Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Striatal-Enriched Protein-Tyrosine Phosphatase (STEP)

  • Pradeep Kurup
  • Jian Xu
  • Manavi Chatterjee
  • Susan Goebel-Goody
  • Surojit Paul
  • Paul Lombroso
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_630

Synonyms

Historical Background

Protein-tyrosine phosphatases (PTPs) play a significant role in diverse signaling mechanisms ranging from cellular differentiation to synaptic plasticity (Paul and Lombroso 2003; Tonks 2006). STriatal-Enriched protein-tyrosine Phosphatase (STEP) is a brain-specific protein tyrosine phosphatase belonging to the non-receptor tyrosine phosphatase family. Although enriched in the striatum, it is also localized to neurons in the cortex, hippocampus, and related brain regions (Boulanger et al. 1995). Interestingly, it is absent in the cerebellum, where a highly related PTP, PTP-STEP-like, is present (Watanabe et al. 1998). STEP exists as two major isoforms, named after their mobility in SDS-PAGE and designated STEP61 and STEP46. These isoforms are produced by alternative splicing of a single STEP (Ptpn5) gene (Bult et al. 1997). Since its discovery 20 years ago (Lombroso et al. 1991), a series of studies have established a role for STEP in opposing the development of synaptic strengthening in neurons. This occurs through STEP-mediated tyrosine (Tyr) dephosphorylation and inactivation of a number of key signaling molecules and receptors that are required for normal synaptic function (Braithwaite et al. 2006; Kamceva et al. 2016; Goebel-Goody et al. 2012a). As will be discussed at length below, disruption of STEP function is implicated in several CNS disorders due to its critical function in the brain.

Domain Structure

Like other PTPs, STEP has a highly conserved catalytic domain ([I/V]HCxAGxxR[S/T]G) within the ∼280 amino acid phosphatase domain that is present at its C-terminal region. In addition to the catalytic domain, various amino acid motifs exist that are responsible for the interaction of STEP isoforms with diverse signaling proteins (Fig. 1). Both STEP61 and STEP46 contain a regulatory kinase-interacting motif (KIM) that is required for the interaction of STEP with its substrates that include Fyn tyrosine kinase and two members of the mitogen-activated protein kinase (MAPK) family, ERK (extracellular-regulated kinase), and p38 MAPKs (Nguyen et al. 2002; Poddar et al. 2010; Pulido et al. 1998). The KIM domain in STEP has a serine phosphorylation site for protein kinase A (PKA), and phosphorylation of this site sterically prevents the interaction of STEP with its substrates (Paul et al. 2000).
Striatal-Enriched Protein-Tyrosine Phosphatase (STEP), Fig. 1

Domain structure of STEP. Alternative splicing of STEP gene produces four STEP isoforms, STEP61, STEP46, STEP38, and STEP20. STEP61 contains two transmembrane (TM) domains and two polyproline-rich sequences (PP) in the N-terminal 172 region, whereas STEP46 lacks this region. Both STEP46 and STEP61 share the binding site for ERK, the kinase-interacting motif (KIM), and the PTP catalytic domain, which contains an 11-amino acid catalytic site (asterisks). STEP61 has two serine residues that are phosphorylated by PKA (S), whereas STEP46 contains one PKA site, within the KIM domain. STEP38 and STEP20 are catalytically inactive, due to the absence of PTP domain and possibly function as dominant-negative variants toward active STEP

STEP61 has an additional 172 amino acids at its N-terminus that consists of two hydrophobic domains, two polyproline-rich regions and PEST sequences (Fig. 1). The hydrophobic domains in STEP61 are responsible for targeting it to membrane compartments, including the endoplasmic reticulum and postsynaptic density (PSD) (Boulanger et al. 1995; Oyama et al. 1995; Lombroso et al. 1993). One of the polyproline-rich domains is necessary for the interaction of STEP61 with its substrate Fyn (Nguyen et al. 2002). The PEST sequences in STEP61 serve as potential signals for proteolytic cleavage sites under certain physiological conditions (Nguyen et al. 1999). Two additional isoforms of STEP are reported (STEP38 and STEP20), which are produced by alternative splicing and lack a catalytic domain (Sharma et al. 1995). The exact functions of these isoforms are not known, but they may act as dominant-negative isoforms to protect STEP substrates from dephosphorylation while trafficking within neurons, and future studies are needed to address the role of these family members.

Regulation of STEP

STEP activity is modulated by phosphorylation, local translation, proteolytic cleavage, ubiquitination, and oligomerization. Alterations in STEP activity by these mechanisms have a significant impact on normal synaptic function as well as various disease states, and these are discussed next.

