Regulation of mTOR complex 1 in response to growth factors and nutrients

Abstract

In multicellular organisms, cells ensure the simultaneous availability of growth factors and nutrients before they invest in cellular processes that lead to growth. The TOR kinase is a master regulator of cellular growth and nucleates two distinct protein complexes known as TOR complex 1 and 2 (TORC1 and 2). The activity of TORC2 is mainly regulated by growth factors, whereas TORC1 activity is responsive to both growth factors and nutrients, and thus acts as a detector of favorable growth conditions. The consequence of TORC1 activation is increased protein translation through its substrates S6K and 4E-BP1. Many of the upstream signals that lead to activation of TOR pathway are tumor suppressors and deregulation of the pathway leads to disease. We aim to better understand the regulation of mammalian TORC1 (mTORC1) by upstream signals. In the work described here, we identified PRAS40 as a new component of mTORC1. PRAS40 is phosphorylated in response to growth factors and this phosphorylation event leads to mTORC1 activation. We also showed that the small GTPase Rheb, a major upstream activator of mTORC1, activates it by directly interacting with mTORC1. Both PRAS40 and Rheb relay information from growth factors to mTORC1, and do not seem to be regulated by nutrients, particularly amino acids. In this work, we also investigated how amino acids lead to mTORC1 activation. We showed that amino acids activate mTORC1 by recruiting the complex to lysosomal surface through the action of evolutionarily conserved Rag GTPases. We also indentified a complex of three proteins (p14, p18 and MP1), that we call the "Ragulator" complex, as Rag GTPase interacting proteins. The Ragulator itself localizes to lysosomes through lipid modifications on p18, and tethers the Rag GTPases on the lysosomal surface. We speculate that amino acid-induced lysosomal localization of mTORC1 enables its encounter with Rheb. Through this work, we propose a model for growth factor and amino acid-induced mTORC1 activation.