The long term goal of this research is to define molecular mechanisms involved in the regulation of adipocyte differentiation and metabolism by insulin and insulin-like growth factors. The signal transduction pathways involved in these processes are not fully understood, though integral components of several insulin-stimulated pathways have been identified and characterized. The central hypothesis of this proposal is that multiple, distinct signals emanate from the insulin receptor cytoplasmic domain upon activation of the receptor tyrosine kinase, and that those signals act separately and/or in combination to elicit the pleiotropic effects on cell fate and metabolism that are characteristic of insulin action. A chimeric receptor cDNA consisting of the extracellular. ligand-binding domain of the colony stimulating factor-l (CSF-l ) receptor spliced to the transmembrane and cytoplasmic domains of the insulin receptor has been constructed to test this hypothesis. Expression of the CSF/IR allows CSF-l to mimic the ability of insulin and IGF I to initiate adipoblast differentiation and to activate glucose transport without activation of endogenous insulin receptors. Furthermore, mutations within the cytoplasmic domain of the CSF IR/IR inhibit discrete actions of insulin while leavened others intact. This model system will be used to examine the molecular mechanisms used by insulin and IGF I to regulate adipocyte differentiation and metabolism including the following: The role of subdomains and phosphorylation sites within the insulin receptor cytoplasmic domain in coupling receptor signals to the induction and activity of important mediators of adipogenesis. The contribution of the Ras proteins in mediating the IGF l/insulin-stimulated induction of adipogenesis The capacity of modulators of Ins Ras/Raf/MEK/MAP kinase pathway to influence the ability of the insulin receptor cytoplasmic domain to induce adipogenesis. The role of subdomains and phosphorylation sites within the insulin receptor cytoplasmic domain in regulation of adipocyte metabolism including activation of glucose transport and inhibition of lipolysis.
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