Phosphorylation

Phosphorylation is an important posttranslational modification that regulates numerous intracellular signaling pathways. Both STEP61 and STEP46 are phosphorylated by protein kinase A (PKA). Dopamine (DA)-mediated D1 receptor (D1R) stimulation leads to activation of adenyl cyclase and increases in intracellular cAMP levels and PKA activity. PKA phosphorylates both STEP61 and STEP46 at a conserved serine residue within the KIM domain (ser49 in STEP46 equivalent to ser 221 in STEP61). STEP61 is also phosphorylated by PKA at an additional site (ser160) in its unique N-terminal domain (Paul et al. 2000). Phosphorylation of the serine residue within the KIM domain renders STEP inactive in terms of its ability to bind to its substrates (Fig. 2a). Additional studies have also shown that psychostimulants such as amphetamine inactivate STEP by promoting a DA-/D1R-/cAMP-/PKA-mediated phosphorylation of this residue, as well as inhibiting dephosphorylation of STEP by PP1 through the PKA activation of DARPP-32 (Valjent et al. 2005).
Striatal-Enriched Protein-Tyrosine Phosphatase (STEP), Fig. 2

Regulation of STEP at synapse. (a) Phosphorylation: Dopamine receptor (D1) stimulation leads to activation of PKA by adenyl cyclase/cAMP pathway, which results in phosphorylation of a regulatory serine within the KIM domain, resulting in inactivation of STEP. Glutamate stimulation reverses the KIM domain phosphorylation of STEP by activating the phosphatase calcineurin/PP1 pathway through NMDAR calcium influx. Thus, STEP is activated by a PKA-/PP2B-/PP1-mediated mechanism. (b) Local translation: mGluR5 activation by the agonist (DHPG) leads to local translation of STEP mRNA. STEP dephosphorylates a regulatory tyrosine residue(s) of the GluA2 subunit of AMPA receptor that results in increased internalization of AMPA receptor subunits from the neuronal surface. FMRP (fragile X mental retardation protein) opposes the translation of STEP. (c) Ubiquitin-proteasome system (UPS) and proteolytic cleavage: Synaptic NMDAR activation recruits ubiquitin enzymes (E1 and E2) and addition of ubiquitin molecules to STEP61 through E3 ligase parkin, which eventually leads to degradation of STEP61 by the proteasome. Stimulation of extrasynaptic NMDARs activate calpain, which proteolytically cleaves STEP within the KIM domain to form a lower molecular weight STEP33 isoform that is unable to bind to STEP substrates. (d) Oligomerization: Aging or oxidative stress induced by H2O2 inactivates STEP61 catalytic activity by homodimerization. This results in increased activation of MAPK signaling molecules, such as p38 and ERK

In contrast, glutamate-mediated stimulation of GluN2B-containing N-methyl-D-aspartate receptors (NMDARs), subsequent influx of Ca2+, and activation of the calcium-dependent phosphatase calcineurin (PP2B) lead to dephosphorylation of the serine residue within the KIM domain. Dephosphorylation of this residue allows STEP to bind to its substrate (Paul and Connor 2010; Paul et al. 2003). Beta-amyloid (Aβ), the peptide implicated in Alzheimer’s disease (AD), has also been shown to modulate the activity of STEP through calcineurin-/PP1-mediated dephosphorylation of this residue. Active STEP, in turn, leads to tyrosine dephosphorylation and subsequent internalization of functional NMDARs (Snyder et al. 2005). Impairment of NMDA receptor trafficking plays a role in the pathogenesis of AD and suggests a role of STEP in AD-related dementia (Kurup et al. 2010b). The role of phosphorylation of ser160 in STEP61 remains unknown, although its proximity to a PEST sequence suggests that it may play a role in the degradation of STEP61 through either ubiquitination or proteolysis, as will be discussed further below.

Local Translation

Local translation is a process by which specific mRNA transcripts are translated at distant dendritic sites upon synaptic activity (Wang et al. 2010). This mechanism helps to remodel spines to either strengthen or weaken synaptic connections, depending on incoming synaptic stimuli. For local translation to occur, mRNA transcripts are transported along dendrites and kept in a repressed state by inhibitory RNA-binding proteins. Upon synaptic stimuli, the repression is removed and the message is translated. STEP mRNA is present in synaptoneurosomal fractions and is translated upon the group I metabotropic glutamate receptor 5 (mGluR5) stimulation (Zhang et al. 2008). mGluR signaling is involved in long-term depression (LTD), and mGluR-dependent translation has been implicated in several disorders including fragile X syndrome (Waung and Huber 2009). STEP translation regulates AMPAR trafficking during mGluR-dependent LTD. In STEP knockout (KO) cultures, mGluR stimulation with the agonist DHPG failed to induce AMPAR endocytosis. Moreover, at baseline, STEP KO mice show increased surface AMPAR subunits (GluA1 and GluA2) (Zhang et al. 2008). These studies indicate that local translation of STEP is required for AMPAR internalization during mGluR-dependent LTD. There are several potential Tyr residues at the carboxy-terminus of GluA2, but whether STEP directly dephosphorylates one or more of these residues to induce endocytosis of GluA1/GluA2 receptor complexes is under investigation (Fig. 2b).

