In response to insulin, glucose transporters redistribute to the plasma membrane, glucose and lipid metabolism shifts into an anabolic mode, lipid kinases generate anti-apoptotic signals, and tyrosine kinases stimulate cell growth. Current models propose that insulin responses arise from the intrinsic ligand-stimulated tyrosine kinase activity of the receptor acting upon a small subset of tyrosine phosphoprotein adapters. Recent work, however, has begun to reveal extensive networks of cross talk between insulin family receptors and other signal transducers including heterotrimeric G proteins and classical receptor tyrosine kinases. In this proposal, we provide preliminary data demonstrating that IGF-1 receptors stimulate the anti-apoptotic IRS1/Phosphatidylinositol 3-kinase/Akt pathway and the proliferative Shc/Grb2-Sos/Ras/ERK1/2 pathway by distinct mechanisms. Whereas IGF- 1 receptor-mediated phosphorylation of IRS proteins controls the antiapoptotic pathway, IGF-1-induced mitogenic signaling requires the release of epidermal growth factor (EGF)like ligands from the cell surface and paracrine """"""""transactivation"""""""" of EGF receptors. Cross talk between IGF- 1 and EGF receptors is mediated by matrix metalloprotease-dependent cleavage of heparin-binding (HB)-EGF, process which also involves pertussis toxin-sensitive heterotrimeric G proteins. The broad goals of this proposal are to characterize the mechanisms of cross talk between insulin/IGF-1 receptors, EGF receptors, and heterotrimeric G proteins, and to determine contribution of these mechanisms to transcriptional regulation and the control of cell proliferation by insulin and IGF- 1 receptors.
One specific aim of this proposal to determine the mechanism whereby insulin and IGF- 1 receptors regulate matrix metalloproteases to control ectodomain shedding of EGF receptor ligands. Another aim is to determine the mechanism of cross talk between insulin/lGF- 1 receptors and heterotrimeric G proteins and to define the role of heterotrimeric G proteins in insulin and IGF- 1 receptor-mediated activation of the ERK1/2 MAP kinase cascade.
The third aim i s to determine the contribution of cross talk between insulin/lGF- 1 receptors, heterotrimeric G proteins and EGF receptors to transcriptional regulation and the control of cell proliferation in a variety of insulin-sensitive cell types. Experiments will employ immortalized cell lines, as well as cultured hepatocyte, adipocyte and muscle cells. Understanding these mechanisms may lead to pharmacologic approaches to dissociate the potentially harmful proliferative effects of insulin family receptors from their anti-apoptotic and metabolic effects.
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