Trends in Cell Biology
Volume 25, Issue 9, September 2015, Pages 545-555
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Review
Regulation of mTORC1 by PI3K signaling

https://doi.org/10.1016/j.tcb.2015.06.002Get rights and content

Highlights

  • mTORC1 activity requires the Rag and Rheb GTPases and signals from amino acids and growth factors.

  • Growth factor-stimulated PI3K–Akt signaling activates Rheb and mTORC1 at the lysosome.

  • Amino acid signaling promotes mTORC1–Rheb colocalization at the lysosome.

  • Akt activates Rheb by inducing dissociation of its GAP, the TSC complex, from the lysosome.

The class I phosphoinositide 3-kinase (PI3K)–mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) signaling network directs cellular metabolism and growth. Activation of mTORC1 [composed of mTOR, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (mLST8), 40-kDa proline-rich Akt substrate (PRAS40), and DEP domain-containing mTOR-interacting protein (DEPTOR)] depends on the Ras-related GTPases (Rags) and Ras homolog enriched in brain (Rheb) GTPase and requires signals from amino acids, glucose, oxygen, energy (ATP), and growth factors (including cytokines and hormones such as insulin). Here we discuss the signal transduction mechanisms through which growth factor-responsive PI3K signaling activates mTORC1. We focus on how PI3K-dependent activation of Akt and spatial regulation of the tuberous sclerosis complex (TSC) complex (TSC complex) [composed of TSC1, TSC2, and Tre2–Bub2–Cdc16-1 domain family member 7 (TBC1D7)] switches on Rheb at the lysosome, where mTORC1 is activated. Integration of PI3K- and amino acid-dependent signals upstream of mTORC1 at the lysosome is detailed in a working model. A coherent understanding of the PI3K–mTORC1 network is imperative as its dysregulation has been implicated in diverse pathologies including cancer, diabetes, autism, and aging.

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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