title: Endogenous S-sulfhydration of PTEN helps protect against modification by nitric oxide.
abstract: Hydrogen sulfide (H2S) is a gaseous regulatory factor produced by several enzymes, and plays a pivotal role in processes such as proliferation or vasodilation. Recent reports demonstrated the physiological and pathophysiological functions of H2S in neurons. PTEN is a target of nitric oxide (NO) or hydrogen peroxide, and the oxidative modification of cysteine (Cys) residue(s) attenuates its enzymatic activity. In the present study, we assessed the effect of H2S on the direct modification of PTEN and the resulting downstream signaling. A modified biotin switch assay in SH-SY5Y human neuroblastoma cells revealed that PTEN is S-sulfhydrated endogenously. Subsequently, site-directed mutagenesis demonstrated that both Cys71 and Cys124 in PTEN are targets for S-sulfhydration. Further, the knockdown of cystathionine β-synthetase (CBS) using siRNA decreased this modification in a manner that was correlated to amount of H2S. PTEN was more sensitive to NO under these conditions. These results suggest that the endogenous S-sulfhydration of PTEN via CBS/H2S plays a role in preventing the S-nitrosylation that would inhibition its enzymatic activity under physiological conditions.
authors.affiliation: Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Ohno
authors.affiliation: Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan.
authors.forename: Kosaku
authors.initials: K
authors.lastname: Okuda
authors.affiliation: Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan. Electronic address: uehara@pharm.okayama-u.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Uehara
mesh_terms: D001710:Biotin / Q000737:chemistry; D045744:Cell Line, Tumor; D003541:Cystathionine beta-Synthase / Q000737:chemistry; D003545:Cysteine / Q000737:chemistry; D006801:Humans; D006862:Hydrogen Sulfide / Q000737:chemistry*; D016297:Mutagenesis, Site-Directed; D009447:Neuroblastoma / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009569:Nitric Oxide / Q000737:chemistry*; D018384:Oxidative Stress; D051059:PTEN Phosphohydrolase / Q000737:chemistry* / Q000235:genetics*; D010957:Plasmids / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D013455:Sulfur / Q000737:chemistry*; D014162:Transfection
chemical_list: D034741:RNA, Small Interfering; D009569:Nitric Oxide; D001710:Biotin; D013455:Sulfur; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D003541:Cystathionine beta-Synthase; D003545:Cysteine; D006862:Hydrogen Sulfide
keywords: Cystathionine β-synthase; Hydrogen sulfide; Nitric oxide; PTEN; S-nitrosylation; S-sulfhydration