The goals of the proposed investigation are to study the regulation of the tyrosine phosphatase STEP. Previous studies established that STEP inactivates ERK1/2, p38 and the tyrosine kinase Fyn. Over the last cycle, we have discovered that STEP also induces NR1/NR2B and GluR1/GluR2 internalization. STEP has been implicated in the pathophysiology of Fragile X syndrome (FXS), Alzheimer's disease (AD), and schizophrenia (SZ). In these disorders, there is an increase in STEP levels. The current model suggests that the increase in STEP leads to the inappropriate internalization of NR1/NR2B and GluR1/GluR2 receptors. However, the mechanisms by which STEP levels are increased differ in these disorders. In AD and SZ, there is a disruption in the ubiquitination and degradation STEP. In FXS, there is an increase in the translation of STEP mRNA due to the absence of FMRP. STEP is rapidly degraded after specific forms of synaptic activity. Synaptic stimulation results in the ubiquitination of STEP, which is then degraded through the proteasome system. We hypothesize that STEP is degraded at synaptic sites to promote synaptic strengthening. Extrasynaptic NMDAR stimulation results in a calpain-mediated proteolysis STEP. We propose that this mechanism prolongs p38 signaling and initiates cell death pathways. The molecular mechanisms that regulate these processes are unknown.
Aim 1 focuses on STEP ubiquitination. We include functional experiments that mutate STEP so that it can no longer be ubiquitinated and degraded. We predict that this construct will disrupt both LTP, as well as the consolidation of fear conditioning after infusion into the amygdala. We will determine the kinases that promote or prevent STEP ubiquitination.
Aim 2 focuses on STEP proteolysis. We include functional studies that disrupt proteolysis of STEP, and will determine the effects this has on cell death using in vivo excitotoxic models. We predict that blocking STEP proteolysis will significantly decrease cell death.
Aim 3 focuses on STEP translation. Two cytoplasmic polyadenylation elements (CPEs) are present in STEP mRNA and we will determine whether these elements regulate the translation of STEP mRNA. We include functional experiments that will mutate these CPEs. We predict this will disrupt the normal function of STEP in the regulation of its substrates, including glutamate receptor trafficking. These studies will advance our understanding of how STEP is involved in normal cognitive processes and possible mechanisms by which it is disrupted in several diseases in which there are significant cognitive deficits.

Public Health Relevance

A major discovery over the last cycle is that STriatal-Enriched tyrosine Phosphatase (STEP) regulates glutamate receptor trafficking, and removes both NR1/NR2B and GluR1/GluR2 receptors from synaptic membranes after specific forms of synaptic stimulation. These latter findings have implicated STEP in the pathophysiology of fragile X syndrome, schizophrenia, and Alzheimer's disease. The proposed studies examine the molecular mechanisms that regulate STEP activity and will clarify how this important family of regulatory proteins are involved in synaptic plasticity, cell death, and human disease.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
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Asanuma, Chiiko
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Yale University
Schools of Medicine
New Haven
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Castonguay, David; Dufort-Gervais, Julien; MĂ©nard, Caroline et al. (2018) The Tyrosine Phosphatase STEP Is Involved in Age-Related Memory Decline. Curr Biol 28:1079-1089.e4
Xu, J; Hartley, B J; Kurup, P et al. (2018) Inhibition of STEP61 ameliorates deficits in mouse and hiPSC-based schizophrenia models. Mol Psychiatry 23:271-281
Xu, Jian; Kurup, Pradeep; Nairn, Angus C et al. (2018) Synaptic NMDA Receptor Activation Induces Ubiquitination and Degradation of STEP61. Mol Neurobiol 55:3096-3111
Tian, Meng; Xu, Jian; Lei, Gang et al. (2016) STEP activation by G?q coupled GPCRs opposes Src regulation of NMDA receptors containing the GluN2A subunit. Sci Rep 6:36684
Xu, Jian; Kurup, Pradeep; Azkona, Garikoitz et al. (2016) Down-regulation of BDNF in cell and animal models increases striatal-enriched protein tyrosine phosphatase 61 (STEP61 ) levels. J Neurochem 136:285-94
Azkona, Garikoitz; Saavedra, Ana; Aira, Zigor et al. (2016) Striatal-enriched protein tyrosine phosphatase modulates nociception: evidence from genetic deletion and pharmacological inhibition. Pain 157:377-86
Saavedra, Ana; PuigdellĂ­vol, Mar; Tyebji, Shiraz et al. (2016) BDNF Induces Striatal-Enriched Protein Tyrosine Phosphatase 61 Degradation Through the Proteasome. Mol Neurobiol 53:4261-4273
Xu, Jian; Kurup, Pradeep; Foscue, Ethan et al. (2015) Striatal-enriched protein tyrosine phosphatase regulates the PTP?/Fyn signaling pathway. J Neurochem 134:629-41
Jang, Sung-Soo; Royston, Sara E; Xu, Jian et al. (2015) Regulation of STEP61 and tyrosine-phosphorylation of NMDA and AMPA receptors during homeostatic synaptic plasticity. Mol Brain 8:55
Kurup, Pradeep K; Xu, Jian; Videira, Rita Alexandra et al. (2015) STEP61 is a substrate of the E3 ligase parkin and is upregulated in Parkinson's disease. Proc Natl Acad Sci U S A 112:1202-7

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