Ubiquitination

Ubiquitination and subsequent degradation of cellular proteins by the ubiquitin-proteasome system (UPS) play a role in the development of synaptic plasticity (Yi and Ehlers 2007). Local degradation of proteins at the synapse increases the efficacy of synaptic signaling in specific regions of the spine and permits spine remodeling (Haas and Broadie 2008). The degradation of STEP is differentially regulated by synaptic and extrasynaptic NMDARs (Xu et al. 2009). Synaptic and extrasynaptic NMDARs are differentially localized in the neuron (Goebel-Goody et al. 2009) and activate distinct signaling pathways (Hardingham and Bading 2003). Synaptic NMDAR stimulation preferentially activates pERK signaling and promotes neuronal survival pathways, whereas stimulation of extrasynaptic NMDARs activates p-p38 signaling and initiates the cell-death pathways (Hardingham et al. 2002). The UPS degrades STEP after synaptic NMDAR stimulation, whereas STEP is proteolytically cleaved by calpain after extrasynaptic stimulation. In both cases, STEP is removed from synaptic sites and is no longer able to dephosphorylate its substrates (Xu et al. 2009).

In primary neuronal cultures, proteasome inhibitor treatment results in an increase of STEP61 levels (Kurup et al. 2010b). The increase in STEP61 is insensitive to transcription or translation inhibitors. Moreover, accumulation of STEP-ubiquitin conjugates is observed in STEP61-transfected HEK cells, as well as in mouse brain tissues (Fig. 2c). In several different AD mouse models, STEP61 levels are elevated due to inhibition of the proteasome system by beta-amyloid oligomers. This results in the accumulation of active STEP61, which subsequently reduces surface NMDAR levels (Kurup et al. 2010b). More details on the role of STEP in Alzheimer’s disease are presented in a separate section below.

Recent studies indicate that STEP ubiquitination is regulated by brain-derived neurotrophic factor (BDNF) signaling. BDNF is a neurotropic factor which plays a vital role in synaptic plasticity and implicated in several CNS disorders (Yoshii and Constantine-Paton 2010). BDNF regulates STEP ubiquitination through TrkB receptor and PLCγ signaling, which leads to subsequent degradation of STEP by the ubiquitin-proteasome system (UPS). As elevated STEP levels oppose the development of synaptic plasticity, these findings suggest that the downregulation of STEP by BDNF is a possible mechanism that promotes synaptic strengthening (Xu et al. 2016a). In agreement with this, downregulation of BDNF expression in cell and animal models increases STEP levels, which is associated with cognitive and motor deficits. Inhibition of STEP activity by a novel phosphatase inhibitor (TC-2153) (Xu et al. 2014) restores BDNF expression and reverses motor and cognitive deficits in a phencyclidine (PCP) model of schizophrenia (Xu et al. 2016b). In summary, these findings suggest that the UPS-mediated degradation of STEP plays a significant role in synaptic plasticity mechanisms and perturbation of this process by altered signaling pathways may have implication in various CNS disorders.

Proteolytic Cleavage

Proteolytic cleavage is another mechanism by which signaling proteins are either activated or inactivated during synaptic signaling (Bingol and Sheng 2011). Exposure to high levels of glutamate leads to overactivation of NMDARs primarily at extrasynaptic sites and influx of Ca2+, which activate a number of proteases including calpain (Doshi and Lynch 2009). Calpain is a Ca2+-dependent cysteine protease that cleaves STEP61 to release a lower MW isoform STEP33 during excitotoxic conditions. Cleavage occurs within the KIM domain to produce STEP33, which no longer has an intact substrate-binding site and can no longer associate with STEP substrates (Xu et al. 2009).

Recent studies have shed light on how extrasynaptic NMDAR stimulation can couple to neuronal cell-death pathways through the STEP-regulated activation of the MAPK family member, p38. STEP dephosphorylates a regulatory tyrosine residue in the activation loop of p38 and thereby blocks p38-mediated signaling (Poddar et al. 2010). Calpain cleavage of STEP61 produces the truncated isoform STEP33 that no longer inactivates p38 and results in sustained activation of p38 and cell-death pathways. Blocking STEP cleavage by a competition peptide corresponding to the calpain cleavage site protected cortical cultures from glutamate-mediated excitotoxicity, as well as cortical slices from neuronal death after oxygen-glucose deprivation (Xu et al. 2009). In summary, this study addresses the mechanisms by which STEP exerts a neuroprotective role or promotes cell-death pathways depending on the type of NMDAR stimulation that occurs (Fig. 2c).

