Growing knowledge of the mTOR signaling network

Abstract

The kinase mTOR (mechanistic target of rapamycin) integrates diverse environmental signals and translates these cues into appropriate cellular responses. mTOR forms the catalytic core of at least two functionally distinct signaling complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 promotes anabolic cellular metabolism in response to growth factors, nutrients, and energy and functions as a master controller of cell growth. While significantly less well understood than mTORC1, mTORC2 responds to growth factors and controls cell metabolism, cell survival, and the organization of the actin cytoskeleton. mTOR plays critical roles in cellular processes related to tumorigenesis, metabolism, immune function, and aging. Consequently, aberrant mTOR signaling contributes to myriad disease states, and physicians employ mTORC1 inhibitors (rapamycin and analogs) for several pathological conditions. The clinical utility of mTOR inhibition underscores the important role of mTOR in organismal physiology. Here we review our growing knowledge of cellular mTOR regulation by diverse upstream signals (e.g. growth factors; amino acids; energy) and how mTORC1 integrates these signals to effect appropriate downstream signaling, with a greater emphasis on mTORC1 over mTORC2. We highlight dynamic subcellular localization of mTORC1 and associated factors as an important mechanism for control of mTORC1 activity and function. We will cover major cellular functions controlled by mTORC1 broadly. While significant advances have been made in the last decade regarding the regulation and function of mTOR within complex cell signaling networks, many important findings remain to be discovered.

Keywords: Amino acids; Energy; Insulin; mTOR; mTORC1; mTORC2.

Figure 1. Regulation of the mTORC1 and mTORC2 signaling network by diverse upstream inputs

Growth factors such as insulin or EGF activate mTORC1 through either the PI3K-Akt or the Ras-MAPK (ERK)-RSK axes, respectively. Growth factor-mediated activation of mTORC1 absolutely requires sufficient levels of amino acids, which are sensed through a variety of factors, as indicated. mTORC1 action also requires sufficient levels of energy (i.e. ATP) and/or oxygen, which are sensed by AMPK, REDD1, and TCA cycle metabolites (i.e. αKG). The TSC complex integrates diverse upstream signals to regulate mTORC1 action. TSC suppresses the conversion of Rheb-GDP to Rheb-GTP, a small GTPase that activates mTORC1. mTORC1 phosphorylates a limited known set of bona fide substrates to drive anabolic and suppress catabolic cellular processes and to mediate negative feedback toward PI3K. Growth factors (i.e. insulin) also activate mTORC2 through poorly defined signaling intermediates.

Figure 2. Rag heterodimers recruit mTORC1 to lysosomal membranes for Rheb-mediated activation

Activation of mTORC1 by amino acids through Rag GTPase heterodimers involves the v-ATPase, ragulator complex, and Rag regulatory factors. The ragulator complex, which acts as a GEF toward RagA/B GTPases, induces formation of active RagA/B^GTP-RagC/D^GDP heterodimers. The GATOR1 complex functions as a GAP (GTPase activating protein) for RagA/B (thus inhibiting Rag heterodimers) while folliculin (FLCN) and its associated proteins (FNIP1/2) functions as a GAP for Rag C/D (thus promoting a Rag heterodimer active state). The GATOR2 complex suppresses GATOR1. Active RagA/B^GTP-RagC/D^GDP heterodimers bind mTORC1 through raptor to recruit mTORC1 to the lysosomal surface where Rheb resides. When loaded with GTP, Rheb activates mTORC1 through a poorly defined mechanism. An “inside-out” model proposes that the v-ATPase and ragulator respond to amino acid levels inside the lysosomal lumen to control Rag nucleotide binding state.

Figure 3. Integration of amino acid and insulin sensing at the lysosome by spatial-temporal regulation of mTORC1 and TSC

Recent data suggest a model in which amino acids and insulin control mTORC1 activity at the lysosome by spatial-temporal regulation of not only mTORC1 but also its inhibitor TSC. In the absence of amino acids and insulin, inactive mTORC1 localizes to the cytosol while active TSC localizes to lysosomal membranes in a Rag-dependent manner. Upon stimulation with amino acids, active RagA/B^GTP-RagC/D^GDP heterodimers recruit mTORC1 to lysosomal membranes where Rheb resides to mediate basal mTORC1 activity; simultaneously, amino acids induce TSC dissociation from lysosomal membranes partially. Similar to amino acids, insulin stimulation induces TSC dissociation from lysosomal membranes. mTORC1 dissociates from lysosomes completely only when both Rag heterodimers and Rheb exist in their inactive states. Conversely, mTORC1 associates with lysosomal membranes fully only when Rag heterodimers and Rheb exist in their active states in the presence of both amino acids and insulin.