Abstract IA-16: Control of growth by mTOR signaling

Abstract

Abstract mTOR is the target of the immunosuppressive drug rapamycin and the central component of a nutrient- and hormone-sensitive signaling pathway that regulates cell growth and proliferation. We now appreciate that this pathway becomes deregulated in many human cancers. We have identified two distinct mTOR-containing proteins complexes, one of which regulates growth through S6K and another that regulates cell survival through Akt. These complexes, mTORC1 and mTORC2, define both rapamycin-sensitive and insensitive branches of the mTOR pathway. I will discuss new results from our lab on the regulation of the mTORC1 and mTORC2 pathways. I will provide an overview of mTOR signaling as well as discuss the regulation of mTORC1 by insulin and nutrients and the role of mTORC2 in cancer. We have recently identified new upstream components of the mTORC1 pathway that are involved in amino acid sensing and are starting to understand some of the molecular mechanisms involved in this process. Current evidence suggests that amino acids regulate the mTORC1 pathway by controlling the intracellular localization of mTORC1. Specifically, amino acids promote the movement of mTORC1 to a part of the endomembrane system that also contains its activator Rheb. Amino acids signal through the conserved Rag family of small GTPases that directly interact with the raptor component of mTORC1 in fashion that depends on the GTP-loaded status of the Rags. In addition, I will present evidence that inhibition of mTORC1 by the novel mTOR-interacting protein Deptor is a mechanism for hyperactivating PI3K signaling in multiple myeloma. Citation Information: Cancer Res 2009;69(23 Suppl):IA-16.