p38γ MAPK Inflammatory and Metabolic Signaling in Physiology and Disease

p38? 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, p38? metabolic signaling is involved in physiological exercise and in pathogenesis of cancer, diabetes, and Alzheimer's disease, indicating its potential as a therapeutic target. p38?phosphorylates at least 19 substrates through which p38? activity is further modified to regulate life-important cellular processes such as proliferation, differentiation, cell death, and transformation, thereby impacting biological outcomes of p38?-driven pathogenesis. P38? 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 p38? inflammation and metabolic signaling in physiology and diseases. Moreover, we will discuss the progress in the development of p38?-specific pharmacological inhibitors for therapeutic intervention in disease prevention and treatment by targeting the p38? signaling network.