title: Overexpression of membrane glycoprotein PC-1 can influence insulin action at a post-receptor site.
abstract: 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.
authors.affiliation: Diabetes and Endocrine Research, Mt. Zion Medical Center, University of California, San Francisco 94115, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kumakura
authors.forename: B A
authors.initials: BA
authors.lastname: Maddux
authors.forename: C K
authors.initials: CK
authors.lastname: Sung
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D010727:Phosphoric Diester Hydrolases; D011505:Protein-Tyrosine Kinases / Q000032:analysis; D011755:Pyrophosphatases; D011972:Receptor, Insulin / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology
chemical_list: D007328:Insulin; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases