Abstract IA07: The TSC complex links PI3K to mTOR and cancer metabolism

Abstract

Abstract Metabolic processes within cells must be managed by integrated control mechanisms that sense the nutrient status of both the cell and organism. The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is a key signaling node, universal to eukaryotic cells, which links the sensing of nutrients to the coordinated regulation of cellular metabolism. mTORC1 has the ability to sense and integrate signals from a variety of sources, including intracellular nutrients and secreted growth factors. mTORC1 senses many of these signals through a small G protein switch involving the TSC1-TSC2-TBC1D7 complex (the TSC complex) and the Ras-related small G protein Rheb. The direct phosphorylation and regulation of the TSC complex by Akt provides the major mechanistic link between PI3K signaling and the control of mTORC1. Recent studies from our lab have revealed the molecular nature of this regulation and how it serves to spatially integrate the major signals upstream of mTORC1. Our studies reveal that the TSC complex blocks mTORC1 activation by inhibiting Rheb on the lysosomal surface, where mTORC1 is recruited in response to amino acids. PI3K-Akt signaling results in acute, phosphorylation-dependent dissociation of the TSC complex from lysosomal Rheb, allowing Rheb to become GTP loaded and activate mTORC1. Importantly, oncogenic PI3K signaling activates mTORC1 in cancer cells by promoting chronic dissociation of the TSC complex from Rheb, resulting in uncontrolled mTORC1 signaling. The physiological and pathological activation of mTORC1 results in downstream changes in cellular metabolism, with a shift from catabolic processes to anabolic biosynthetic processes required for cell growth and proliferation. Through unbiased genomic and metabolomic approaches, we have found that, in addition to its established role in promoting protein synthesis, mTORC1 stimulates changes in specific metabolic pathways through transcriptional and post-translational effects on metabolic enzymes. In this manner, mTORC1 serves to link growth signals to metabolic processes that promote growth, including the de novo synthesis of proteins, lipids, and nucleic acids. In addition, we have recently uncovered a novel and surprising role for mTORC1 in controlling cellular protein and amino acid homeostasis through the coordinated induction of both protein synthesis and proteasome-dependent protein degradation. This seemingly paradoxical function of mTORC1 serves as both a quality control mechanism to handle the increase in misfolded proteins that accompanies elevated rates of protein synthesis and as a means of maintaining adequate pools of intracellular amino acids to sustain new protein synthesis. The potential implications of these novel downstream functions of mTORC1 under physiological and pathological states will be discussed. Citation Format: Brendan D. Manning. The TSC complex links PI3K to mTOR and cancer metabolism. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr IA07.