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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Metabolism Study Section (MET)
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Sato, Sheryl M
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Oregon Health and Science University
Schools of Medicine
United States
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Rotwein, Peter (2018) The insulin-like growth factor 2 gene and locus in nonmammalian vertebrates: Organizational simplicity with duplication but limited divergence in fish. J Biol Chem 293:15912-15932
Rotwein, Peter (2018) The complex genetics of human insulin-like growth factor 2 are not reflected in public databases. J Biol Chem 293:4324-4333
Rotwein, Peter (2017) Large-scale analysis of variation in the insulin-like growth factor family in humans reveals rare disease links and common polymorphisms. J Biol Chem 292:9252-9261
Alzhanov, Damir; Rotwein, Peter (2016) Characterizing a distal muscle enhancer in the mouse Igf2 locus. Physiol Genomics 48:167-72
Gross, Sean M; Rotwein, Peter (2016) Mapping growth-factor-modulated Akt signaling dynamics. J Cell Sci 129:2052-63
Gross, Sean M; Rotwein, Peter (2016) Unraveling Growth Factor Signaling and Cell Cycle Progression in Individual Fibroblasts. J Biol Chem 291:14628-38
Gardner, Samantha; Gross, Sean M; David, Larry L et al. (2015) Separating myoblast differentiation from muscle cell fusion using IGF-I and the p38 MAP kinase inhibitor SB202190. Am J Physiol Cell Physiol 309:C491-500
Rotwein, Peter S (2015) Editorial: is it time for an evolutionarily based human endocrinology? Mol Endocrinol 29:487-9
Gross, Sean M; Rotwein, Peter (2015) Akt signaling dynamics in individual cells. J Cell Sci 128:2509-19
Rotwein, Peter (2014) Editorial: the fall of mechanogrowth factor? Mol Endocrinol 28:155-6

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