Abstract
BackgroundThe phosphatase PTEN governs the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway which is arguably the most important pro-survival pathway in neurons. Recently, PTEN has also been implicated in multiple important CNS functions such as neuronal differentiation, plasticity, injury and drug addiction. It has been reported that loss of PTEN protein, accompanied by Akt activation, occurs under excitotoxic conditions (stroke) as well as in Alzheimer's (AD) brains. However the molecular signals and mechanism underlying PTEN loss are unknown.ResultsIn this study, we investigated redox regulation of PTEN, namely S-nitrosylation, a covalent modification of cysteine residues by nitric oxide (NO), and H2O2-mediated oxidation. We found that S-nitrosylation of PTEN was markedly elevated in brains in the early stages of AD (MCI). Surprisingly, there was no increase in the H2O2-mediated oxidation of PTEN, a modification common in cancer cell types, in the MCI/AD brains as compared to normal aged control. Using several cultured neuronal models, we further demonstrate that S-nitrosylation, in conjunction with NO-mediated enhanced ubiquitination, regulates both the lipid phosphatase activity and protein stability of PTEN. S-nitrosylation and oxidation occur on overlapping and distinct Cys residues of PTEN. The NO signal induces PTEN protein degradation via the ubiquitin-proteasome system (UPS) through NEDD4-1-mediated ubiquitination.ConclusionThis study demonstrates for the first time that NO-mediated redox regulation is the mechanism of PTEN protein degradation, which is distinguished from the H2O2-mediated PTEN oxidation, known to only inactivate the enzyme. This novel regulatory mechanism likely accounts for the PTEN loss observed in neurodegeneration such as in AD, in which NO plays a critical pathophysiological role.
Highlights
The phosphatase PTEN governs the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway which is arguably the most important pro-survival pathway in neurons
S-nitrosylated PTEN levels are increased in mild cognitive impairment (MCI)/AD brains, correlating with reduced PTEN and elevated P-Akt Initially, we sought to investigate whether S-nitrosylated PTEN (SNO-PTEN) is produced in neurodegenerative disorders associated with high levels of nitrosative stress such as stroke, AD and Parkinson’s disease (PD)
We included in our tests those specimens taken from autopsy patients diagnosed at an early stage of AD, called mild cognitive impairment (MCI), and compared them to aged matched control brain specimens
Summary
The phosphatase PTEN governs the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway which is arguably the most important pro-survival pathway in neurons. PTEN has been implicated in multiple important CNS functions such as neuronal differentiation, plasticity, injury and drug addiction. Multiple mechanisms might be involved in a decrease or loss of PTEN function, in addition to gene mutation and deletion. These mechanisms may include transcription and post-translational modifications (PTMs) which include phosphorylation, acetylation, oxidation and ubiquitination [14]. The ubiquitin-mediated proteasomal pathway is an important mechanism regulating PTEN protein stability. We recently identified NEDD4-1 as the first ubiquitin ligase (E3) for PTEN that regulates PTEN degradation in multiple cancer types and in neurons [15,18]
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