Oligomerization

Dimerization is a well-known regulatory mechanism for transmembrane proteins that include tyrosine phosphatases (den Hertog et al. 2008). A recent study showed that homodimerization of STEP61 is readily detectable under basal condition in the hippocampus, cortex, as well as cultured neurons (Deb et al. 2011). Dimerization of STEP61 involves intermolecular disulfide bond formation between two cysteine residues present in the hydrophobic region at the N-terminus and involves a domain that is not conserved among tyrosine phosphatases (Fig. 2d). Oxidative stress leads to increase in dimerization and higher-order oligomer formation of STEP61 resulting in reduced phosphatase activity. STEP46 does not form dimers under basal condition, but does following oxidative stress, resulting in subsequent loss of activity. The precise implication of oxidative stress-induced oligomerization of STEP in neurons is not well understood. However, a concomitant increase in the phosphorylation of ERK MAPK, a physiological substrate of STEP, was observed in neurons treated with hydrogen peroxide, suggesting the inability of oligomerized STEP to inactivate it. Consistent with these findings, a recent study showed increased STEP dimerization and loss of STEP activity in cortex and hippocampal regions with aging (Rajagopal et al. 2016). These findings suggest that STEP inactivation by oligomerization could play a role in the etiology of age-related neurodegenerative disorders by promoting chronic activation of ERK- and p38 MAPK-mediated proapoptotic pathways.

STEP Substrates

Mitogen-Activated Protein Kinases (MAPKs)

MAPKs play an important role in transducing extracellular signals to intracellular targets (Keshet and Seger 2010). ERK1/ERK2 and p38 are members of the MAPK family and are phosphorylated and activated by their respective MEKs in cells. MEK is a dual-specificity kinase that phosphorylates at tyrosine and threonine/serine residues. ERK1 and ERK2 are widely expressed  protein kinases whose functions include the development of synaptic plasticity, the regulation of transcription and translation, and the consolidation of long-term memory (Sweatt 2001). Many different stimuli, including growth factors and ligands for heterotrimeric G protein-coupled receptors, activate the ERK1/ERK2 pro-survival pathways, while p38 MAPK responds to stress stimuli and its activation initiates cell-death pathways.

ERK1/ERK2: ERK1 and ERK2 are substrates of STEP (Munoz et al. 2003; Paul et al. 2003). Most of the studies on STEP and ERK were carried out with ERK2 isoform, so we focus here mainly on ERK2. Activated ERK2 strengthens synaptic plasticity by promoting local translation of proteins, initiating gene transcription, neurotransmitter release, and spine reorganization (Sweatt 2001). Both STEP61 and STEP46 dephosphorylate a regulatory tyrosine residue (Tyr187) in ERK2, thereby inactivating it. Thus, STEP regulates the duration of ERK2 signaling in neurons (Paul et al. 2003). STEP interacts with ERK through its KIM domain, and PKA phosphorylation of STEP prevents this interaction and prolongs ERK activity in neurons. In STEP KO brain tissues (e.g., the striatum, hippocampus, amygdala), activated pERK1/pERK2 levels are significantly increased. In comparison to wild-type neuronal cultures, STEP KO neuronal cultures show exaggerated activation of active ERK after group I metabotropic glutamate receptor (mGluR) stimulation with DHPG (Venkitaramani et al. 2009).

Activated ERK2 is required for memory consolidation. The inactivation of ERK2 opposes this process, and a role for STEP was demonstrated in Pavlovian fear conditioning learning in rats (Paul et al. 2007). Infusion of a substrate-trapping mutant of STEP, which binds to ERK2 and does not release it, blocked translocation of ERK2 to the nucleus and prevented consolidation of fear conditioning learning. These results support a role of STEP in normally opposing long-term memory formation.

Recent studies have indicated that subunits of NMDARs can differentially regulate ERK2 activation. The activation of NMDARs leads to a rapid influx of calcium and transient activation of ERK initially, which is dependent of GluN2A subunit. In contrast, delayed calcium influx through GluN2B-containing receptors results in inactivation of ERK2 through activation of the calcineurin/PP1 pathway and dephosphorylation of STEP (Paul and Connor 2010).

p38: Both STEP46 and STEP61 isoforms bind p38 and inactivate it. The contribution of STEP in p38-mediated cell death was discussed above. In summary, glutamate stress or physiological stress induced by oxygen-glucose deprivation induces p38 activation. This is due in part to the calpain-mediated cleavage of STEP to its lower MW inactive isoform STEP33, which no longer dephosphorylates p38 and results in activation of cell-death pathways (Xu et al. 2009). Taken together with the earlier ERK studies, these findings point to the important role of STEP in regulating MAPKs in the development of both synaptic plasticity and activation of neuronal cell-death pathways.

