The long term goal of this research is to define molecular mechanisms involved in the regulation of cell growth and development by insulin. The signal transduction pathways involved in these processes are not fully understood, through important integral components of several insulin-stimulated pathways have been identified and characterized. The central hypothesis of this proposal is that multiple, distinct signals manage from the insulin receptor (IR) 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. This hypothesis will be tested by analysis of putative effectors of insulin action and manipulation of a chimeric receptor encoding the extracellular ligand binding domain of the colony-stimulation factor-1 receptor (CSF1R) and the cytoplasmic domain of the insulin receptor. Expression of the CSF1R/1R allows CSF-1 to mimic the ability of insulin and IGF I to initiate adipoblast differentiation and activate glucose transport without activation of endogenous insulin receptors Mutations within the cytoplasmic domain of the CSF1R/IR have been useful in examining potential intracellular mediators of insulin action. This model system will be used to examine the molecular mechanisms used by insulin and IGFI to regulate cell growth and development with emphasis on the following: The contribution of IR effectors and pathways to the mitogenic and differentiation-inducing effects of insulin. The potential of IR effectors to manipulate adipocyte gene expression and function. The mechanisms used by IR effectors to transmit insulin-induced survival signals.
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