Regulation of the mTOR growth pathway by nutrients

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DESCRIPTION (provided by applicant): Growth (mass accumulation) is a critical determinant of cell, organ, and body size and is often deregulated in diseases such as cancer and diabetes. Our long-term research goal is to identify and characterize the molecular mechanisms that control growth and to elucidate their roles in the normal and diseased physiology of mammals. We are studying the mammalian TOR (mTOR) pathway, a conserved signaling system that is emerging as a critical regular of growth in eukaryotes and is the target of the FDA-approved immunosuppressant rapamycin. Recent clinical trials indicate that rapamycin may also be useful for treating certain cancers and autoimmune diseases and for preventing the restenosis of vessels opened with balloon angioplasty. From human cells we recently purified an mTOR-containing protein complex and identified several novel proteins essential for the function of the mTOR pathway within cells. One of these proteins, which we termed raptor, controls the mTOR kinase activity by binding to mTOR in a nutrient-regulated fashion. Our preliminary evidence indicates that the mTOR-raptor complex does not sense nutrients directly but responds, through an unknown mechanism(s), to a signal(s) generated by mitochondria through the metabolism of nutrients. In addition, in certain human cancer cells the regulation of the mTOR pathway is deranged so that neither the mTOR-raptor association nor the activity of downstream effects of mTOR, such as S6K1, responds to nutrients or mitochondrial function. To understand how nutrients regulate the mTOR growth pathway we propose to: (1) identify and characterize the nutrient-regulated post-translational mechanisms that control the mTOR-raptor association and pathway; (2) determine why GbetaL, a novel 36 kDa mTOR-binding protein we discovered in our preliminary studies, is essential for nutrients to regulate the raptor-mTOR association; and (3) determine the mechanisms that cause the mTOR-raptor association and pathway to become nutrient-insensitive in certain human cancer cells and to understand the role of this type of deregulation in the formation and growth of tumors in vivo. Our work will not only lead to a fundamental advance in our understanding of the mechanisms that regulate growth in mammals, but also to the discovery of novel signaling mechanisms that are likely of value as targets for drug development.