In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 108, No. 25 ( 2011-06-21), p. 10349-10354
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.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1103503108
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2011
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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