MAPKs and Their Inhibitors in Neuronal Differentiation

Mitogen-activated protein kinases (MAPKs) are a family of serine-threonine kinases that respond to various extracellular signals and are involved in many cellular processes. The MAPK family consists of four major groups extracellular signal regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK), p38 and ERK5. Additional MAPKs (ERK3, ERK4, ERK7, ERK8) have been identified on the basis of their homology with the ERK1/2 sequence but their functions and activation have not yet been fully described. MAPKs are activated by a “three kinase cascade” and after activation they phosphorylate specific cytoplasmic and nuclear substrates. MAPK activity is specifically regulated by phosphatases and by interaction with scaffold and/or anchor proteins. MAPK inhibitors are useful tools for studying MAPK requirements in physiological and pathological processes and it is thought that they may constitute a promising new therapeutic strategy for the treatment of tumors, inflammatory and neurodegenerative diseases. MAPK inhibitors are specific to each member of the MAPK family and can act at different levels of the MAPK cascades. These inhibiting molecules may be ATP-competitive or ATP-noncompetitive depending on their binding sites. Other classes of MAPK inhibitors are represented by peptide inhibitors whose sequences derive from scaffold protein sequences, and by low molecular weight compounds that interact with specific MAPK docking domains. MAPKs play an important role in the nervous system. In vitro studies using cell lines and primary neuronal cultures have demonstrated that MAPKs play a crucial role in neuronal survival and differentiation, apoptotic and non-apoptotic neuronal death, neuronal plasticity, learning and memory. In this review, we summarize the studies in which MAPK involvement in neuronal differentiation and neuritogenesis of different cellular models has been demonstrated by MAPK inhibitors.