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

为了阐明蛋白酪氨酸磷酸酶（PTP 1B，LAR和LRP）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胰岛素信号和胰岛素作用，因为在高糖条件下，几种PTP 1B（PTP 1B，LAR和LRP）被激活，并且我们发现胰岛素信号转导被减弱，导致胰岛素抵抗。此外，PTP 1B的过度表达，胞浆PTP 1B的一个导致减弱胰岛素信号转导。因此，这些PTK似乎是胰岛素信号转导的负调节剂。另一方面，SHP-2是一种独特的PTB，其N端含有Src同源2区，并且引入显性负性SHP-2抑制胰岛素信号转导。因此，这种PTK被认为是胰岛素信号转导的正调节剂。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，我们制造了表达显性阴性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。

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.