OVEREXPRESSION OF MEMBRANE GLYCOPROTEIN PC-1 CAN INFLUENCE INSULIN ACTION AT A POSTRECEPTOR SITE

An elevated content of membrane glycoprotein PC-1 has been observed in cells and tissues of insulin resistant patients. In addition, in vitr o overexpression of PC-1 in cultured cells induces insulin resistance associated with diminished insulin receptor tyrosine kinase activity. We now find that PC-1 overexpression also influences insulin receptor signaling at a step downstream of insulin receptor tyrosine kinase, in dependent of insulin receptor tyrosine kinase. In the present studies, we employed Chinese hamster ovary cells that overexpress the human in sulin receptor (CHO IR cells; similar to 10(6) receptors per cell), an d transfected them with human PC-1 c-DNA(CHO IR PC-1). In CHO IR PC-1 cells, insulin receptor tyrosine kinase activity was unchanged, follow ing insulin treatment of cells. However, several biological effects of insulin, including glucose and amino acid uptake, were decreased. In CHO IR PC-1 cells, insulin stimulation of mitogen-activated protein (M AP) kinase activity was normal, suggesting that PC-1 overexpression di d not affect insulin receptor activation of Pas, which is upstream of MAP kinase. Also, insulin-stimulated phosphatidylinositol (PI)-3-kinas e activity was normal, suggesting that PC-1 overexpression did not int erfere with the activation of this enzyme by insulin receptor substrat e-1. In these cells, however, insulin stimulation of p70 ribosomal S6 kinase activity was diminished. These studies suggest, therefore, that , in addition to blocking insulin receptor tyrosine kinase activation, PC-1 can also block insulin receptor signaling at a post-receptor sit e. (C) 1998 Wiley-Liss, Inc.