Specific inhibition by hGRB10ζ of insulin-induced glycogen synthase activation:: evidence for a novel signaling pathway

Grb10 is a member of a family of adapter proteins that binds to to tyrosine-phosphorylated receptors including the insulin receptor kinase: (IRK). In this study recombinant adenovirus was used to over-express hGrb10 zeta, a new Grb10 isoform. in primary rat hepatocytes and the consequences for insulin signaling were evaluated. Over-expression of hGrb10 zeta; resulted in 50%, inhibition of insulin-stimulated IRK autophosphorylation and activation. Analysis of downstream events showed that hGrb10 zeta over-expression specifically inhibits insulin-stimulated glycogen synthase (GS) activity and glycogen synthesis without affecting insulin-induced IRS1/2 phosphorylation. PI3-kinase activation. insulin like growth factor binding protein-1 (IGFBP-1) mRNA expression. and ERK1/2 MAP kinase activity. The classical pathway from PI3-kinase through Akt-PKB/GSK-3 leading to GS activation by insulin was also not affected by hGrb10 zeta over-expression. These results indicate that hGrb10 zeta inhibits a novel and presently unidentified insulin signaling pathway leading to GS activation in liver. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.