NMDARs

Glutamate receptors are required for the development of synaptic plasticity and consolidation of long-term memories (Peng et al. 2011). NMDARs are ligand-gated ionotropic channels and are named for the selective agonist that binds to NMDARs but not to other glutamate receptors. A unique property of the NMDAR is its voltage-dependent activation, a result of ion channel block by extracellular Mg2+ ions. The NMDARs form a heterotetramer between two GluN1 and two GluN2 subunits (Paoletti and Neyton 2007). The surface expression of NMDARs is regulated by various kinases and phosphatases during long-term potentiation (LTP). LTP-inducing stimuli promote trafficking of GluN1/GluN2B complexes to neuronal surfaces (Grosshans et al. 2002) and activate a number of proteins required for synaptic strengthening.

Dysregulation of NMDAR trafficking is found in several neuropsychiatric diseases, including Alzheimer’s disease and schizophrenia (Lau and Zukin 2007). STEP directly binds to GluN1 subunit of the NMDAR complex and inhibits high-frequency stimulation (HFS)-LTP (Pelkey et al. 2002). Moreover, trafficking of GluN1/GluN2B complex to neuronal surfaces is regulated by STEP (Braithwaite et al. 2006; Snyder et al. 2005; Zhang et al. 2010). STEP directly dephosphorylates Tyr1472 (Y1472) in the GluN2B subunit, leading eventually to clathrin-mediated internalization of GluN1/GluN2B (Braithwaite et al. 2006; Roche et al. 2001; Snyder et al. 2005).

Fyn

Fyn is a member of the Src family of non-receptor tyrosine kinases. Fyn phosphorylates tyrosine residues on multiple targets to initiate several signaling pathways. Fyn is activated by autophosphorylation of its tyrosine residue (Y420) to generate a binding site that recruits other signaling molecules. Conversely, STEP61 inactivates Fyn by binding to it via the proline-rich domain present in STEP61 and by dephosphorylating Tyr420 (Nguyen et al. 2002). Fyn regulates NMDAR trafficking by diretly phosphorylating Tyr (Y1472) on the GluN2B subunit (Dunah et al. 2004; Nakazawa et al. 2001). STEP thereby opposes the surface expression of GluN2B-containing NMDARs in two ways: by decreasing Fyn-mediated phosphorylation of Tyr1472 and by directly dephosphorylating the GluN2B subunit at Y1472 (Baum et al. 2010; Braithwaite et al. 2006).

Pyk2

Pyk2 is a member of the focal adhesion kinase family, expressed in the CNS and involved in synaptic plasticity events (Lev et al. 1995; Girault et al. 1999; Barsacchi et al. 1999). Pyk2 is autophosphorylated at Tyr402 in response to a rise in intercellular calcium levels, which eventualy exposes a docking site for the binding of the SH2 domain of Fyn, and and its subsequent activation, suggesting autophosphorylation of Pyk2 at Tyr402, is a critical event to regulate the activity of src family proteins including Fyn. Our studies demonstrated Pyk2 is a direct susbtrate of STEP61, which dephosphorylates the Tyr402 of Pyk2 and opposes the activation of array of signaling events in the postsynaptic density involved in synaptic plasticity (Xu et al. 2012).

PTPα

PTPα is a receptor-type protein tyrosine phosphatase that is widely expressed in many tissues including the brain (Sahin et al. 1995; Sap et al. 1990). Within the CNS, PTPα is implicated in the development of synaptic plasticity and long-term potentiation (LTP) through its ability to activate Fyn and potentiate NMDA receptor signaling (Skelton et al. 2003; Petrone et al. 2003). Phosphorylation at Tyr789 and translocation between cytoplasm and lipid rafts are essential for its activity and signal transduction (den Hertog et al. 1994; Zheng et al. 2000; Maksumova et al. 2005; Gibb et al. 2011). Recently, we identified PTPα as another substrate of STEP61 (Xu et al. 2015). STEP61 binds to and dephosphorylates PTPα at Tyr789 and blocks its translocation from the cytoplasm to lipid rafts. In contrast, elevated phosphorylation of PTPα at Tyr789 and increased lipid rafts localization were found in STEP KO mouse striatum and when STEP61 was inactivated by PKA-mediated phosphorylation. In an ethanol-consumption mouse model, we demonstrated that PKA-mediated inactivation of STEP61 is required for the activation and translocation of PTPα and subsequent ethanol-related behavioral changes (Wang et al. 2007; Ben Hamida et al. 2013; Xu et al. 2015; Legastelois et al. 2015). This finding suggests a synergistic regulation of Fyn by STEP and PTPα, i.e., STEP dephosphorylates, and inactivates Fyn directly (Nguyen et al. 2002); at the same time, it also dephosphorylates and suppresses PTPα function, blocking PTPα-mediated Fyn activation (Engen et al. 2008; Ingley 2008). See Fig. 3 for the list of STEP substrates.
Striatal-Enriched Protein-Tyrosine Phosphatase (STEP), Fig. 3

