p38γ MAPK Inflammatory and Metabolic Signaling in Physiology and Disease

Abstract

p38γ MAPK (also called ERK6 or SAPK3) is a family member of stress-activated MAPKs and has common and specific roles as compared to other p38 proteins in signal transduction. Recent studies showed that, in addition to inflammation, p38γ metabolic signaling is involved in physiological exercise and in pathogenesis of cancer, diabetes, and Alzheimer's disease, indicating its potential as a therapeutic target. p38γphosphorylates at least 19 substrates through which p38γ activity is further modified to regulate life-important cellular processes such as proliferation, differentiation, cell death, and transformation, thereby impacting biological outcomes of p38γ-driven pathogenesis. P38γ signaling is characterized by its unique reciprocal regulation with its specific phosphatase PTPH1 and by its direct binding to promoter DNAs, leading to transcriptional activation of targets including cancer-like stem cell drivers. This paper will review recent findings about p38γ inflammation and metabolic signaling in physiology and diseases. Moreover, we will discuss the progress in the development of p38γ-specific pharmacological inhibitors for therapeutic intervention in disease prevention and treatment by targeting the p38γ signaling network.

Keywords: cancer; p38γ; signal transduction.

Figure 1

p38γ signaling network in diseases. The number after each protein indicates the reference number in which the phosphorylation was demonstrated. The reciprocal effects of p38γ and PTPH1 were illustrated with PTPH1 substrates (EGFR and ER) also listed. p38γ may cooperate with one or more substrates to impact pathogenesis of a disease (highlighted inside the box below) and one phosphorylation event may be involved in several diseases. * indicates a specific phosphorylation by p38γ and not by its family member p38α, whereas & shows a PDZ-dependent reaction. $ indicates that EGFR depends on p38γ PDZ motif and phosphorylation to form a complex with both p38γ and PTPH1.