NO signaling and S-nitrosylation regulate PTEN inhibition in neurodegeneration
<p>Abstract</p> <p>Background</p> <p>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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2010-11-01
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| Series: | Molecular Neurodegeneration |
| Online Access: | http://www.molecularneurodegeneration.com/content/5/1/49 |
| _version_ | 1819043184701865984 |
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| author | Lipton Stuart A Hsu Janet Chen Yaomin Zhang Xue Diao Shiyong Ma Tao Kwak Young-Don Masliah Eliezer Xu Huaxi Liao Francesca-Fang |
| author_facet | Lipton Stuart A Hsu Janet Chen Yaomin Zhang Xue Diao Shiyong Ma Tao Kwak Young-Don Masliah Eliezer Xu Huaxi Liao Francesca-Fang |
| author_sort | Lipton Stuart A |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>In this study, we investigated redox regulation of PTEN, namely S-nitrosylation, a covalent modification of cysteine residues by nitric oxide (NO), and H<sub>2</sub>O<sub>2</sub>-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 H<sub>2</sub>O<sub>2</sub>-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.</p> <p>Conclusion</p> <p>This study demonstrates for the first time that NO-mediated redox regulation is the mechanism of PTEN protein degradation, which is distinguished from the H<sub>2</sub>O<sub>2</sub>-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.</p> |
| first_indexed | 2024-12-21T09:52:45Z |
| format | Article |
| id | doaj.art-b69295b712df4755bc1d135ced1a505c |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-12-21T09:52:45Z |
| publishDate | 2010-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj.art-b69295b712df4755bc1d135ced1a505c2022-12-21T19:08:08ZengBMCMolecular Neurodegeneration1750-13262010-11-01514910.1186/1750-1326-5-49NO signaling and S-nitrosylation regulate PTEN inhibition in neurodegenerationLipton Stuart AHsu JanetChen YaominZhang XueDiao ShiyongMa TaoKwak Young-DonMasliah EliezerXu HuaxiLiao Francesca-Fang<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>In this study, we investigated redox regulation of PTEN, namely S-nitrosylation, a covalent modification of cysteine residues by nitric oxide (NO), and H<sub>2</sub>O<sub>2</sub>-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 H<sub>2</sub>O<sub>2</sub>-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.</p> <p>Conclusion</p> <p>This study demonstrates for the first time that NO-mediated redox regulation is the mechanism of PTEN protein degradation, which is distinguished from the H<sub>2</sub>O<sub>2</sub>-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.</p>http://www.molecularneurodegeneration.com/content/5/1/49 |
| spellingShingle | Lipton Stuart A Hsu Janet Chen Yaomin Zhang Xue Diao Shiyong Ma Tao Kwak Young-Don Masliah Eliezer Xu Huaxi Liao Francesca-Fang NO signaling and S-nitrosylation regulate PTEN inhibition in neurodegeneration Molecular Neurodegeneration |
| title | NO signaling and S-nitrosylation regulate PTEN inhibition in neurodegeneration |
| title_full | NO signaling and S-nitrosylation regulate PTEN inhibition in neurodegeneration |
| title_fullStr | NO signaling and S-nitrosylation regulate PTEN inhibition in neurodegeneration |
| title_full_unstemmed | NO signaling and S-nitrosylation regulate PTEN inhibition in neurodegeneration |
| title_short | NO signaling and S-nitrosylation regulate PTEN inhibition in neurodegeneration |
| title_sort | no signaling and s nitrosylation regulate pten inhibition in neurodegeneration |
| url | http://www.molecularneurodegeneration.com/content/5/1/49 |
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