Antagonistic roles for STYX pseudophosphatases in neurite outgrowth

Mitogen-activated protein kinases (MAPKs) are essential players in important neuronal signaling pathways including neuronal development, plasticity, survival, learning, and memory. The inactivation of MAPKs is tightly controlled by MAPK phosphatases (MKPs), which also are important regulators of these neuronal processes. Considering that MAPKs and MKPs are major players in neuronal signaling, it follows that their misregulation is pivotal in neurodegenerative diseases such as Alzheimer's, Huntington's, Parkinson's, and amyotrophic lateral sclerosis. In contrast, the actions of their noncatalytic homologs, or pseudoenzymes, have received minimal attention as important regulators in neuronal signaling pathways and relevant diseases. There is compelling evidence, however, that pseudophosphatases, such as STYX (phospho-serine-threonine/tyrosine-binding protein) and MAPK-STYX (MK-STYX), are integral signaling molecules in regulating pathways involved in neuronal developmental processes such as neurite outgrowth. Here, we discuss how the dynamics of MK-STYX in the stress response pathway imply that this unique member of the MKP subfamily has the potential to have a major role in neuronal signaling. We further compare the actions of STYX in preventing neurite-like outgrowths and MK-STYX in inducing neurite outgrowths. The roles of these pseudophosphatases in neurite outgrowth highlight their emergence as important candidates to investigate in neurodegenerative disorders and diseases.