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

Galia Maik-Rachline,Lucia Lifshits,Rony Seger

doi:10.3390/ijms21176102

Galia Maik-Rachline, Lucia Lifshits + Show 1 more

Open Access

https://doi.org/10.3390/ijms21176102

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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/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.

Highlights

The p38 mitogen-activated protein kinase (p38MAPK, termed here p38) is a signaling protein kinase that operates within a signaling cascade to transmit extracellular signals to their intracellular targets
We focus on p38 [9,10], whose cascade is composed of many kinases at the MAP4K and MAP3K levels, MKK3/6, and perhaps MKK4 at the MAPKK tier, p38α−δ at the MAPK tier, and several MKs at the tier (MNK1/2, MSK1/2, MK2/3, and MK5)
We demonstrated that the nuclear translocation of p38α/β is important for the induction of inflammation, which may further lead to the development of some cancers

Summary

Introduction

The p38 mitogen-activated protein kinase (p38MAPK, termed here p38) is a signaling protein kinase that operates within a signaling cascade to transmit extracellular signals to their intracellular targets. Additional information has been accumulated over the years on the role of p38α/β in activating their downstream protein kinases (MKs), transcription factors, and other regulatory elements [6,9] The phosphorylation of these substrates is important for orchestrating the various cellular processes that may be, under certain circumstances, opposing signals. A list of various p38α/β substrates, which includes several transcription factors but mostly other proteins (Table 1), indicates that about 30% of the p38α/β substrates are confined to the nucleus under most/all conditions, and their phosphorylation upon stimulation should be nuclear Almost all these proteins were shown to participate in the regulation of cancer and inflammation at least under some conditions. The results demonstrate that inhibiting the nuclear translocation of p38α/β may serve as a therapeutic strategy to combat various cancers as well as inflammatory diseases (Table 1)

Role of Phosphorylation

Involvement in Cancer

Involvement in Inflammation

Localization Nuclear Export

Findings

Concluding Remarks