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 hGrb10ζ, a new Grb10 isoform, in primary rat hepatocytes and the consequences for insulin signaling were evaluated. Over-expression of hGrb10ζ 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 hGrb10ζ over-expression. These results indicate that hGrb10ζ inhibits a novel and presently unidentified insulin signaling pathway leading to GS activation in liver.
Molecular and Cellular Endocrinology173, no. 1-2 (19 February 2001): 15–27.