NO signaling and S-nitrosylation regulate PTEN inhibition in neurodegeneration

Young Don Kwak, Tao Ma, Shiyong Diao, Xue Zhang, Yaomin Chen, Janet Hsu, Stuart A. Lipton, Eliezer Masliah, Huaxi Xu, Francesca-Fang Liao

Research output: Contribution to journalArticle

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Abstract

Background. The 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. Results. In 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 H2O 2-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. Conclusion. This study demonstrates for the first time that NO-mediated redox regulation is the mechanism of PTEN protein degradation, which is distinguished from the H2O 2-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.

Original languageEnglish (US)
Article number49
JournalMolecular Neurodegeneration
Volume5
Issue number1
DOIs
StatePublished - Nov 12 2010

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PTEN Phosphohydrolase
Nitric Oxide
Ubiquitination
Proteolysis
Oxidation-Reduction
Brain
Neuronal Plasticity
1-Phosphatidylinositol 4-Kinase
Protein Stability
Proteasome Endopeptidase Complex
Ubiquitin
Phosphoric Monoester Hydrolases
Substance-Related Disorders
Cysteine
Stroke
Inhibition (Psychology)
Lipids
Neurons
Wounds and Injuries
Enzymes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

NO signaling and S-nitrosylation regulate PTEN inhibition in neurodegeneration. / Kwak, Young Don; Ma, Tao; Diao, Shiyong; Zhang, Xue; Chen, Yaomin; Hsu, Janet; Lipton, Stuart A.; Masliah, Eliezer; Xu, Huaxi; Liao, Francesca-Fang.

In: Molecular Neurodegeneration, Vol. 5, No. 1, 49, 12.11.2010.

Research output: Contribution to journalArticle

Kwak, YD, Ma, T, Diao, S, Zhang, X, Chen, Y, Hsu, J, Lipton, SA, Masliah, E, Xu, H & Liao, F-F 2010, 'NO signaling and S-nitrosylation regulate PTEN inhibition in neurodegeneration', Molecular Neurodegeneration, vol. 5, no. 1, 49. https://doi.org/10.1186/1750-1326-5-49
Kwak, Young Don ; Ma, Tao ; Diao, Shiyong ; Zhang, Xue ; Chen, Yaomin ; Hsu, Janet ; Lipton, Stuart A. ; Masliah, Eliezer ; Xu, Huaxi ; Liao, Francesca-Fang. / NO signaling and S-nitrosylation regulate PTEN inhibition in neurodegeneration. In: Molecular Neurodegeneration. 2010 ; Vol. 5, No. 1.
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AU - Hsu, Janet

AU - Lipton, Stuart A.

AU - Masliah, Eliezer

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AB - Background. The 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. Results. In 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 H2O 2-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. Conclusion. This study demonstrates for the first time that NO-mediated redox regulation is the mechanism of PTEN protein degradation, which is distinguished from the H2O 2-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.

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