A STEP forward in neural function and degeneration

Abstract

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.

Acknowledgements

We thank the members of our laboratory and Marilee Ogren for helpful discussions and critical reading of the manuscript. The work was funded by The American Health Assistance Foundation, the Institute for the Study of Aging, and NIH grants MH01527 and MH52711 to P.J.L.

Figures and Tables

Figure 1 STEP functions and regulation. (A) STEP activity opposes the development of synaptic plasticity by dephosphorylating and inactivating ERK and Fyn and leading to the endocytosis of AMPA and NMDA receptors. STEP is itself regulated by (B) phosphorylation, (C) local translation, (D) ubiquitination and degradation and (E) proteolytic cleavage. (B) STEP is inactivated by PKA-phosphorylation after dopamine stimulation and activated by calcineurin/PP1 dephosphorylation of this residue after α7nAChR and NMDAR stimulation. (C) Stimulation of mGluR5 leads to local translation of STEP. (D) STEP is normally degraded by the ubiquitin proteasome system (UPS), but in the presence of Aβ, the UPS is impaired, causing the accumulation of polyubiquitinated STEP. (E) Activation of extrasynaptic NMDARs triggers calpain to cleave STEP61 into STEP33, which prevents STEP from regulating its substrates and leads to the release of p38 from inhibition and activation of cell death pathways. These regulatory pathways may contribute to the pathophysiology of Alzheimer's if disrupted, and also implicate STEP as an excellent target for drug discovery.