On-off system for PI3-kinase-Akt signaling through S-nitrosylation of phosphatase with sequence homology to tensin (PTEN)

Naoki Numajiri, Kumi Takasawa, Tadashi Nishiya, Hirotaka Tanaka, Kazuki Ohno, Wataru Hayakawa, Mariko Asada, Hiromi Matsuda, Kaoru Azumi, Hideaki Kamata, Tomohiro Nakamura, Hideaki Hara, Masabumi Minami, Stuart A. Lipton, Takashi Uehara

Research output: Contribution to journalArticle

102 Citations (Scopus)

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 bymeans of S-nitrosylation, resulting in an "on - off" pattern of control of Akt signaling.

Original languageEnglish
Pages (from-to)10349-10354
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number25
DOIs
Publication statusPublished - Jun 21 2011

Keywords

  • Apoptosis
  • Ischemia
  • Oxidation

ASJC Scopus subject areas

  • General

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    Numajiri, N., Takasawa, K., Nishiya, T., Tanaka, H., Ohno, K., Hayakawa, W., Asada, M., Matsuda, H., Azumi, K., Kamata, H., Nakamura, T., Hara, H., Minami, M., Lipton, S. A., & Uehara, T. (2011). On-off system for PI3-kinase-Akt signaling through S-nitrosylation of phosphatase with sequence homology to tensin (PTEN). Proceedings of the National Academy of Sciences of the United States of America, 108(25), 10349-10354. https://doi.org/10.1073/pnas.1103503108