1] Key Laboratory of Systems Biomedicine (Ministry of Education) of Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui-Jin 2nd Road, Shanghai 200025, China [2] Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, 351 Guo Shou-Jing Road, Shanghai 201203, China.
Cell Res. 2013 Nov;23(11):1310-21. doi: 10.1038/cr.2013.99. Epub 2013 Jul 30.
IRTKS encodes a member of the IRSp53/MIM homology domain family, which has been shown to play an important role in the formation of plasma membrane protrusions. Although the phosphorylation of IRTKS occurs in response to insulin stimulation, the role of this protein in insulin signaling remains unknown. Here we show that IRTKS-deficient mice exhibit insulin resistance, including hyperglycemia, hyperinsulinemia, glucose intolerance, decreased insulin sensitivity, and increased hepatic glucose production. The administration of ectopic IRTKS can ameliorate the insulin resistance of IRTKS-deficient and diabetic mice. In parallel, the expression level of IRTKS was significantly decreased in diabetic mouse model. Furthermore, DNA hypermethylation of the IRTKS promoter was also observed in these subjects. We also show that IRTKS, as an adaptor of the insulin receptor (IR), modulates IR-IRS1-PI3K-AKT signaling via regulating the phosphorylation of IR. These findings add new insights into our understanding of insulin signaling and resistance.
IRTKS 编码了一个 IRSp53/MIM 同源结构域家族的成员，该家族已被证明在质膜突起的形成中发挥重要作用。尽管 IRTKS 的磷酸化是对胰岛素刺激的反应，但该蛋白在胰岛素信号转导中的作用尚不清楚。在这里，我们显示 IRTKS 缺陷小鼠表现出胰岛素抵抗，包括高血糖、高胰岛素血症、葡萄糖不耐受、胰岛素敏感性降低和肝葡萄糖生成增加。异位 IRTKS 的给药可以改善 IRTKS 缺陷和糖尿病小鼠的胰岛素抵抗。平行地，在糖尿病小鼠模型中也观察到 IRTKS 的表达水平显著降低。此外，在这些受试者中还观察到 IRTKS 启动子的 DNA 超甲基化。我们还表明，IRTKS 作为胰岛素受体 (IR) 的衔接子，通过调节 IR-IRS1-PI3K-AKT 信号转导来调节 IR 的磷酸化。这些发现为我们理解胰岛素信号转导和抵抗提供了新的见解。
