Insulin-like growth factors I and II exert pleiotropic effects on diverse cell types and have a broad range of functions in the embryo, fetus, and adult. Each IGF interacts with a unique high-affinity receptor located within the plasma membrane of responsive cells. Actions of both IGFs are mediated through interaction with the IGF-I receptor, a ligand-stimulated tyrosine protein kinase structurally related to the insulin receptor. By contrast the role of the IGF-II receptor in IGF-II action is controversial, although its function in mediating lysosomal enzyme transport is well-documented. As a further complexity, effects of both IGFs on target tissues may be modified through interactions with locally- secreted IGF binding proteins. As part of long-term efforts to understand the mechanisms by which the actions of the IGFs, their receptors, and binding proteins are integrated within the cell and in the whole organism, the focus of this application will be on the functions and regulation of IGF-II, the IGF-II receptor, and a newly-characterized IGF binding protein, IGFBP-5, in a model developmental system, the differentiating myoblast, and in the developing mouse embryo. Toward this end the following four Specific Aims are proposed: 1. To determine the role of IGF-II in muscle differentiation and to define its mechanism of action. 2. To elucidate the molecular pathway responsible for developmental regulation of IGF-II gene expression. 3. To determine the functions of the IGF-II receptor in muscle differentiation and in mouse development, and to characterize the mechanisms responsible for the developmental control of receptor gene expression. 4. To elucidate the functions of IGFBP-5 in muscle differentiation and in development, and to determine the steps involved in regulation of binding protein gene expression.
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