PEA15, also known as Phospho-enriched protein in astrocytes 15kDa, is a protein primarily found in the central nervous system, particularly in astrocytes. This protein contains a death effector domain (DED) and plays a crucial role in regulating various cellular functions, including cell death (apoptosis), cell growth and division (proliferation), glucose uptake and utilization, cell adhesion, and cell movement (migration). Notably, elevated levels of PEA15 have been linked to the development and progression of cancer, and its overexpression is observed in conditions like breast cancers, gliomas, and type 2 diabetes. PEA15 exerts its effects by influencing multiple signaling pathways within cells. It counteracts the inhibitory action of Ras on integrin activation, modulates the ERK MAP kinase signaling cascade, and sequesters RPS6KA3 in the cytoplasm, inhibiting its activity. Furthermore, PEA15 suppresses the activity of CASP8, a key protein involved in apoptosis, mediated by both TNFRSF6 and TNFRSF1A receptors. PEA15 is found throughout the body, with higher concentrations in tissues that heavily rely on glucose for energy, such as the heart, brain, muscles, and adipose tissue. Conversely, tissues involved in glucose production exhibit lower PEA15 levels. Interestingly, individuals with type 2 diabetes tend to have elevated PEA15 expression in their tissues compared to healthy individuals. Moreover, PEA15 expression serves as a valuable prognostic indicator in ovarian cancer.
PEA-15 was first identified and cloned from astrocytes, which are star-shaped glial cells in the brain and spinal cord. Astrocytes perform many functions, including biochemical support of endothelial cells that form the blood-brain barrier, provision of nutrients to nervous tissue, and maintenance of extracellular ion balance.
PEA-15 is a phosphoprotein, meaning it undergoes phosphorylation, a process that adds a phosphate group to the protein, altering its function and activity. This protein acts as a cytoplasmic anchor for extracellular signal-regulated kinases 1 and 2 (ERK1/2), preventing their nuclear localization and thereby reducing ERK1/2-dependent gene expression . This regulation is crucial for controlling cell proliferation and apoptosis.
PEA-15 has been shown to have significant roles in various cellular processes:
Recent studies have linked PEA-15 to metabolic diseases. For instance, it has been found to regulate adipose tissue expansion. In mice deficient in PEA-15, there is increased body weight and greater white adipose tissue expansion due to increased adipocyte cell size, which is consistent with greater lipid storage capacity . Interestingly, these mice also exhibited improvements in whole-body insulin sensitivity, lower hepatic weight, and decreased serum triglycerides, indicating a protective phenotype .
Given its role in regulating cell proliferation and apoptosis, PEA-15 has potential therapeutic implications in various diseases, including cancer and vascular diseases. For example, in vascular smooth muscle cells, PEA-15 regulates ERK1/2-dependent proliferation, which is crucial in conditions like neointimal hyperplasia following angioplasty . Maintaining PEA-15 expression could be a novel therapeutic target in vascular disease .