| Research Abstract |
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.
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