Insulin-like growth factors I and II exert pleiotropic effects on diverse cell types. Although current evidence supports a role for IGF-I as a major postnatal growth factor, regulated in part by growth hormone, the functions of IGF-II in growth and development remain undefined. Each IGF interacts initially with a unique high-affinity receptor located in the plasma membrane of responsive cells. Many of the actions of both peptides are mediated by the IGF-I receptor, a ligand-activated tyrosine-specific protein kinase structurally related to the insulin receptor. By contrast the role of the IGF-II receptor in IGF signaling is unclear, despite its apparent identity with the cation-independent mannose-6phosphate receptor involved in targeting lysosomal enzymes. As an additional complexity actions of both IGFs in target tissues may be modified by interaction with various locally-secreted binding proteins. As part of a long-term goal to define the mechanisms by which the actions of the IGFs are integrated within the cell, the focus of this application will be on the functions and regulation of IGF-II, the IGF-II receptor, and a novel IGF binding protein in a model cell system, the differentiating myoblast. 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 mechanisms of qlction. 2.To dissect the functions of the IGF-II gene promoter, in order to define and characterize the elements required for induction of gene expression during myoblast differentiation. 3.To define the function of the IGF-II receptor in muscle differentiation and to characterize the mechanisms involved in regulation of receptor gene expression in this model system. 4.To determine the mechanisms of action and the regulation of a novel IGF binding protein whose secretion is induced during myoblast differentiation.
Showing the most recent 10 out of 63 publications
