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

Abstract

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/b functions. Finally, we also provide information on the mechanisms of nuclear p38α/b translocation and its use as a therapeutic target for p38α/β-dependent diseases.

Channeling macrophage polarization by rocaglates increases macrophage resistance to Mycobacterium tuberculosis

“…We propose that low doses of IFNγ are necessary to initiate the STAT1 dimer formation and binding to the IRF1 promoter, while the p38 activation by rocaglates and STAT1 Ser-727 phosphorylation boosts and sustains the Irf1 transcription, most likely, by facilitating interactions of STAT1 with transcriptional co-activators. This hypothesis is further supported by the fact that p38 is known to translocate to the nucleus and phosphorylate chromatin-associated substrates ( Maik-Rachline et al., 2020 ).…”

Osteoclasts Differentiation from Murine RAW 264.7 Cells Stimulated by RANKL: Timing and Behavior

“…Usually, p38 MAPK is localized in the cytoplasm of resting cells and translocates to the nucleus after extracellular stimulation [ 23 ]. The ability of p38 to shuttle to the nucleus and back after extracellular stimulation is well known, even though it does not contain nuclear localization or nuclear export signals [ 24 ]. Nevertheless, in a few cases, p38 has been detected in the nucleus of resting cells, thus, suggesting its dual ability to phosphorylate substrates in the cytoplasm as well as in the nucleus [ 24 ].…”

Atorvastatin Attenuates Isoflurane-Induced Activation of ROS-p38MAPK/ATF2 Pathway, Neuronal Degeneration, and Cognitive Impairment of the Aged Mice

“…p38MAPK is a member of the MAPKs, which are a family of serine-threonine protein kinases. The p38MAPK signaling pathway is mainly involved in the regulation of intracellular oxidative stress, inflammation, cell proliferation, and apoptosis ( Maik-Rachline et al, 2020 ). Various physical and chemical stimuli, such as ROS, could activate classic MAP3K MKK3/6 and further phosphorylate p38MAPK.…”