S-nitrosylation-dependent inactivation of Akt/protein kinase B in insulin resistance - PubMed (original) (raw)
. 2005 Mar 4;280(9):7511-8.
doi: 10.1074/jbc.M411871200. Epub 2005 Jan 4.
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- PMID: 15632167
- DOI: 10.1074/jbc.M411871200
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S-nitrosylation-dependent inactivation of Akt/protein kinase B in insulin resistance
Takashi Yasukawa et al. J Biol Chem. 2005.
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Abstract
Inducible nitric-oxide synthase (iNOS) has been implicated in many human diseases including insulin resistance. However, how iNOS causes or exacerbates insulin resistance remains largely unknown. Protein S-nitrosylation is now recognized as a prototype of a redox-dependent, cGMP-independent signaling component that mediates a variety of actions of nitric oxide (NO). Here we describe the mechanism of inactivation of Akt/protein kinase B (PKB) in NO donor-treated cells and diabetic (db/db) mice. NO donors induced S-nitrosylation and inactivation of Akt/PKB in vitro and in intact cells. The inhibitory effects of NO donor were independent of phosphatidylinositol 3-kinase and cGMP. In contrast, the concomitant presence of oxidative stress accelerated S-nitrosylation and inactivation of Akt/PKB. In vitro denitrosylation with reducing agent reactivated recombinant and cellular Akt/PKB from NO donor-treated cells. Mutated Akt1/PKBalpha (C224S), in which cysteine 224 was substituted by serine, was resistant to NO donor-induced S-nitrosylation and inactivation, indicating that cysteine 224 is a major S-nitrosylation acceptor site. In addition, S-nitrosylation of Akt/PKB was increased in skeletal muscle of diabetic (db/db) mice compared with wild-type mice. These data suggest that S-nitrosylation-mediated inactivation may contribute to the pathogenesis of iNOS- and/or oxidative stress-involved insulin resistance.
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- R01DK058127/DK/NIDDK NIH HHS/United States
- R01GM055082/GM/NIGMS NIH HHS/United States
- R01 GM055082/GM/NIGMS NIH HHS/United States
- R01GM031569/GM/NIGMS NIH HHS/United States
- R01GM061411/GM/NIGMS NIH HHS/United States
- GM21700/GM/NIGMS NIH HHS/United States
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