Neuroprotective Role of a Brain-Enriched Tyrosine Phosphatase, STEP, in Focal Cerebral Ischemia

Deb, Ishani; Manhas, Namratta; Poddar, Ranjana; Rajagopal, Sathyanarayanan; Allan, Andrea M.; Lombroso, Paul J.; Rosenberg, Gary A.; Candelario‐Jalil, Eduardo; Paul, Surojit

doi:10.1523/jneurosci.2346-12.2013

Cited by 38 publications

(46 citation statements)

References 43 publications

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“…Indeed, the amount and the activity of STEP are reduced after transient cerebral ischemia (20). Furthermore, ischemic stroke-induced tissue damage, as well as neurological deficits, is exacerbated in STEP KO mice, suggesting a neuroprotective role for STEP-mediated dephosphorylation of proteins after ischemic stroke (21).…”

Section: Tyrosine Phosphorylation Of Glutamate Receptors In the Ischementioning

confidence: 99%

Protein Tyrosine Phosphorylation in the Ischemic Brain

Takagi

2014

J Pharmacol Sci

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Cerebral ischemiaThe pathophysiologic alterations are not the same for all cells in the ischemic brain. The progress of ischemic damage is determined by several factors including the duration of the ischemic episode and the properties of the affected cells (1, 2). An interruption in cerebral blood flow, which limits oxygen and glucose, causes energy depletion, leads to a disturbance in ionic gradients, and thereby a collapse of the membrane potential of neuronal cells. The subsequent membrane depolarization induces a marked increase in the release of neurotransmitters such as excitatory amino acids. Furthermore, energy failure impairs re-uptake of the excitatory neurotransmitters by the high-affinity transporters on the surrounding Protein Tyrosine Phosphorylation in the Ischemic BrainNorio Takagi 1, * Hachioji, Tokyo 192-0392, Japan Received March 30, 2014; Accepted May 26, 2014 Abstract. Cerebral ischemia, a pathological condition in which brain tissue experiences a shortage of cerebral blood flow, is associated with cerebrovascular disease, brain trauma, epilepsy, and cardiac arrest. A reduction in blood flow leaves the brain tissue unsupplied with oxygen and glucose, thus leading to cell death in the ischemic core as well as subsequent peripheral injury in the penumbra. Neurons in the penumbra, where reperfusion occurs, are functionally inactive but still viable. Many biochemical changes, which may lead to neuronal cell death, thereby induce dysfunction of the central nervous system. However, the mechanisms responsible for ischemic stroke-induced cell damage remain to be determined. Protein phosphorylation has been implicated in the regulation of diverse cellular responses in the brain. Initially, tyrosine phosphorylation was considered to be involved in the regulation of cell growth and development. In addition, a variety of synaptic and cellular functions mediated by tyrosine phosphorylation in the brain were found to be associated with relatively high levels of protein tyrosine kinase activity. However, the involvement of this protein tyrosine kinase activity in ischemic cell death is still not fully understood. This review summarizes recent advances dealing with the possible implications of protein tyrosine phosphorylation in the ischemic brain.

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Section: Tyrosine Phosphorylation Of Glutamate Receptors In the Ischementioning

confidence: 99%

Protein Tyrosine Phosphorylation in the Ischemic Brain

Takagi

2014

J Pharmacol Sci

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“…In contrast, dephosphorylation of this residue following glutamate-NMDA receptor mediated activation of calcineurin allows STEP to bind to its substrates and inhibit their activities (21). This dephosphorylated form of STEP also referred to as the active form has been shown to contribute to neuroprotection in cell culture models of excitotoxicity and oxygen glucose deprivation (23,24). Evidence for a neuroprotective role of STEP also comes from in vivo studies demonstrating that degradation of active STEP following an ischemic insult allows activation of detrimental cascades involved in neuronal injury and brain damage.…”

mentioning

confidence: 99%

“…Evidence for a neuroprotective role of STEP also comes from in vivo studies demonstrating that degradation of active STEP following an ischemic insult allows activation of detrimental cascades involved in neuronal injury and brain damage. In contrast, restoration of STEP function, using a brain-permeable STEP-derived peptide, is effective in limiting ischemic brain injury (24).…”

mentioning

confidence: 99%

Zn2+-dependent Activation of the Trk Signaling Pathway Induces Phosphorylation of the Brain-enriched Tyrosine Phosphatase STEP

