Cellular Effects of Small Molecule PTP1B Inhibitors on Insulin Signaling
详细信息 查看全文
- 作者：Laiping Xie ; Seung-Yub Lee ; Jannik N. Andersen ; Steve Waters ; Kui Shen ; Xiao-Ling Guo ; Niels Peter H. Moller ; Jerrold M. Olefsky ; David S. Lawrence ; and Zhong-Yin Zhang
- 刊名：Biochemistry
- 出版年：2003
- 出版时间：November 11, 2003
- 年：2003
- 卷：42
- 期：44
- 页码：12792 - 12804
- 全文大小：412K
- 年卷期：v.42,no.44(November 11, 2003)
- ISSN：1520-4995
文摘
Protein tyrosine phosphatase 1B (PTP1B) is implicated as a negative regulator of insulin receptor(IR) signaling and a potential drug target for the treatment of type 2 diabetes and other associated metabolicsyndromes. To further define the role of PTP1B in insulin signaling and to test the hypothesis that blockingthe activity of PTP1B would augment the action of insulin, we prepared several cell permeable, potentand selective, small molecule PTP1B inhibitors, and evaluated their biological effects in several insulinsensitive cell lines. Our data indicate that PTP1B inhibitors bind to and colocalize with PTP1B on thesurface of the endoplasmic reticulum and PTP1B exerts its negative effect on insulin signaling upstreamof phosphatidylinositol 3-kinase and MEK1. Treatment of cells with PTP1B inhibitors, both in the presenceand in the absence of insulin, markedly enhances IR
and IRS-1 phosphorylation, Akt and ERK1/2activation, Glut4 translocation, glucose uptake, and Elk1 transcriptional activation and cell proliferation.These results indicate that small molecule inhibitors targeted to PTP1B can act as both insulin mimeticsand insulin sensitizers. Taken together, our findings combined with results from PTP1B knockout, antisense,and biochemical studies provide strong evidence that PTP1B negatively regulates insulin signaling andthat small molecule PTP1B inhibitors have the ability to potentiate and augment the action of insulin.
and IRS-1 phosphorylation, Akt and ERK1/2activation, Glut4 translocation, glucose uptake, and Elk1 transcriptional activation and cell proliferation.These results indicate that small molecule inhibitors targeted to PTP1B can act as both insulin mimeticsand insulin sensitizers. Taken together, our findings combined with results from PTP1B knockout, antisense,and biochemical studies provide strong evidence that PTP1B negatively regulates insulin signaling andthat small molecule PTP1B inhibitors have the ability to potentiate and augment the action of insulin.