STEP substrates. Active STEP dephosphorylates critical tyrosine residues in its substrates (Tyr182 of p38, Tyr187 of ERK2) to inactivate them. Active Fyn phosphorylates Tyr1472 residue in GluN2B and facilitates the exocytosis of NMDARs to the neuronal surfaces. STEP dephoshorylates Tyr420 of Fyn and inactivates it, thereby opposing surface expression of NMDARs. STEP dephosphorylates PTPα at its regulatory Tyr789 and prevents its ability to translocate and activate Fyn at synaptic membranes. STEP also dephoshorylates Tyr402 of Pyk2 and opposes its translocation to PSD (postsynaptic density) by inactivating it. STEP directly dephosphorylates Tyr1472 residue of the GluN2B subunit to internalize surface GluA1/GluA2B. STEP also dephosphorylates unidentified tyrosine residue(s) in the GluA2 subunit of AMPARs that promotes internalization of surface AMPAR

STEP Knockout Mice

The current model of STEP function is that it opposes synaptic strengthening and memory consolidation by inactivating a number of synaptic proteins. A prediction of this hypothesis would therefore be that loss of STEP might facilitate learning and memory in certain cognitive tasks. STEP KO mice were generated using a target vector to replace 1.3 kb genomic region containing the phosphatase domain with the neomycin gene in ES cells by homologous recombination (Venkitaramani et al. 2009). STEP KO mice are viable, fertile, and with no obvious phenotypic abnormalities, suggesting that STEP is not essential for embryonic or postnatal survival. Biochemically, STEP KO progeny shows no expression of STEP, but has increased tyrosine phosphorylation of STEP substrates. STEP KOs have increased synaptosomal membrane expression of glutamate receptors, including both NMDARs (Zhang et al. 2010) and AMPARs (Zhang et al. 2008), confirming the critical role STEP plays in the regulation of glutamate receptor trafficking.

Recent studies with STEP KO mice have clarified the role of STEP on hippocampal-dependent learning and memory (Venkitaramani et al. 2011). When subjected to the Morris water maze and radial arm maze, STEP KO mice show enhanced cognitive flexibility and fewer working memory errors than wild-type (WT) littermates. STEP KO mice show improved performance in these tasks, correlating with enhanced tyrosine phosphorylation of ERK1/ERK2, the GluN2B subunit of the NMDAR, as well as increased phosphorylation of the transcription factors CREB and Elk-1 downstream of ERK1/ERK2 activation (Venkitaramani et al. 2011). These findings suggest a role for STEP in negatively regulating hippocampal-dependent memory.

Diseases

Alzheimer’s Disease

Alzheimer’s is the most common neurodegenerative disorder associated with loss of memory and other cognitive symptoms. A hallmark of AD is the accumulation of beta-amyloid (Aβ) peptide in brains, a process that has been implicated in the progression of the disease (Selkoe 2002). Aβ peptides are formed from amyloid precursor protein (APP) by the sequential cleavage of β- and γ-secreteases (Turner et al. 2003). APP overexpressing transgenic mouse models mimic some, but not all, of the biochemical and behavioral defecits observed in AD (Elder et al. 2010). These models have been used in efforts to uncover the molecular basis and pathophysiology of AD.

STEP has recently been shown to play a role in the etiology of AD. STEP levels are elevated in the brains of human AD as well as in several mouse AD models (Chin et al. 2005; Kurup et al. 2010b). Elevated STEP levels were associated with increased internalization of surface NMDARs (Snyder et al. 2005) and AMPARs (Zhang et al. 2008). An earlier study found that Aβ leads to activation of STEP through a calcineurin-/PP1-mediated dephosphorylation of STEP. Aβ directly bound to α7 nicotinic acetylcholine receptor (α7nAChR) on neuronal surface, leading to calcium influx and activation of calcineurin and PP1. This pathway dephosphorylates STEP at the regulatory KIM domain serine residue and activates STEP. STEP is now able to dephosphorylate its substrates. STEP dephopshorylates Y1472 of GluN2B and causes internalization of GluN1/GluN2B receptor complexes. This study also showed that the effect of Aβ was blocked by transducing a dominant-negative STEP, which competes for endogenous STEP binding to GluN2B. This model was confirmed using STEP KO neuronal cultures in which Aβ failed to induce NMDAR endocytosis, and internalization was rescued after the addition of membrane-permeable active STEP protein back into the cultures prior to Aβ treatment (Kurup et al. 2010a).

