Serine/threonine phosphorylation of IRS-1 triggers its degradation - Possible regulation by tyrosine phosphorylation
Serine/threonine phosphorylation of IRS-1 triggers its degradation - Possible regulation by tyrosine phosphorylation
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DOI：
10.2337/diabetes.50.1.24
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发表时间：
2001-01-01
期刊：
影响因子：
7.7
通讯作者：
Rondinone, CM
中科院分区：
文献类型：
--
作者：
Pederson, TM;Kramer, DL;Rondinone, CM
在许多胰岛素抵抗状态中，胰岛素受体底物(IRS)-1蛋白的表达显著降低，尽管这种下调的机制尚不清楚。在这项研究中，我们研究了胰岛素途径中触发IRS-1降解的早期事件。脂肪细胞与胰岛素孵育后，IRS-1的凝胶迁移率发生快速变化，随后蛋白质发生降解。Wortmannin和雷帕霉素阻断IRS-1的这种迁移率变化，维持胰岛素诱导的IRS-1的酪氨酸磷酸化，并阻止其降解。相反，糖原合成酶激酶3抑制剂、有丝分裂原激活的蛋白激酶/细胞外调节的蛋白激酶抑制剂和各种蛋白激酶C抑制剂都没有作用。冈田酸可促进IRS-1丝氨酸/苏氨酸的磷酸化及其类似于胰岛素的降解，其作用可被蛋白酶体抑制剂lactacystin和雷帕霉素所阻断。在胰岛素或冈田酸存在的情况下，用酪氨酸磷酸酶抑制剂原钒酸处理细胞，可部分抑制IRS-1的降解。我们认为，雷帕霉素依赖的途径作为IRS-1的负调节因子参与，增加其丝氨酸/苏氨酸磷酸化，从而触发降解。因此，调节丝氨酸/苏氨酸相对于酪氨酸的磷酸化可能会调节IRS-1的降解，从而影响胰岛素敏感性。
Insulin receptor substrate (IRS)-1 protein expression is markedly reduced in many insulin-resistant states, although the mechanism for this downregulation is unclear. In this study, we have investigated the early events in the insulin pathway that trigger the degradation of IRS-1. Incubation of the adipocytes with insulin induced a fast electrophoretic mobility shift of IRS-1 and a subsequent degradation of the protein. Wortmannin and rapamycin blocked this mobility shift of IRS-1, maintained the insulin-induced tyrosine phosphorylation of IRS-1, and blocked its degradation. In contrast, a glycogen synthase kinase 3 inhibitor, a mitogen-activated protein kinase/extracellular-regulated kinase inhibitor, and various protein kinase C inhibitors had no effect. Incubation with okadaic acid increased the serine/threonine phosphorylation of IRS-1 and its degradation, mimicking insulin, and its effect was prevented by the proteasome inhibitor lactacystin, as well as by rapamycin. Treatment of the cells with the tyrosine phosphatase inhibitor orthovanadate in the presence of insulin or okadaic acid partially inhibited the degradation of IRS-1. We propose that a rapamycin-dependent pathway participates as a negative regulator of IRS-1, increasing its serine/threonine phosphorylation, which triggers degradation. Thus, regulation of serine/ threonine versus tyrosine phosphorylation may modulate IRS-1 degradation, affecting insulin sensitivity.