title: On-off system for PI3-kinase-Akt signaling through S-nitrosylation of phosphatase with sequence homology to tensin (PTEN).
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.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Numajiri
authors.forename: Kumi
authors.initials: K
authors.lastname: Takasawa
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nishiya
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Tanaka
authors.forename: Kazuki
authors.initials: K
authors.lastname: Ohno
authors.forename: Wataru
authors.initials: W
authors.lastname: Hayakawa
authors.forename: Mariko
authors.initials: M
authors.lastname: Asada
authors.forename: Hiromi
authors.initials: H
authors.lastname: Matsuda
authors.forename: Kaoru
authors.initials: K
authors.lastname: Azumi
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kamata
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hara
authors.forename: Masabumi
authors.initials: M
authors.lastname: Minami
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lipton
authors.forename: Takashi
authors.initials: T
authors.lastname: Uehara
mesh_terms: D000818:Animals; D017209:Apoptosis; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D017385:Sequence Homology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D009569:Nitric Oxide; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human