Trends in Cell Biology
ReviewRegulation of mTORC1 by PI3K signaling
Section snippets
Introduction to PI3K and mTORC1 signaling
Signaling networks endow cells with the ability to sense their internal and external environment in an integrated manner and mount coordinated responses involving processes such as growth, proliferation, survival, and differentiation. Cells of multicellular organisms must simultaneously take into account intracellular levels of nutrients and stress, cell–cell contacts, and organismal metabolism and stress conditions. The relay of such information between cells and tissues is mediated in part by
The primary pathway from PI3K to mTORC1: switching on Rheb
A little more than a decade ago, the PI3K–Akt pathway and mTOR pathway were both known to be important, growth factor-sensitive regulators of protein synthesis and cell growth, but whether they functioned within a linear pathway or in parallel remained an unresolved question [14]. Genetic and biochemical studies unified these pathways through identification of two missing links between Akt and mTORC1: the small GTPase Rheb and its negative regulator, the TSC complex 15, 16, 17, 18, 19, 20, 21,
PRAS40 phosphorylation
In addition to activating mTORC1 by stimulating GTP loading on Rheb, PI3K signaling negatively regulates PRAS40, an inhibitory subunit of mTORC1. PRAS40, which binds and inhibits mTORC1 under conditions of low PI3K–mTORC1 signaling, is thought to compete with other substrates for their interaction with Raptor, the substrate-binding subunit of mTORC1 43, 106, 107. When PI3K–mTORC1 signaling is stimulated, PRAS40 dissociates from mTORC1. This requires simultaneous phosphorylation of PRAS40 on
The lysosome: key site of mTORC1 regulation by PI3K signaling
The Akt–TSC complex–Rheb axis is the primary link between PI3K and mTORC1. However, multiple mechanisms have been proposed to explain how phosphorylation of TSC2 by Akt prevents the TSC complex from inhibiting Rheb. Akt has been suggested to inhibit the TSC complex by inducing its degradation 120, 121 or disassembly 22, 23, 122, 123. However, analyses of endogenous TSC complexes from growth factor-stimulated cells have confirmed that the complex remains stable and intact under conditions where
A model of mTORC1 activation by PI3K signaling and amino acids at the lysosome
Insights into mTORC1 regulation continue to emerge at a rapid pace and several recent findings have yielded as many questions as answers. Keeping this in mind, we summarize a working model of mTORC1 activation by PI3K signaling at the lysosome that builds directly on the established model of amino acid sensing by mTORC1 at this compartment and draws on the groundbreaking work of many groups delineating the components and wiring of the pathway 1, 2, 3, 4, 6, 11, 12, 13 (Figure 2).
First, mTORC1
Concluding remarks
Understanding at a fine scale how signals are transduced through the PI3K–mTORC1 pathway can shed light on physiological processes such as insulin-regulated glucose metabolism and pathological conditions such as cancer and diabetes. Here we have focused on how growth factor-stimulated PI3K signaling activates Rheb and is integrated with nutrient signaling at the lysosome to activate mTORC1. We do not yet completely understand how key pathway components traffic to the lysosome, how the TSC
Acknowledgments
The authors thank Alex Toker, Brendan Manning, Kristin Brown, and Evan Lien for helpful comments. This work was supported by National Institutes of Health grants K99-CA194314 (C.C.D.) and R01-GM041890 (L.C.C.).
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