Insulin-stimulated hydrogen peroxide reversibly inhibits protein-tyrosine phosphatase 1B in vivo and enhances the early insulin action cascade
Insulin-stimulated hydrogen peroxide reversibly inhibits protein-tyrosine phosphatase 1B in vivo and enhances the early insulin action cascade
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DOI：
10.1074/jbc.c100109200
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发表时间：
2001-06-15
影响因子：
4.8
通讯作者：
Goldstein, BJ
中科院分区：
文献类型：
--
作者：
Mahadev, K;Zilbering, A;Goldstein, BJ
胰岛素信号通路由胰岛素受体和关键受体后底物蛋白的酪氨酸磷酸化激活，并通过特定蛋白酪氨酸磷酸酶（PTPases）的作用来平衡，而PTPase的活性在体内则受到涉及催化所需的半胱氨酸硫醇部分的氧化/还原反应的高度调节。在这里，我们表明胰岛素刺激在胰岛素敏感的肝癌和脂肪细胞中产生细胞内H2O2爆发，这与高达62%的细胞总PTPase活性的可逆氧化抑制有关，这是通过一种严格厌氧条件下的新方法测量的。胰岛素刺激后，免疫沉淀的PTP1B特异性活性也被高达88%的胰岛素刺激强烈抑制。过氧化氢酶预处理消除了胰岛素刺激下H2O2的产生，抑制了包括PTP1B在内的细胞PTPase，并与胰岛素刺激下酪氨酸受体和高M-r胰岛素受体底物（IRS）蛋白的磷酸化减少有关。这些数据提供了令人信服的新证据，证明氧化还原信号通过PTP1B和其他酪氨酸磷酸酶的氧化失活，增强了早期胰岛素刺激的酪氨酸磷酸化级联反应。
The insulin signaling pathway is activated by tyrosine phosphorylation of the insulin receptor and key postreceptor substrate proteins and balanced by the action of specific protein-tyrosine phosphatases (PTPases), PTPase activity, in turn, is highly regulated in vivo by oxidation/reduction reactions involving the cysteine thiol moiety required for catalysis, Here we show that insulin stimulation generates a burst of intracellular H2O2 in insulin-sensitive hepatoma and adipose cells that is associated with reversible oxidative inhibition of up to 62% of overall cellular PTPase activity, as measured by a novel method using strictly anaerobic conditions. The specific activity of immunoprecipitated PTP1B, a PTPase homolog implicated in the regulation of insulin signaling, was also strongly inhibited by up to 88% following insulin stimulation, Catalase pretreatment abolished the insulin-stimulated production of H2O2 as well as the inhibition of cellular PTPases, including PTP1B, and was associated with reduced insulin-stimulated tyrosine phosphorylation of its receptor and high M-r insulin receptor substrate (IRS) proteins. These data provide compelling new evidence for a redox signal that enhances the early insulin-stimulated cascade of tyrosine phosphorylation by oxidative inactivation of PTP1B and possibly other tyrosine phosphatases.