Abstract: PEA-15 is a small protein (15 kDa) that was first identified as an abundant phosphoprotein in brain astrocytes and subsequently shown to be widely expressed in different tissues and highly conserved among mammals. It is composed of an N-terminal death effector domain (DED) and a C-terminal tail of irregular structure. PEA-15 is regulated by multiple calcium-dependent phosphorylation pathways. PEA-15 is ideally positioned to play a major role in signal integration. Accordingly, it has been demonstrated that PEA-15 diverts astrocytes from TNFα-triggered apoptosis and regulates the actions of the ERK MAP kinase cascade by binding to ERK and altering its subcellular localization. Expression of PEA-15 directs TNFα outcomes toward survival, whereas its absence allows the development of the cytokine-induced cell death.