Specific inhibition by hGRB10zeta of insulin-induced glycogen synthase activation: evidence for a novel signaling pathway

Mol Cell Endocrinol. 2001 Feb 28;173(1-2):15-27. doi: 10.1016/s0303-7207(00)00439-1.

Abstract

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 hGrb10zeta, a new Grb10 isoform, in primary rat hepatocytes and the consequences for insulin signaling were evaluated. Over-expression of hGrb10zeta resulted in 50% inhibition of insulin-stimulated IRK autophosphorylation and activation. Analysis of downstream events showed that hGrb10zeta 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 hGrb10zeta over-expression. These results indicate that hGrb10zeta inhibits a novel and presently unidentified insulin signaling pathway leading to GS activation in liver.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cells, Cultured
  • Enzyme Activation / drug effects
  • GRB10 Adaptor Protein
  • Glycogen / biosynthesis
  • Glycogen Synthase / metabolism*
  • Glycogen Synthase Kinase 3
  • Hepatocytes / drug effects
  • Hepatocytes / enzymology
  • Hepatocytes / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin / pharmacology*
  • Insulin-Like Growth Factor Binding Protein 1 / genetics
  • Male
  • Mitogen-Activated Protein Kinases / metabolism
  • Organometallic Compounds / pharmacology
  • Phenanthrolines / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / drug effects
  • Protein Tyrosine Phosphatases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteins / genetics
  • Proteins / metabolism*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Insulin / antagonists & inhibitors
  • Receptor, Insulin / metabolism
  • Signal Transduction / drug effects
  • Transcription, Genetic / drug effects

Substances

  • Insulin
  • Insulin-Like Growth Factor Binding Protein 1
  • Organometallic Compounds
  • Phenanthrolines
  • Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • GRB10 Adaptor Protein
  • bisperoxo(1,10-phenanthroline)oxovanadate(1-)
  • Glycogen
  • Glycogen Synthase
  • Phosphatidylinositol 3-Kinases
  • Receptor, Insulin
  • AKT1 protein, human
  • Akt1 protein, rat
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • insulin receptor serine kinase
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinases
  • Glycogen Synthase Kinase 3
  • Protein Tyrosine Phosphatases