Disruption of striatal-enriched protein tyrosine phosphatase (STEP) function in neuropsychiatric disorders

Abstract

Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific tyrosine phosphatase that plays a major role in the development of synaptic plasticity. Recent findings have implicated STEP in several psychiatric and neurological disorders, including Alzheimer's disease, schizophrenia, fragile X syndrome, Huntington's disease, stroke/ischemia, and stress-related psychiatric disorders. In these disorders, STEP protein expression levels and activity are dysregulated, contributing to the cognitive deficits that are present. In this review, we focus on the most recent findings on STEP, discuss how STEP expression and activity are maintained during normal cognitive function, and how disruptions in STEP activity contribute to a number of illnesses.

Keywords: Alzheimer's disease; Fragile X syndrome; Huntington's disease; STEP; Schizophrenia; Stroke.

Figure 1

Structure of STEP. Two splice variants are shown, and their names are based on their mobility in SDS-gel electrophoresis. Both STEP₆₁ (541 amino acids) and STEP₄₆ (369 amino acids) have conserved PTP catalytic domain at the C-terminal and contain a KIM (kinase-interacting motif) domain. STEP₆₁ has an additional N-terminal 172 amino acids that contain polyproline-rich domains (PP) and transmembrane domains (TM). Each of PPs is required for binding to Fyn and Pyk2, an interaction that also requires the KIM domain. The phosphorylation site within the KIM domain (S²²¹ or S⁴⁹) is phosphorylated by PKA. The S¹⁶⁰ in STEP₆₁ is also phosphorylated by PKA but its role remains unknown. The cysteine residues (C⁶⁵ and C⁷⁶) mediate STEP dimerization.

Figure 2

Regulation of STEP expression and activity. NMDAR activation leads to dephosphorylation of STEP through the activation of a PP2B (calcineurin) / PP1 pathway, and dephosphorylation of STEP results its activation. D1 receptor stimulation induces phosphorylation and inactivation of STEP via PKA signaling. Phosphorylated STEP undergoes ubiquitination, which results in proteasomal degradation of STEP.