Specific inhibition by hGRB10zeta 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 tyrosine-phosphorylated receptors including the insulin receptor kinase (IRK). In this study recombinant adenovirus was used to over-express hGrb10\u3b6, a new Grb10 isoform, in primary rat hepatocytes and the consequences for insulin signaling were evaluated. Over-expression of hGrb10\u3b6 resulted in 50% inhibition of insulin-stimulated IRK autophosphorylation and activation. Analysis of downstream events showed that hGrb10z 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\u3b6 over-expression. These results indicate that hGrb10\u3b6 inhibits a novel and presently unidentified insulin signaling pathway leading to GS activation in liver.NRC publication: Ye