A Phosphotyrosyl Mimetic Peptide Reverses Impairment of Insulin-Stimulated Translocation of GLUT4 Caused by Overexpression of PTP1B in Rat Adipose Cells
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- 作者：Hui Chen ; Li-Na Cong ; Yunhua Li ; Zhu-Jun Yao ; Li Wu ; Zhong-Yin Zhang ; Terrence R. Burke ; Jr. ; and Michael J. Quon
- 刊名：Biochemistry
- 出版年：1999
- 出版时间：January 5, 1999
- 年：1999
- 卷：38
- 期：1
- 页码：384 - 389
- 全文大小：70K
- 年卷期：v.38,no.1(January 5, 1999)
- ISSN：1520-4995
文摘
Biological actions of insulin are initiated by activation of the insulin receptor tyrosine kinase.Protein tyrosine phosphatases (PTPases) PTP1B and PTP
are known to dephosphorylate the insulinreceptor and may contribute to insulin resistance in diseases such as diabetes. We previously reportedthat overexpression of PTP1B in rat adipose cells significantly impairs insulin-stimulated translocation ofGLUT4 [Chen, H., et al. (1997) J. Biol. Chem. 272, 8026]. In the present study, we treated adipose cellswith a PTPase inhibitor containing the phosphotyrosyl mimetic difluorophosphonomethyl phenylalanine(F2Pmp) to determine whether we could improve the insulin resistance caused by overexpression of PTP1Bor PTP. Rat adipose cells transfected by electroporation with either PTP1B or PTP were treated withoutor with the inhibitor, and effects on insulin-stimulated translocation of a cotransfected epitope-taggedGLUT4 were studied. The IC50 of the F2Pmp-containing inhibitor is 180 nM for PTP1B and 10 mM forPTP in vitro. As expected, in the absence of the inhibitor, overexpression of either PTP1B or PTPcaused a significant decrease in the amount of GLUT4 at the cell surface both in the absence and in thepresence of insulin when compared with control cells transfected with epitope-tagged GLUT4 alone.Interestingly, the insulin resistance caused by overexpression of PTP1B (but not PTP) was reversed bytreating the transfected cells with the F2Pmp-containing inhibitor. Furthermore, the inhibitor blocked theinsulin-stimulated association of PTP1B with the insulin receptor. We conclude that the F2Pmp-containingcompound is a potent and specific inhibitor of overexpressed PTP1B that may be useful for designingrational therapies for treating insulin resistant diseases such as diabetes.
are known to dephosphorylate the insulinreceptor and may contribute to insulin resistance in diseases such as diabetes. We previously reportedthat overexpression of PTP1B in rat adipose cells significantly impairs insulin-stimulated translocation ofGLUT4 [Chen, H., et al. (1997) J. Biol. Chem. 272, 8026]. In the present study, we treated adipose cellswith a PTPase inhibitor containing the phosphotyrosyl mimetic difluorophosphonomethyl phenylalanine(F2Pmp) to determine whether we could improve the insulin resistance caused by overexpression of PTP1Bor PTP. Rat adipose cells transfected by electroporation with either PTP1B or PTP were treated withoutor with the inhibitor, and effects on insulin-stimulated translocation of a cotransfected epitope-taggedGLUT4 were studied. The IC50 of the F2Pmp-containing inhibitor is 180 nM for PTP1B and 10 mM forPTP in vitro. As expected, in the absence of the inhibitor, overexpression of either PTP1B or PTPcaused a significant decrease in the amount of GLUT4 at the cell surface both in the absence and in thepresence of insulin when compared with control cells transfected with epitope-tagged GLUT4 alone.Interestingly, the insulin resistance caused by overexpression of PTP1B (but not PTP) was reversed bytreating the transfected cells with the F2Pmp-containing inhibitor. Furthermore, the inhibitor blocked theinsulin-stimulated association of PTP1B with the insulin receptor. We conclude that the F2Pmp-containingcompound is a potent and specific inhibitor of overexpressed PTP1B that may be useful for designingrational therapies for treating insulin resistant diseases such as diabetes.