On–off system for PI3-kinase–Akt signaling through S -nitrosylation of phosphatase with sequence homology to tensin (PTEN)
Open Access
- 6 June 2011
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 108 (25), 10349-10354
- https://doi.org/10.1073/pnas.1103503108
Abstract
Nitric oxide (NO) physiologically regulates numerous cellular responses through S-nitrosylation of protein cysteine residues. We performed antibody-array screening in conjunction with biotin-switch assays to look for S-nitrosylated proteins. Using this combination of techniques, we found that phosphatase with sequence homology to tensin (PTEN) is selectively S-nitrosylated by low concentrations of NO at a specific cysteine residue (Cys-83). S-nitrosylation of PTEN (forming SNO-PTEN) inhibits enzymatic activity and consequently stimulates the downstream Akt cascade, indicating that Cys-83 is a critical site for redox regulation of PTEN function. In ischemic mouse brain, we observed SNO-PTEN in the core and penumbra regions but found SNO-Akt, which is known to inhibit Akt activity, only in the ischemic core. These findings suggest that low concentrations of NO, as found in the penumbra, preferentially S-nitrosylate PTEN, whereas higher concentrations of NO, known to exist in the ischemic core, also S-nitrosylate Akt. In the penumbra, inhibition of PTEN (but not Akt) activity by S-nitrosylation would be expected to contribute to cell survival by means of enhanced Akt signaling. In contrast, in the ischemic core, SNO-Akt formation would inhibit this neuroprotective pathway. In vitro model systems support this notion. Thus, we identify unique sites of PTEN and Akt regulation by means of S-nitrosylation, resulting in an “on–off” pattern of control of Akt signaling.This publication has 47 references indexed in Scilit:
- Structural profiling of endogenous S-nitrosocysteine residues reveals unique features that accommodate diverse mechanisms for protein S-nitrosylationProceedings of the National Academy of Sciences of the United States of America, 2010
- Transnitrosylation of XIAP Regulates Caspase-Dependent Neuronal Cell DeathMolecular Cell, 2010
- A protein microarray-based analysis of S -nitrosylationProceedings of the National Academy of Sciences of the United States of America, 2009
- Protein S-nitrosylation in health and disease: a current perspectiveTrends in Molecular Medicine, 2009
- S-Nitrosylation of Drp1 Mediates β-Amyloid-Related Mitochondrial Fission and Neuronal InjuryScience, 2009
- S-nitrosylation of peroxiredoxin 2 promotes oxidative stress-induced neuronal cell death in Parkinson's diseaseProceedings of the National Academy of Sciences of the United States of America, 2007
- PCAF Modulates PTEN ActivityOnline Journal of Public Health Informatics, 2006
- Crystal Structure of the PTEN Tumor Suppressor: Implications for Its Phosphoinositide Phosphatase Activity and Membrane AssociationCell, 1999
- Negative Regulation of PKB/Akt-Dependent Cell Survival by the Tumor Suppressor PTENCell, 1998
- PTEN , a Putative Protein Tyrosine Phosphatase Gene Mutated in Human Brain, Breast, and Prostate CancerScience, 1997