A recent study established a second mechanism by which STEP levels are elevated in AD (Kurup et al. 2010b). STEP is normally degraded by the ubiquitin-proteasome system (UPS). In human AD brains, proteasome activity is decreased and associates with an accumulation of ubiquitin-immunoreactive inclusion bodies (Lam et al. 2000; Mori et al. 1987). Aβ peptide inhibits proteasome activity, which leads to the accumulation of numerous proteins normally degraded by the UPS. Treatment of cortical cultures with Aβ-enriched medium (7PA2-conditioned medium) results in an increase in STEP61 levels, which are insensitive to translational or transcriptional inhibitors. STEP61- and STEP61-ubiquitin conjugates are increased upon Aβ treatment, suggesting that there is a blockade in proteasomal degradation and clearance of ubiquitinated proteins. These observations were confirmed in an AD mouse model (Tg2576 mouse), which show progressive increases in STEP61 levels and STEP61-ubiquitin conjugates in the cortex over the first year of life that correlates with an increase in Aβ levels and a decrease in surface glutamate receptor levels. Taken together, these studies indicate that Aβ regulates STEP through two pathways (Fig. 4): (1) by favoring calcineurin-/PP1-mediated dephosphorylation and activation of STEP and (2) by blocking the proteasome-mediated degradation of STEP61, thereby accumulating active STEP61 (Fig. 4).
Striatal-Enriched Protein-Tyrosine Phosphatase (STEP), Fig. 4

Regulation of STEP in Alzheimer’s disease. STEP levels and activity are regulated by beta-amyloid (Aβ) peptide. Aβ binds to the α7 nicotinic acetylcholine receptor (α7nAChR), which results in calcium influx and activation of calcineurin and PP1. This pathway dephosphorylates STEP at the regulatory KIM domain serine residue and activates STEP. Active STEP then dephosphorylates GluN2B at Tyr1472 and causes the internalization of GluN1/GluN2B receptor complexes from neuronal surfaces. In addition, STEP inactivates Fyn and blocks exocytosis of NMDARs to the neuronal surface. Aβ peptide also inhibits proteasome activity to block normal degradation of STEP. This leads to an increase in active STEP levels in the presence of Aβ and internalization of NMDA receptors. Thus, Aβ lowers surface expression of NMDARs by two parellel pathways that involve STEP. STEP inhibitor (TC-2153) inactivates STEP by covalent modification of its active site and opposes the internalization of NMDA receptors

The aforementioned studies demonstrate a role for STEP61 in AD and suggest that genetic reduction of STEP might rescue the cognitive deficits in AD mouse models. We tested this hypothesis by crossing a well-estabilished AD model (triple transgenic mice, 3xTg-AD) with STEP KO mice to obtain progeny with elevated Aβ levels but null for STEP (double mutant, DM). Characterization of DM mice using several behavioral tests indicates significantly improved cognitive performance in spatial and nonspatial hippocampal-dependent memory tasks compared to 3xTg-AD. These behavioral improvements in DM mice are associated with increase in surface levels of NMDAR subunits (GluN1/GluN2B) and increase in active ERK (pERK) and active Fyn (pY420 Fyn) (Zhang et al. 2010). As we discussed earlier, both ERK and Fyn are STEP substrates. ERK mediates synaptic strengthening in part via regulating gene expression and local translation, while Fyn directly phosphorylates GluN2B at Y1472 and promotes increased surface expression of NMDARs. Thus, loss of STEP restores cognitive function in the 3xTg-AD mouse model by increasing tyrosine phosphorylation of its substrates and by favoring glutamate receptor surface expression (Zhang et al. 2010).

Status Epilepticus

Status epilepticus (SE) is a severe condition consisting of a prolonged seizure. SE often leads to long-lasting changes in hippocampal synaptic physiology that result in the development of temporal lobe epilepsy. A prominent feature of SE is the reduction of GABAergic hippocampal interneurons. A recent study demonstrates that STEP is highly expressed in hilar somatostatin-sensitive interneurons. Moreover, the abundance of STEP in these neurons renders them more vulnerable to SE-induced cell death by opposing ERK/MAPK activation. Activation of the ERK/MAPK cascade leads to expression of neuroprotective factors, whereas high expression of STEP in these interneurons suppresses the ERK-/MAPK-mediated neuroprotective responses. Accordingly, blocking calcineurin-/PP1-mediated activation of STEP using the calcineurin inhibitor (FK506) rescues cell death in the pilocarpine-induced SE model (Choi et al. 2007). These findings suggest that a reduction of STEP in these interneurons might increase their resistance to pilocarpine-induced SE. A follow-up study extended these findings in the STEP KO model. STEP KO mice display a higher seizure thereshold for the development of pilocarpine-induced SE compared to WT littermates (Briggs et al. 2011). This inherent property is due to increased excitation of inhibitory hilar neurons and reduced excitation of dentate gyrus granular cells. Enhanced inhibitory input to granule cell neurons in STEP KOs compared to WT increases their resistance to the development of seizures. These data suggest that targeted inhibition of STEP in hilar interneurons region may prove beneficial for the treatment of seizure disorders.

