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 Presentation

"Insulin action: The key roles of insulin receptor kinase (IRK) activation and internalization in effecting signaling"

Dr. Barry Posner (biography)
English - 2002-04-26 - 39 minutes
(28 slides)

Summary :
The insulin receptor (IR) is a heterotetrameric molecule consisting of two extracelleular alpha chains and two transmembrane beta chains linked by disulfide bonds. Each beta chain contains a tyrosine kinase activity in its cytosolic extension. The binding of a single insulin molecule into a pocket created by the two alpha chains effects a conformational change in the IR so that the beta chains approximate one another and carry out transphosphorylation on tyrosine residues. The autophosphorylated IR kinase (IRK) is capable of phosphorylating other substrates including IRSs 1 to 4, Shc, cbl and Gab 1. The IRK is rapidly internalized into endosomes (ENs) following the binding of insulin. The endosomal system has been shown to be a site where insulin signaling is regulated. Degradation of endosomal insulin, and a conformational change in the IRK so as to reduce its activity as a tyrosine kinase, for example, occur there. The endosomal system is thus a key site for effecting and regulating insulin signaling. It represents a candidate location where factors promoting insulin resistance may operate.


Learning objectives :
The participant will gain insight into how the insulin signaling pathway itself might be involved in insulin resistance. Specifically, the internalization of the ligand-bound insulin receptor kinase (IRK) and its processing in the endosome sheds light on where the pathway might be flawed, thus leading to insulin resistance.


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

Mounier C, Lavoie L, Dumas V, Mohammad-Ali K, Wu J, Nantel A, Bergeron JJ, Thomas DY, Posner BI.

The Polypeptide Hormone Laboratory, McGill University, Strathcona Building, 3640 University Street, Quebec, H3A 2B2, Montreal, Canada.

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.

Mol Cell Endocrinol 2001 Feb 28;173(1-2):15-27



   


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