Abstract A22: Identification of a novel protein that blocks the Rag-Ragulator interaction and inhibits mTORC1

mTORC1 controls key pathways that maintain cell viability, including translation, ribosome biogenesis and autophagy. Amino acids are a crucial input to mTORC1 activation, resulting in the recruitment of the complex to the surface of lysosomal membrane. The kinase activity of mTORC1 is subsequently turned on at the lysosome downstream of growth factor signaling. mTORC1 is brought to the lysosome by the Rag GTPases, which are tethered to the membrane by their lysosomal scaffold and guanine nucleotide exchange factor, Ragulator. We have identified a novel regulator of mTORC1 activity that inhibits mTORC1 through binding to the Ragulator. This binding prevents the interaction between the Ragulator and its only known substrate, the Rag GTPases, both in cells and in vitro. This disruption of the Rag-Ragulator interaction results in impaired mTORC1 activation by amino acids. However, the novel Ragulator-interacting protein is not regulated by amino acids; it behaves as a link that integrates another signal transduction pathway that inhibits mTORC1 regardless of the presence of amino acids. Citation Format: Lawrence D. Schweitzer, David M. Sabatini. Identification of a novel protein that blocks the Rag-Ragulator interaction and inhibits mTORC1. [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 A22.