Trends in Cell Biology
ReviewRegulation of mTORC1 by amino acids
Section snippets
Overview of mTORC1 signaling
Growth is a fundamental biological process that is highly influenced by an organism's environment. For multicellular eukaryotes, including mammals, nutrient availability within the local environment is a major determinant of growth and is sensed through central signaling pathways that engage anabolic programs necessary to increase cell and body size. By coupling nutrient-sensing to long-range growth factor and hormonal signaling networks, animals are able to readily adjust their growth and
Amino acid signaling and mTORC1 localization
Early investigations revealed that amino acids are necessary to stimulate protein synthesis in rat skeletal muscles [28], a process now known to be under the control of mTORC1. Subsequent studies in cultured mammalian cells confirmed that a mixture of all 20 amino acids activated mTORC1 and that the combination of amino acid and growth factor signaling was necessary for the phosphorylation of canonical mTORC1 substrates 29, 30. Whether all amino acids, one particular amino acid, or an amino
The lysosome: key site of amino acid sensing
Extracellular amino acids must cross the plasma membrane to reactivate mTORC1 after their depletion from cell culture media [31]. Nevertheless, treating cells with cycloheximide, a protein synthesis inhibitor, preserves sufficient intracellular pools of amino acids to rescue mTORC1 signaling even in the absence of extracellular amino acids. This finding argues that the sensing mechanism must occur within the cell and not at its periphery [34]. The use of a cell-free reconstitution assay
The Rag GTPases mediate the amino acid signal to mTORC1
For a long time it was believed that the amino acid signal impinged on the TSC complex–Rheb axis; however, the development of TSC2−/− mice suggested otherwise. mTORC1 signaling remained sensitive to a change in amino acid levels in mouse embryonic fibroblasts (MEFs) obtained from these animals 40, 41, implicating an alternative route for sensing. This alternative pathway, identified by biochemical and genetic screens 34, 42, centers around the Rag GTPases which lay the molecular foundation for
Regulation of the Rag GTPases
The Rags are critical for proper amino acid sensing because their tight coordination with amino acid levels prevents deregulation of mTORC1 signaling. This coordination depends on Rag GTPase activators and inhibitors which modulate their nucleotide-bound state. The recent identification of some of these regulators highlights a complex signaling network upstream of the Rag GTPases (Figure 1).
Spatial regulation of the TSC complex
A new rigorous study shows that that, like mTORC1, the TSC complex translocates to and from the lysosomal surface in response to insulin signaling but not to amino acid levels [73]. Akt-dependent phosphorylation of TSC2, presumed by many to inhibit TSC complex GAP activity, is responsible for driving the TSC complex off the lysosomal surface, allowing mTORC1 activation by removing TSC from Rheb, the target of its GAP activity [73]. Given the number of signals upstream of mTORC1 that converge on
Concluding remarks
This is an exciting time to study how amino acids are sensed by mTORC1. With the discovery of so many new pathway components there remain many more questions than answers. Clearly, understanding the interplay between positive and negative regulators, and the existence of additional human pathologies associated with these factors are of high interest (Box 3). With the use of a combination of bioinformatic and systems-biology approaches together with more traditional discovery platforms, the
Acknowledgments
We thank Lynne Chantranupong and Shuyu Wang for helpful suggestions and Tom DeCesare for figure design. This work was supported by grants from the National Institutes of Health (CA103866 and AI47389) and Department of Defense (W81XWH-07-0448) to D.M.S. L.B.P is the Lallage Feazel Wall Fellow of the Damon Runyon Cancer Research Foundation (DRG-2178-14). D.M.S. is an investigator of the Howard Hughes Medical Institute.
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