The tyrosine phosphatase STEP: implications in schizophrenia and the molecular mechanism underlying antipsychotic medications.

Glutamatergic signaling through N-methyl-D-aspartate receptors (NMDARs) is required for synaptic plasticity. Disruptions in glutamatergic signaling are proposed to contribute to the behavioral and cognitive deficits observed in schizophrenia (SZ). One possible source of compromised glutamatergic function in SZ is decreased surface expression of GluN2B-containing NMDARs.

Genetic manipulation of STEP reverses behavioral abnormalities in a fragile X syndrome mouse model.

Fragile X syndrome (FXS), the most common inherited form of intellectual disability and prevailing known genetic basis of autism, is caused by an expansion in the Fmr1 gene that prevents transcription and translation of fragile X mental retardation protein (FMRP). FMRP binds to and controls translation of mRNAs downstream of metabotropic glutamate receptor (mGluR) activation. Recent work shows that FMRP interacts with the transcript encoding striatal-enriched protein tyrosine phosphatase (STEP; Ptpn5).

Therapeutic implications for striatal-enriched protein tyrosine phosphatase (STEP) in neuropsychiatric disorders.

Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific phosphatase that modulates key signaling molecules involved in synaptic plasticity and neuronal function. Targets include extracellular-regulated kinase 1 and 2 (ERK1/2), stress-activated protein kinase p38 (p38), the Src family tyrosine kinase Fyn, N-methyl-D-aspartate receptors (NMDARs), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). STEP-mediated dephosphorylation of ERK1/2, p38, and Fyn leads to inactivation of these enzymes, whereas STEP-mediated dephosphorylation of surface NMDARs and AMPARs promotes their endocytosis.

Taking STEPs forward to understand fragile X syndrome.

A priority of fragile X syndrome (FXS) research is to determine the molecular mechanisms underlying the functional, behavioral, and structural deficits in humans and in the FXS mouse model. Given that metabotropic glutamate receptor (mGluR) long-term depression (LTD) is exaggerated in FXS mice, considerable effort has focused on proteins that regulate this form of synaptic plasticity. STriatal-Enriched protein tyrosine Phosphatase (STEP) is a brain-specific phosphatase implicated as an "LTD protein" because it mediates AMPA receptor internalization during mGluR LTD.