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.

Pirfenidone ameliorates alcohol-induced promotion of breast cancer in mice

“…p38γ MAPK has been shown to regulate cell cycle transition, cell mobility, metastasis, EMT, CSC population, and tumorigenesis ( 10 , 36 – 39 ). Importantly, p38γ MAPK is overexpressed and implicated in several types of cancers including colorectal cancer, liver cancer, pancreatic cancer, and breast cancer ( 16 , 37 , 40 , 41 ); increased p38γ MAPK expression predicts a poor clinical prognosis ( 18 , 36 ).…”

“…Overexpression of p38γ MAPK increases CSCs and tumorspheres ( 38 ), suggesting that p38γ MAPK may regulate CSC population and cancer aggressiveness. Therefore, targeting p38γ MAPK signaling network could be an important strategy for therapeutic intervention of cancers ( 39 ). PFD is identified as a pharmacological inhibitor of p38γ MAPK ( 14 – 16 ).…”

“…Due to the regulatory role of p38γ MAPK in tumorigenesis and progression, development of more specific p38γ MAPK inhibitors other than PFD becomes an important and exciting future research direction. There are some p38γ MAPK inhibitors with varied efficacy and specificity ( 39 ). Recently, some novel p38γ MAPK inhibitors with higher specificity are developed ( 41 , 45 ).…”

Alzheimer's disease, a metabolic disorder: Clinical advances and basic model studies (Review)

“…The aforementioned results demonstrate the role of PKCα in regulating neuronal insulin resistance and diabetes and open new avenues for the treatment of metabolic disorders and neurodegeneration ( 34 ). P38γ signal transduction is characterized by its unique reciprocal regulation of the phosphatase protein tyrosine phosphatase H1 antibody, and by its direct binding to promoter DNA, which is also involved in the pathogenesis of diabetes and AD, suggesting its potential as a therapeutic target ( 35 ).…”

Lycium Barbarum Glycopeptide Alleviates Retinal Inflammation by Suppressing Microglial M1 Polarization via NF-κB/MAPK Pathways

“…The underlining pathways involved in microglial transformation are the nuclear factor-κB (NF-κB) p65 and mitogen-activated protein kinase (MAPK) p38, a set of signaling molecules that are pivotal in regulating the expression of pro-inflammatory cytokines [12,13]. Activation of the MAPK signaling pathway aids in mediating the production of pro-inflammatory factors by microglia following retinal injury [14].…”