a proline-directed ser/thr MAP kinase, and one of four p38 kinases that play important roles in cellular responses to inflammatory cytokines, DNA damage, oxidative stress, and some GPCRs. Directly activate transcription factors and of other downstream kinases including MSK1, MSK2, eEF2K, MK2, and PRAK. MSK1 and -2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli. MK2 and -3 control gene expression mostly at the post-transcriptional level. eEF2K is important for the elongation of mRNA during translation. 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, which then cleaves the ectodomain of TGF-alpha family ligands, a process leading to the activation of EGFR signaling and cell proliferation. 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, CHOPO, 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. Interacts directly with HDAC3 interacts directly and selectively to repress ATF2 transcriptional activity, and regulate TNF gene expression in LPS-stimulated cells. Plays a role in myoblast differentiation and also in the down-regulation of cyclin D1 in response to hypoxia in adrenal cells suggesting that it may inhibit cell proliferation while promoting differentiation. Regulates UV-induced checkpoint signaling and repair of UV-induced DNA damage and G2 arrest after gamma-radiation exposure. Involved in the regulation of GLUT1 expression and basal glucose uptake in L6 myotubes; and negatively regulates GLUT4 expression and contraction-mediated glucose uptake in adult skeletal muscle. C- Jun phosphorylation is stimulated by p38-alpha and inhibited by p38-gamma, leading to a distinct AP-1 regulation. Required for the normal kinetochore localization of PLK1, prevents chromosomal instability and supports mitotic cell viability. Positively regulates the expansion of transient amplifying myogenic precursor cells during muscle growth and regeneration. Its expression is down-regulation by p38-alpha activation. Highly expressed in skeletal muscle and heart. Note: This description may include information from UniProtKB.
Protein type: EC 18.104.22.168; Kinase, protein; Protein kinase, Ser/Thr (non-receptor); Protein kinase, CMGC; CMGC group; MAPK family; MAPK/p38 subfamily; p38 subfamily
SS: The number of records in which this modification site was determined using site-specific methods. SS methods include amino acid sequencing, site-directed mutagenesis, modification site-specific antibodies, specific MS strategies, etc.