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 Serine-Threonine Kinases / metabolism
-
Protein Tyrosine Phosphatases / antagonists & inhibitors
-
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
-
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