Fragile X Syndrome

Fragile X syndrome (FXS) is an X-linked inherited neurodevelopmental disorder associated with intellectual disability. FXS is caused by an increase in the number of CGG repeats located in the first exon of the fragile X mental retardation 1 (FMR1) gene, which encodes a RNA-binding protein called FMRP (Jayaseelan and Tenenbaum 2012). FMRP acts as a translational silencer (Laggerbauer et al. 2001) of mRNAs and regulates the expression of several synaptic proteins (Bear et al. 2004). STEP mRNA is known to associate with FMRP, and studies in our lab showed that STEP levels are upregulated in the synaptosomal fractions of FMR1 KO mice (Darnell et al. 2011; Goebel-Goody et al. 2012b). In continutaion of this observation, to understand the role of STEP in behavioral abrormalities associated with FMR1 KO mice, STEP expression was genetically reduced by crossing FMR1 KO mice with STEP KO mice. The FMR1 progeny null for STEP was charecterized with battery of behavioral tests including audiogenic seizure susceptibility and anxiety-related abnormalities. These studies demonstrated that FMR1 progeny null for STEP has diminished audiogenic seizures, and a reversal of social and nonsocial anxiety-related abnormalities in respective behavioral tests suggesting overactivation of STEP contribute to the distinct behavioral symptoms associated with the FXS (Goebel-Goody et al. 2012b).

Parkinson’s Disease

Parkinson’s disease (PD) is a common movement disorder with hallmarks that include selective loss of dopaminergic neurons in the substantia nigra, progressive depletion of striatal dopamine, and altered striatal plasticity which contribute to motor abnormalities (Saiki et al. 2012). Recently, it was demonstrated that STEP is a target of E3 ligase parkin and is implicated in both genetic and sporadic PD (Kurup et al. 2015). STEP protein levels are critically maintained by E3 ligase parkin by the UPS. Compromised parkin activity due to genetic mutations or environmental toxins leads to abnormal accumulation of STEP in neurons, which in turn downregulates synaptic proteins such as ERK1/ERK2 and CREB and opposes striatal synaptic plasticity. The role of STEP in PD was futher supported by the observation of increased levels of STEP and downregulated phosphorylation levels of ERK1/ERK2 and CREB in human PD striatum as well as in neurotoxin (MPTP)-induced animal models of PD (Kurup et al. 2015). These findings validate the role of STEP in yet another common neurodegenerative disorder.

STEP Inhibitors

It is clear that STEP is overactive in several CNS disorders, suggesting that STEP inhibitors may have thereupetic potential to treat these conditions. In an effort to find STEP inhibitors, we screened a library of 150,000 small molecules and identified a lead compound, 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (known as TC-2153). TC-2153 efficiently inhibits STEP in vitro (IC50 ∼= 25 nM), in neuronal cultures, and in wild-type mice. Additional results indicate that TC-2153 is relatively specific toward STEP compared to other PTPs (Xu et al. 2014). The mechanism of action has been described and involves the binding to the active catalytic site of STEP (Xu et al. 2014). Further proof of concept studies were carried out in a AD mouse model (3×Tg-AD). Three hours after a single intraperitoneal injection of TC-2153, there was asignificant improvement in cognitive function in three behavioral tasks (Y-maze, novel object recognition, and Morris water maze), without changes in Aβ levels or tau phosphorylation levels (Xu et al. 2014). These results are in agreement with previous findings in which a genetic reduction of STEP in 3×Tg-AD mice also significantly improved cognitive function (Zhang et al. 2010) and indicate that direct inhibition of STEP activity is sufficient to reverse cognitive deficits in AD mice.

Summary

STEP is a non-receptor tyrosine phosphatase uniquely expressed in the brain. It plays a significant role in synaptic plasticity by regulating MAPK signaling and glutamate receptor trafficking. Several STEP substrates have been identified that include ERK1/ERK2, p38, Fyn, Pyk2, and GluN2B. STEP dephosphorylates these substrates and thereby opposes the development of synaptic plasticity and the consolidation of long-term memories. STEP activity is regulated by PKA-mediated KIM domain phosphorylation, local translation, degradation by the ubiquitin-proteasome system, and proteolytic cleavage. There is a significant increase in STEP activity in several CNS disorders, demonstrating an imporant role in normal brain physiology. Overall, these studies suggest that designing candidate molecules which target STEP function might have potential therapeutic implications.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Pradeep Kurup
    • 1
  • Jian Xu
    • 1
  • Manavi Chatterjee
    • 1
  • Susan Goebel-Goody
    • 1
  • Surojit Paul
    • 1
    • 2
  • Paul Lombroso
    • 1
  1. 1.Child Study CenterYale University, School of MedicineNew HavenUSA
  2. 2.NeurologyUniversity of New Mexico Health Sciences CenterAlbuquerqueUSA