The insulin and insulin-like growth factor I (IGF-1) signaling pathways are characterized by close homologies in hormone structure, receptor structure, and the signaling intermediates activated as a consequence of hormone binding. However, despite these marked similarities, insulin functions primarily as a metabolic regulatory hormone and IGF-I primarily as a growth factor. The long-term goals of this project are to define the molecular mechanisms that establish specificity in the insulin and IGF-I pathways, and extent of physiologically important interactions between insulin and the IGFS. Two-hybrid cloning studie during the previous grant period identified Grb10 as a novel protein that bind to the intracellular domain of activated insulin receptors but not IGF-1 receptors. This occurs through two receptor-binding sites in Grb10, an SH2 domain and a previously uncharacterized protein interaction motif. Grb10 co-precipitates with additional proteins besides the insulin receptor.
The specific aims of this project are: (1) to investigate Grb10 function by introducing various constructs of this protein into insulin-responsive cell systems using recombinant adenovirus, (2) to identify proteins in addition to the insulin receptor that bind to Grb10 by both two-hybrid cloning and GST-Grb 10 fusion protein interaction methods, (3) to investigate the multiple isoform of Grb10 that have been identified, (4) to investigate the sites and functiona importance of Grb10 phosphorylation, and (5) to determine the structural basis for GrblO binding to the insulin receptor.
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