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Review
. 2012 Jan;64(1):65-87.
doi: 10.1124/pr.110.003053. Epub 2011 Nov 16.

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

Susan M Goebel-Goody  1 , Matthew Baum, Constantinos D Paspalas, Stephanie M Fernandez, Niki C Carty, Pradeep Kurup, Paul J Lombroso
Affiliations
Review

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

Susan M Goebel-Goody et al. Pharmacol Rev. 2012 Jan.

Abstract

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. Accordingly, the current model of STEP function posits that it opposes long-term potentiation and promotes long-term depression. Phosphorylation, cleavage, dimerization, ubiquitination, and local translation all converge to maintain an appropriate balance of STEP in the central nervous system. Accumulating evidence over the past decade indicates that STEP dysregulation contributes to the pathophysiology of several neuropsychiatric disorders, including Alzheimer's disease, schizophrenia, fragile X syndrome, epileptogenesis, alcohol-induced memory loss, Huntington's disease, drug abuse, stroke/ischemia, and inflammatory pain. This comprehensive review discusses STEP expression and regulation and highlights how disrupted STEP function contributes to the pathophysiology of diverse neuropsychiatric disorders.

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Figures

Fig. 1.
Fig. 1.
STEP61 protein is captured in dendritic spine membranes in the macaque monkey prefrontal cortex, area 46. A1–B2, STEP-immunogold is found extrasynaptically (A1 and A2, arrowheads) and perisynaptically at a perforated synapse (B1 and B2, arrowheads); synaptic profiles are outlined in A2 and B2 to illustrate the synaptic, perisynaptic, and extrasynaptic membranes (color-coded). Double arrowheads point to the synapse active zone. C1–E2, when visualized with peroxidase, STEP61 marks perisynaptic and extrasynaptic membranes and is also found at the postsynaptic density of asymmetric, presumed glutamatergic, axospinous synapses. The raw data have been manipulated in the corresponding C2, D2, and E2 using image editing software to facilitate visualization of the immunoprecipitate against the postsynaptic density (between arrowheads). A nonreactive spine is shown in E1 and E2 (asterisk) for comparison. Arrowheads pointing to immunoreactive membranes are color-coded similarly to A2 and B2. For a technical account, please refer to Paspalas et al., 2009. The STEP antibody used was 23E5 (Boulanger et al., 1995). Scale bars, 200 nm.
Fig. 2.
Fig. 2.
Schematic of STEP. There are four alternatively spliced variants of STEP (STEP61, STEP46, STEP38, and STEP20) and one calpain cleavage product (STEP33). STEP61 and STEP46 are the major isoforms expressed in the CNS. The KIM domain is required for substrate binding, and the consensus PTP sequence, [I/V]HCxAGxxR[S/T]G, is necessary for phosphatase activity. STEP38 and STEP20 do not contain the PTP sequence and are inactive variants of STEP with unknown function. It is possible that these two inactive isoforms function as dominant-negative variants that compete with active STEP variants for substrate binding, or they possess other functions yet to be discovered. STEP38 and STEP20 contain a unique 10-amino acid sequence at their carboxyl termini that is introduced during splicing. STEP33 is generated by calpain cleavage within the KIM domain between Ser224 and Leu225. Cleavage at this site disrupts the ability of STEP33 to interact with its substrates. STEP61 also contains an additional 172 amino acids in its amino-terminal region, which contains two transmembrane (TM) domains, two PP-rich regions, and an adjacent PEST sequence (not labeled). The TM regions target STEP61 to the endoplasmic reticulum, as well as the PSD. The KIM domain is required for binding to all substrates, whereas the PP regions impart substrate specificity. PKA phosphorylates STEP within the KIM domain (Ser221 and Ser49 on STEP61 and STEP46, respectively), as well as in the region adjacent to the PP regions (Ser160 on STEP61). Although the function of Ser160 phosphorylation on STEP61 remains unclear, current investigations are aimed at determining whether phosphorylation at this or other sites is a signal for calpain-mediated cleavage and/or ubiquitination. Finally, two cysteine residues Cys65 and Cys76 are found in the TM region that mediates STEP dimerization and reduces its phosphatase activity.
Fig. 3.
Fig. 3.
