Since the establishment of a link between growth factors and mTORC1 activation via the interaction of Akt and the Tuberous sclerosis complex (TSC) more than a decade ago (1
), our understanding of the mechanism and players involved has increased substantially. In contrast, the picture of how nutrients activate mTORC1 is far less complete and we are just beginning to add pieces to a puzzle that remained virtually unknown until 2008, with the identification of the Rag GTPases as a direct link between amino acids and mTORC1 (3
Although both growth factors and nutrients culminate in the activation of mTORC1, the means by which each input does suggests cooperation in their ability to trigger mTORC1-based responses. Growth factor signaling drives kinase activation of mTORC1 through a process that starts at the plasma membrane with the transduction of a signal evoked by protein hormones like insulin, via tyrosine kinase receptors and activation of PI3K. PI3K, in turn, activates Akt, which phosphorylates and inhibits TSC (1
), a complex with GTPase activating protein (GAP) activity towards the Rheb GTPase (5
), responsible for direct kinase activation of mTORC1. Nutrient signaling operates in a different manner: when the Rag GTPases where discovered, the originally puzzling observation that the activity of purified mTORC1 was not affected in vitro
by the Rag GTPases lead to the realization that a different mechanism was responsible for Rag-dependent activation of mTORC1. Upon nutrient sufficiency, the Rag GTPases interact with and recruit mTORC1 to the outer lysosomal surface, where the Rag and Rheb GTPases reside (4
), allowing mTORC1 kinase activation by the latter. This mechanistic insight explains why both nutrient and growth factor inputs cannot substitute each other and must simultaneously occur in a cell to achieve activation of mTORC1, and shows that these inputs cooperate to activate mTORC1. Logically, a cell that would trigger anabolism and increase its mass needs to engage cellular processes that are energetically expensive and regulated by mTORC1. Hence, such cooperation warrants that the cell will fully commit to it when 1) long-range growth factor signals are present and 2) local nutrient sensing by the Rag GTPases assures the availability of building blocks and energy.
There are, however, some aspects of Rheb and Rag –dependent regulation of mTORC1 that are similar. In particular, they both reside at the lysosomal surface, and they are both GTPases that change their nucleotide state upon physiological fluctuations of their upstream signals. In the case of Rheb, activation of TSC leads to Rheb loading with GDP, and conversely, TSC inactivation by Akt leads to Rheb loading with GTP, and activation of mTORC1. The four members of the Rag GTPase family behave conceptually differently to most GTPases, as they exist as obligate dimers, where RagA (or RagB) interacts with RagC (or RagD), and their nucleotide state is opposite. Nutrient availability leads to the loading of RagA/B with GTP and C/D with GDP, and its absence loads RagA/B with GDP and C/D with GTP. The role of RagA/B versus C/D is not identical, as single amino acid substitutions in RagA/B that mimic a constitutive loading with GTP, leads to constitutive recruitment (and activation) of mTORC1 regardless of the loading status of RagC/D.