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 acts by binding to a high-affinity cell- surface receptor located within the plasma membrane of responsive cells. Actions of both IGFs are regulated by the IGF-I receptor, a ligand- stimulated tyrosine protein kinase structurally related to the insulin receptor. By contrast the IGF-II receptor appears not to mediate growth factor signaling but rather to facilitate clearance of IGF-II from the extracellular environment in a manner analogous with its other role in targeting and reclaiming lysosomal enzymes. As a further complexity, effects of IGFs on target tissues may be modified through interactions with locally-secreted IGF binding proteins. The focus of this application will be on the role of the IGF system in muscle development, and represents part of a long-term effort to understand the mechanisms by which actions of IGFs, their receptors, and binding proteins are integrated within the cell and in the whole organism. Based on current observations, we now postulate that two key functions for IGFs in muscle are to stimulate cell survival during the transition from proliferating to differentiating myoblasts, and to potentiate terminal differentiation. The following four Specific Aims are proposed to test these hypotheses: 1. To determine the roles of the phosphatidylinositol 3-kinase and Akt signaling pathways in mediating IGF-stimulated myoblast survival. 2. To determine if the cyclin-dependent kinase inhibitor, p21/WAF-1/CIP-1, and myogenic transcription factors, MyoD and myogenin, are downstream effectors of IGF-promoted muscle cell survival. 3. To define the signaling pathways and mediators of IGF-potentiated muscle differentiation. 4. To elucidate the functions of IGFBP-5 in muscle development and to define the mechanisms of regulation of IGFBP-5 gene transcription during myoblast differentiation.
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