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Roles of stimulatory and inhibitory protein-tyrosine phosphatase in pathogenesis of insulin resistance

刺激性和抑制性蛋白酪氨酸磷酸酶在胰岛素抵抗发病机制中的作用

基本信息

批准号：
08671148
负责人：
MAEGAWA Hiroshi
金额：
$ 1.41万
依托单位：
Shiga University of Medical Science
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08671148/
关键词：
PTPase SHP-2 Janus kinase 2 Trasgenic mice Insulin resistance Crk-associated substrate SHP-2 Janus kinase 2 (JAK2)SHPTP2

项目摘要

To clarify the roles of protein-tyrosine phosphatase (PTPase) in pathogenesis of insulin resistance, we first investigated insulin signal and insulin action in the cells cultured in high glucose condition, because several species of PTPase (PTP1B,LAR and LRP) were activated in the high-glucose condition, and we found that and insulin signal transduction was attenuated, resulting in insulin resistance. Furthermore, overeexpression of PTP1B,one of the cytosolic PTPase led to attenuated insulin signal transduction. Thus, these PTPase seem to be negative regulator of insulin signal transduction. One the other hand, SHP-2 was a unique PTPase containing Src homology 2 regions on its N-terminus, and the introduction of a dominant negative SHP-2 inhibited insulin signal transduction. Thus, this PTPase is considered to be a positive regulator of insulin signal transduction. Furthermore, we found this SHP-2 interacted with Janus kinase 2 and Crk-associated substrate, and SHP-2 might regulate their functions. Finally, we made transgenic mice expressing our dominant negative SHP-2, and these mice showed insulin resistance. Now, we are studying the mechanism of insulin resistance in these Tg mice.

为了阐明蛋白酪氨酸磷酸酶（PTPase）在胰岛素抵抗发病机制中的作用，我们首先研究了高糖条件下培养的细胞中的胰岛素信号和胰岛素作用，因为几种PTP酶（PTP1B、LAR和LRP）在高糖条件下被激活，我们发现胰岛素信号转导减弱，导致胰岛素反抗。此外，PTP1B（一种胞质 PTP 酶）的过度表达会导致胰岛素信号转导减弱。因此，这些 PTPase 似乎是胰岛素信号转导的负调节因子。另一方面，SHP-2是一种独特的PTPase，其N末端含有Src同源2区域，并且显性失活SHP-2的引入抑制了胰岛素信号转导。因此，这种 PTPase 被认为是胰岛素信号转导的正调节因子。此外，我们发现SHP-2与Janus激酶2和Crk相关底物相互作用，并且SHP-2可能调节它们的功能。最后，我们制作了表达显性失活 SHP-2 的转基因小鼠，这些小鼠表现出胰岛素抵抗。现在，我们正在研究这些Tg小鼠的胰岛素抵抗机制。