Poddar¹,

Rajagopal²,

Shuttleworth

et al. 2016

Journal of Biological Chemistry

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Excessive release of Zn 2؉ in the brain is implicated in the progression of acute brain injuries. Although several signaling cascades have been reported to be involved in Zn 2؉ -induced neurotoxicity, a potential contribution of tyrosine phosphatases in this process has not been well explored. Here we show that exposure to high concentrations of Zn 2؉ led to a progressive increase in phosphorylation of the striatal-enriched phosphatase (STEP), a component of the excitotoxic-signaling pathway that plays a role in neuroprotection. Zn 2؉ -mediated phosphorylation of STEP 61 at multiple sites (hyperphosphorylation) was induced by the up-regulation of brain-derived neurotropic factor (BDNF), tropomyosin receptor kinase (Trk) signaling, and activation of cAMP-dependent PKA (protein kinase A). Mutational studies further show that differential phosphorylation of STEP 61 at the PKA sites, Ser-160 and Ser-221 regulates the affinity of STEP 61 toward its substrates. Consistent with these findings we also show that BDNF/Trk/PKA mediated signaling is required for Zn 2؉ -induced phosphorylation of extracellular regulated kinase 2 (ERK2), a substrate of STEP that is involved in Zn 2؉ -dependent neurotoxicity. The strong correlation between the temporal profile of STEP 61 hyperphosphorylation and ERK2 phosphorylation indicates that loss of function of STEP 61 through phosphorylation is necessary for maintaining sustained ERK2 phosphorylation. This interpretation is further supported by the findings that deletion of the STEP gene led to a rapid and sustained increase in ERK2 phosphorylation within minutes of exposure to Zn 2؉ . The study provides further insight into the mechanisms of regulation of STEP 61 and also offers a molecular basis for the Zn 2؉ -induced sustained activation of ERK2.A growing body of evidence indicates that Zn 2ϩ , the second most abundant transition metal in the brain, is released at high concentrations during excitotoxic neurological conditions and can contribute to neuronal injury (1-7). The proposed mechanisms associated with Zn 2ϩ -dependent neurotoxicity include alteration of activity of a diverse group of post-synaptic receptors like ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), 3 N-methyl-D-aspartic acid (NMDA), voltagegated calcium channels and neurotrophic receptors (7-12). Receptor activation in turn modulates the function of several intracellular kinases including protein kinase C, mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (ERK MAPK), and the Src family of tyrosine kinases resulting in impaired energy production, excitability and oxidative stress (8,9,(13)(14)(15). However, the role of phosphatases in Zn 2ϩ -induced neurotoxicity is currently not well understood.The intracellular tyrosine phosphatase, STEP (striatalenriched tyrosine phosphatase, also known as PTPN5) is expressed exclusively in the central nervous system (16,17) and is emerging as a key regulator of neuronal survival and death. The STEP-family of PTPs includes both membrane-assoc...

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“…Whole STEP plays an initial role in neuroprotection by disrupting the p38MAPK pathway. 38 However, the degradation of active STEP is associated with the secondary activation of p38MAPK. The application of a cell-permeable STEP-derived peptide, Tat-STEP, which is resistant to degradation and binds to p38MAPK, protects cultured neurons from hypoxia-reoxygenation injury and reduces ischemic brain damage.…”

Section: Downstream Molecules Of Nnosmentioning

confidence: 99%

“…The application of a cell-permeable STEP-derived peptide, Tat-STEP, which is resistant to degradation and binds to p38MAPK, protects cultured neurons from hypoxia-reoxygenation injury and reduces ischemic brain damage. 38,39 Because CAPON, dexras1, PARS, p38MAPK, and STEP are all downstream molecules of nNOS and represent part of the nNOS signal, blocking any of them does not completely inhibit the destructive effect of nNOS. Thus, the combined application of these types of drugs or their use as an alternative treatment for PSd-95-nNOS uncouplers is supported.…”

Section: Downstream Molecules Of Nnosmentioning

confidence: 99%