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Signal integration by mTORC1 coordinates nutrient input with biosynthetic output

Nature Cell Biology volume 15, pages 555–564 (2013)Cite this article

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Abstract

Flux through metabolic pathways is inherently sensitive to the levels of specific substrates and products, but cellular metabolism is also managed by integrated control mechanisms that sense the nutrient and energy status of a cell or organism. The mechanistic target of rapamycin complex 1 (mTORC1), a protein kinase complex ubiquitous to eukaryotic cells, has emerged as a critical signalling node that links nutrient sensing to the coordinated regulation of cellular metabolism. Here, we discuss the role of mTORC1 as a conduit between cellular growth conditions and the anabolic processes that promote cell growth. The emerging network of signalling pathways through which mTORC1 integrates systemic signals (secreted growth factors) with local signals (cellular nutrients — amino acids, glucose and oxygen — and energy, ATP) is detailed. Our expanding understanding of the regulatory network upstream of mTORC1 provides molecular insights into the integrated sensing mechanisms by which diverse cellular signals converge to control cell physiology.

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Figure 1: mTORC1 signalling links cellular growth conditions with metabolic processes underlying anabolic cell growth and proliferation.
Figure 2: Secreted growth factors stimulate mTORC1 activity through the PI(3)K–Akt and Ras–Erk pathways.
Figure 3: Model of the Rag-dependent recruitment of mTORC1 to the lysosome in response to amino acids and the integration with Rheb-dependent growth factor signalling.
Figure 4: Transcriptional and post-translational regulation of mTORC1 by glucose, oxygen and cellular energy.

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Acknowledgements

We apologize to our colleagues whose work we were not able to cover in this Review owing to space constraints. C.C.D. is supported by NIH grant 5T32HL007893-15. Research in the Manning laboratory related to this subject is supported by NIH grants R01-CA122617 and P01-CA120964, DOD grants TS093033 and TS110065, a Sanofi Innovation Award, and grants from the American Diabetes Association and Ellison Medical Foundation.

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  1. Christian C. Dibble is in the Division of Signal Transduction, and the Systems Biology Department, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA, Harvard Medical School, Boston, Massachusetts 02115, USA,

    Christian C. Dibble

  2. Brendan D. Manning is in the Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA,

    Brendan D. Manning

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Dibble, C., Manning, B. Signal integration by mTORC1 coordinates nutrient input with biosynthetic output. Nat Cell Biol 15, 555–564 (2013). https://doi.org/10.1038/ncb2763

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