Regulation of STEP phosphorylation. D1R activation stimulates cAMP synthesis and activates PKA, which phosphorylates STEP61 at Ser221 in the KIM domain. Phosphorylation at Ser221 sterically inhibits the binding of STEP61 to its substrates. PKA also leads to phosphorylation and activation of DARPP-32 at Thr34. When phosphorylated at this site, DARPP-32 inhibits PP1 activity, which is the phosphatase that dephosphorylates Ser221 and promotes the interaction of STEP61 with its substrates. Conversely, NMDAR (or α7nAChR) stimulation initiates calcium influx and activation of calcineurin/PP2B to dephosphorylate and inactivate DARPP-32, thereby reducing DARPP-32-mediated inhibition of PP1 and increasing STEP61 activity by reducing phosphorylation of Ser221.
Fig. 4.
Fig. 4.
STEP substrates. When dephosphorylated at Ser221, STEP binds to and desphosphorylates ERK1/2, p38, Fyn, Pyk2, the NMDAR subunit GluN2B, and the AMPAR subunit GluA2. STEP dephosphorylates the regulatory active sites on ERK1/2 (Tyr204/187), p38 (Tyr182), Fyn (Tyr420) and Pyk2 (Tyr402) leading to their inactivation. STEP61 regulates the phosphorylation of GluN2B-containing NMDARs by two parallel mechanisms. First, when Fyn is inactivated by STEP61, Fyn-mediated phosphorylation of GluN2B Tyr1472 is reduced. Second, STEP61 dephosphorylates GluN2B Tyr1472 directly. Dephosphorylation of Tyr1472 promotes the interaction of GluN2B with clathrin adaptor proteins and leads to endocytosis of these receptors. It is noteworthy that in this model, dephosphorylation of GluN2B Tyr1472 is depicted to occur extrasynaptically, where clathrin adaptor proteins reside to mediate receptor internalization. This event must occur with a prior signal triggering movement of GluN2B-containing receptors from synaptic sites to extrasynaptic sites. Another possibility is that GluN2B Tyr1472 dephosphorylation occurs synaptically, and this event acts as the signal to trigger lateral movement of GluN2B-containing receptors to extrasynaptic sites. Further work is required to address these two possibilities. In addition, Pyk2 is upstream of Fyn-mediated phosphorylation and enhancement of GluN2B-containing NMDARs. STEP61 is also required for the internalization of GluA1/GluA2-containing AMPARs after mGluR stimulation. Although the molecular mechanisms underlying tyrosine-dependent internalization of AMPARs remains incompletely understood, STEP61 seems to promote the endocytosis of AMPARs in a manner similar to that in which it promotes NMDARs, by dephosphorylating a key tyrosine residue.
Fig. 5.
Fig. 5.
Disruptions in STEP associated with excitotoxicity, Alzheimer's disease, and drugs of abuse. A, extrasynaptic NMDAR stimulation invokes calpain-mediated proteolysis of STEP61 producing the truncated cleavage product STEP33. STEP33 is unable to bind to and dephosphorylate its substrates. The stress-activated MAPK p38 is preferentially activated by extrasynaptic NMDAR stimulation, and the cell death pathways are subsequently initiated. Cleavage of STEP61 is therefore likely to be a component of excitotoxic insults associated with stroke/ischemia and Huntington's disease. On the other hand, synaptic NMDAR stimulation leads to the activation of multiple kinases responsible for phosphorylating STEP61 and recruiting the ubiquitin proteasome system to dendritic spines. Preliminary evidence suggests that phosphorylation of STEP61 at Ser221 is required, but not sufficient, for ubiquitination of STEP61 (P. Kurup and P. J. Lombroso, unpublished observations). Synaptic NMDAR stimulation results in the degradation of STEP61, leads to an increase in ERK1/2 activation, and promotes neuronal survival. Ub, ubiquitin. B, in Alzheimer's disease, Aβ binding to α7nAChRs and synaptic NMDAR stimulation invoke activation of PP2B/calcineurin and PP1 to dephosphorylate STEP61 at Ser221, thereby increasing the affinity of STEP61 for its substrates. In a second pathway, Aβ inhibits the ubiquitin proteasome system and prevents degradation of STEP61. The net result is an accumulation of unphosphorylated and active STEP61 protein levels in AD, which leads to inappropriate dephosphorylation of GluN2B Tyr1472 and internalization of GluN2B-containing NMDARs. C, drugs of abuse, such as amphetamine, stimulate release of dopamine and glutamate and activate D1Rs and NMDARs, respectively. Stimulation of D1Rs initiates PKA-mediated phosphorylation of STEP61 and DARPP-32, which in turn inhibits PP1 activity. These two parallel pathways result in greater phosphorylation of STEP61 and less dephosphorylation of STEP61 substrates, including ERK1/2. A converging pathway is the NMDAR-mediated activation of MAPK kinase to phosphorylate and activate ERK1/2. Increased phosphorylation of ERK1/2 subsequently initiates gene transcription and promotes neuroadaptive changes that underlie behavioral abnormalities associated with drugs of abuse.
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