of work: Insulin elicits pleiotropic and highly integrated series of metabolic and mitogenic responses via its intracellular signaling systems. Upon insulin binding, the intrinsic tyrosine kinase activity of the insulin receptor is activated, thereby leading to phosphorylation of the receptor and its substrates on tyrosine residues. Phosphorylation of these intracellular substrates leads to their association with SH2 domain-containing molecules to generate downstream signals. The defect that causes the characteristic diminution of tissue responses to insulin (also termed insulin resistance) in obesity-related type 2 diabetics is thought to be downstream of the insulin receptor. However, evidence has been presented which supports the notion that maintaining the steady-state phosphorylation of the insulin receptor may represent a valid therapeutic approach for attacking pathologic insulin resistance. Using synthetic peptides derived from unique sequences in the insulin receptor cytoplasmic domain, we have identified a peptide (termed peptide HC) capable of enhancing selectively insulin receptor function both in vitro and in intact cells, while having no effect on insulin-like growth factor 1 (IGF-1) receptor function. We also reported the binding of this peptide to the insulin receptor beta-subunit in cells, thus providing one of few evidences for synergistic interaction between receptor domains. Our laboratory has recently developed a minigene approach that allows stable expression of a receptor fragment that can specifically modulate insulin receptor functions in cells. In addition, a mutant insulin receptor that lacks this receptor fragment has been constructed and expressed stably in Chinese hamster ovary cells. We plan to examine the effect such mutation will have on insulin receptor-mediated signals, and determine whether introduction of the missing fragment by the minigene approach will restore insulin responsiveness to control levels.
| Bernier, Michel; Kwon, Yong-Kook; Pandey, Sanjay K et al. (2006) Binding of manumycin A inhibits IkappaB kinase beta activity. J Biol Chem 281:2551-61 |
| Pandey, Sanjay K; He, Hua-Jun; Chesley, Alan et al. (2002) Wortmannin-sensitive pathway is required for insulin-stimulated phosphorylation of inhibitor kappaBalpha. Endocrinology 143:375-85 |
