Nuclear P38: Roles in Physiological and Pathological Processes and Regulation of Nuclear Translocation

The p38 mitogen-activated protein kinase (p38MAPK, termed here p38) cascade is a central signaling pathway that transmits stress and other signals to various intracellular targets in the cytoplasm and nucleus. More than 150 substrates of p38α/β have been identified, and this number is likely to increase. The phosphorylation of these substrates initiates or regulates a large number of cellular processes including transcription, translation, RNA processing and cell cycle progression, as well as degradation and the nuclear translocation of various proteins. Being such a central signaling cascade, its dysregulation is associated with many pathologies, particularly inflammation and cancer. One of the hallmarks of p38α/β signaling is its stimulated nuclear translocation, which occurs shortly after extracellular stimulation. Although p38α/β do not contain nuclear localization or nuclear export signals, they rapidly and robustly translocate to the nucleus, and they are exported back to the cytoplasm within minutes to hours. Here, we describe the physiological and pathological roles of p38α/β phosphorylation, concentrating mainly on the ill-reviewed regulation of p38α/β substrate degradation and nuclear translocation. In addition, we provide information on the p38α/β ’s substrates, concentrating mainly on the nuclear targets and their role in p38α/β functions. Finally, we also provide information on the mechanisms of nuclear p38α/β translocation and its use as a therapeutic target for p38α/β-dependent diseases.