Biological actions of insulin are initiated by activation of the insulin receptor tyrosine kinase.Protein tyrosine phosphatases (PTPases) PTP1B and PTP
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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(F
2Pmp) to determine whether we could improve the insulin resistance caused by overexpression of PTP1Bor PTP
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. Rat adipose cells transfected by electroporation with either PTP1B or PTP
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were treated withoutor with the inhibitor, and effects on insulin-stimulated translocation of a cotransfected epitope-taggedGLUT4 were studied. The IC
50 of the F
2Pmp-containing inhibitor is 180 nM for PTP1B and 10 mM forPTP
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in vitro. As expected, in the absence of the inhibitor, overexpression of either PTP1B or PTP
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caused 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
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) was reversed bytreating the transfected cells with the F
2Pmp-containing inhibitor. Furthermore, the inhibitor blocked theinsulin-stimulated association of PTP1B with the insulin receptor. We conclude that the F
2Pmp-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.