It is the overall objective of this proposal to understand the nature of the transmembrane signal produced by the interaction of insulin and IGF-1 with their respective cell-surface receptors. These hormone/growth factors are ancestrally related polypeptides that mediate a similar pleiotropic response in target cells as a consequence of ligand binding to receptor. The receptors for insulin and IGF-1 also seem to be closely related proteins that share a complex disulfide-linked tetrameric subunit composition, and also share ligand-dependent, tyrosine-specific protein kinase activity. The major difference in them is that IGF-1 receptors can elicit a mitogenic signal in many cells and insulin receptors generally do not, although both receptors may be present on the cell surface. The biochemical and/or physical nature of any transmembrane signal that results from either ligand interacting with its receptor is not known. By undertaking detailed structure/function studies of the receptors, it is expected that information will be obtained that will lead to a description of the transmembrane signalling process. The techniques to this end are those of protein chemistry and cell biology. Thus, the insulin binding domain and protein kinase domain of the affinity-purified insulin receptor will be identified by site-specific chemical modification. The IGF-1 receptor will be purified and the compositional features of the two pure receptors will be compared. At present, receptor autophosphorylation is the only consequence of the receptors' intrinsic kinase activity demonstrable in vivo. Additional possible cellular substrates for the protein kinase activity of both receptors will be sought, and the cellular location of receptor dephosphorylation will be determined. Because of the central role of the insulin receptor in the regulation of carbohydrate metabolism, and the likely role of the IGF-1 receptor in growth regulation, the results of the proposed studies are of potential interest in the understanding of diabetes as well as in understanding conditions of aberrant growth regulation, e.g. cancer.
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