Rag GTPases in mTOR regulation and physiological functions

University Of California, San Diego, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): The mammalian target of rapamycin, mTOR (also known as mechanistic target of rapamycin) controls cell growth. Dysregulation of mTOR has been implicated in many human diseases and drugs inhibiting mTOR have been approved for cancer treatment. mTOR forms two distinct structural and functional complexes, mTORC1 and mTORC2. mTORC1 is the rapamycin sensitive target and plays a major role in cell growth by promoting protein synthesis and anabolism, and inhibiting autophagy. The precise regulation of mTORC1 is critically important for cell growth and organism development. mTORC1 activity is controlled by cellular energy levels, nutrients, and growth factors. Amino acids have emerged as a major signal for mTORC1. The Rag family GTPases has been identified as key mediators relaying amino acid signals to mTORC1 activation. However, the physiological function of Rag GTPases and their role in mTORC1 regulation in vivo are largely unknown. The major goal of this proposal is to determine the in vivo function of Rag GTPases in mTORC1 regulation and physiology using genetically altered mouse models. In addition, we have discovered that amino acids can still activate mTORC1 even when the RagA and RagB genes are deleted. We will investigate the Rag-independent amino acid signaling to mTORC1 activation.