoptosis, is degraded by the proteasome, regulated by p38 MAPK phosphorylation. MAPK14 phosphorylates the ubiquitin ligase SIAH2, regulating its activity towards EGLN3. MAPK14 may inhibit autophagy by interfering with ATG9 trafficking. It also regulates membrane receptor endocytosis by affecting RAB5A. Clathrin-mediated EGFR internalization is dependent on MAPK14 phosphorylation of EGFR and RAB5A effectors. p38 MAPKs regulate ectodomain shedding of transmembrane proteins. They phosphorylate ADAM17 in response to inflammatory stimuli, leading to TGF-alpha family ligand shedding, EGFR signaling activation, and cell proliferation. FGFR1 is another p38 MAPK substrate, translocated from the extracellular space to the cytosol and nucleus, regulating rRNA synthesis and cell growth. This translocation requires p38 MAPK activation. In the nucleus, p38 MAPKs phosphorylate and activate various transcription factors, including ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53, MEF2C, and MEF2A. p38 MAPKs regulate gene expression by modifying and remodeling chromatin. IL6, IL8, and IL12B promoters show p38 MAPK-dependent enrichment of H3S10ph in LPS-stimulated myeloid cells. This phosphorylation enhances NF-kappa-B binding site accessibility, leading to increased NF-kappa-B recruitment. MAPK14 phosphorylates CDC25B and CDC25C, required for 14-3-3 protein binding, initiating G2 delay after UV radiation. It also phosphorylates TIAR following DNA damage, releasing TIAR from GADD45A mRNA and preventing mRNA degradation. p38 MAPKs may have kinase-independent roles, binding to targets without phosphorylation. MAPK14 regulates OGT activity by interacting with it, even though OGT is not phosphorylated by MAPK14. This interaction is increased by glucose deprivation and may recruit OGT to targets like neurofilament H, stimulating O-Glc-N-acylation. MAPK14 is essential for mid-fetal blood vessel growth in the placenta and for developmental and stress-induced erythropoiesis by regulating EPO gene expression. Isoform MXI2 is activated by mitogens and oxidative stress, weakly phosphorylating ELK1 and ATF2. Isoform EXIP may contribute to early apoptosis. MAPK14 phosphorylates S100A9 at Thr-113. It phosphorylates NLRP1 downstream of MAP3K20/ZAK in response to UV-B irradiation and ribosome collisions, activating the NLRP1 inflammasome and pyroptosis. MAPK14 is activated by phosphorylation by M.tuberculosis EsxA in T-cells, inhibiting IFN-gamma production. This phosphorylation occurs within 15 minutes and is blocked by SB203580 and siRNA. MAPK14 is part of a signaling complex containing AKAP13, PKN1, MAPK14, ZAK, and MAP2K3. Within this complex, AKAP13 interacts with PKN1, which recruits MAPK14, MAP2K3, and ZAK. MAPK14 binds to a kinase interaction motif in PTPRR, keeping it in the cytoplasm and preventing nuclear accumulation. It interacts with SPAG9, GADD45A, CDC25B, CDC25C, DUSP1, DUSP10, DUSP16, NP60, SUPT20H, TAB1, CSNK2A1, CSNK2B, PPM1D, and CDK5RAP3. It recruits PPM1D to MAPK14, potentially regulating its dephosphorylation. MAPK14 interacts with DUSP2, which does not activate DUSP2 or dephosphorylate MAPK14.

MAPK14 is also known as CSBP, CSBP1, CSBP2, CSPB1, EXIP, Mxi2, PRKM14, PRKM15, RK, SAPK2A, p38, p38ALPHA.

Associated Diseases

WES Whole Exome Sequencing