An elevated content of
membrane glycoprotein PC-1 has been observed in cells and tissues of
insulin resistant patients. In addition, in vitro 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, independent of
insulin receptor tyrosine kinase. In the present studies, we employed Chinese hamster ovary cells that overexpress the human
insulin receptor (CHO IR cells; approximately 10(6) receptors per cell), and 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, following
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 (MAP)
kinase activity was normal, suggesting that PC-1 overexpression did not affect
insulin receptor activation of Ras, which is upstream of MAP
kinase. Also,
insulin-stimulated
phosphatidylinositol (PI)-3-kinase activity was normal, suggesting that PC-1 overexpression did not interfere with the activation of this
enzyme by
insulin receptor substrate-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 site.