A STEP forward in neural function and degeneration.

STriatal-Enriched Phosphatase (STEP) is a brain-specific protein tyrosine phosphatase that plays a role in synaptic plasticity and has recently been implicated in neurodegenerative disease. STEP opposes the development of synaptic strengthening by dephosphorylating and inactivating key signaling proteins that include the MAP kinases ERK1/2 and p38, as well as the tyrosine kinase Fyn. STEP also dephosphorylates the GluR2 subunit of the AMPAR and the NR2B subunit of the NMDAR, which leads to internalization of the NR1/NR2B and GluR1/GluR2 receptors. STEP levels and activity are regulated through phosphorylation, local translation, ubiquitination and degradation and proteolytic cleavage. Here we review recent progress in understanding the normal regulation of STEP and how this regulation is disrupted in Alzheimer's disease, in which abnormally increased STEP levels and activity contribute to the cognitive deficits.