mTORC1 signaling and the metabolic control of cell growth

https://doi.org/10.1016/j.ceb.2017.02.012Get rights and content

mTOR [mechanistic target of rapamycin] is a serine/threonine protein kinase that, as part of mTORC1 (mTOR complex 1), acts as an important molecular connection between nutrient signals and the metabolic processes indispensable for cell growth. While there has been pronounced interest in the upstream mechanisms regulating mTORC1, the full range of downstream molecular targets through which mTORC1 signaling stimulates cell growth is only recently emerging. It is now evident that mTORC1 promotes cell growth primarily through the activation of key anabolic processes. Through a diverse set of downstream targets, mTORC1 promotes the biosynthesis of macromolecules, including proteins, lipids, and nucleotides to build the biomass underlying cell, tissue, and organismal growth. Here, we focus on the metabolic functions of mTORC1 as they relate to the control of cell growth. As dysregulated mTORC1 underlies a variety of human diseases, including cancer, diabetes, autoimmune diseases, and neurological disorders, understanding the metabolic program downstream of mTORC1 provides insights into its role in these pathological states.

Introduction

Cellular metabolic homeostasis requires the coordinated conversion of nutrients (e.g., glucose and amino acids) and energy (ATP) into macromolecules (e.g., proteins, nucleic acids, and lipids) through anabolic processes and the recycling of these macromolecules back into their nutrient components, which can be further catabolized to produce energy (Figure 1a). With a continuous input of nutrients, this interconversion of nutrients and macromolecules can, theoretically, be self-sustaining. However, cells and organisms possess distinct systems to sense fluctuations in nutrients and energy to properly adapt their metabolic state to nutrient availability (feast) or depletion (famine) [1]. At the cellular level, these nutrient sensing mechanisms involve transcription factors, such as hypoxia-inducible factor 1 (HIF1) and sterol regulatory element-binding protein (SREBP), which can alter the metabolic program of the cell through the expression of nutrient transporters and metabolic pathway-specific enzymes. In addition, acute adaptations to changes in intracellular nutrients and energy can be achieved through nutrient sensing signaling proteins, such as the protein kinases glucose non-fermenting 2 (GCN2) and AMP-activated protein kinase (AMPK). Here, we discuss the mechanistic (or mammalian) target of rapamycin (mTOR) complex 1 (mTORC1) as a nutrient sensing protein kinase that acts as a master regulator of cellular metabolism. Through a network of upstream signaling pathways, mTORC1 integrates signals from intracellular nutrients and energy with endocrine and paracrine signals reflecting the status of the system or tissue, in the form of exogenous growth factors, hormones, and cytokines, to reciprocally regulate a variety of anabolic and catabolic processes (Figure 1b). Through its control of cellular metabolism, mTORC1 promotes the production of biomass to support growth and proliferation or the stable storage of energy in highly reduced macromolecules, such as lipids. The importance of coordinated regulation of distinct biosynthetic processes and metabolic pathways that support anabolic metabolism downstream of mTORC1 is discussed below.

Section snippets

An upstream signaling network regulates mTORC1 through the Rag and Rheb (Ras homology enriched in brain) GTPases

The activation state of mTORC1 is tightly controlled by numerous upstream signaling pathways that respond to either exogenous growth factors through cell surface receptors or changes in intracellular nutrients and energy through cytosolic sensors. These mTORC1 regulatory pathways, which have been extensively reviewed in recent years [2, 3], impinge on two systems of small G proteins and their regulators that reside, at least in part, on the cytosolic face of lysosomes (Figure 2). The Rag

mTORC1 activation promotes anabolic metabolism

Through a variety of transcriptional, translational, and post-translational mechanisms, mTORC1 stimulates an increase in biosynthetic processes that are otherwise maintained at basal, homeostatic states. As such, it should be emphasized that mTORC1 is not required for the anabolic processes described below, but serves as an essential link between growth signals and heightened biosynthetic activities.

Autophagy and lysosomal degradation

Autophagy is a highly conserved catabolic pathway that is activated in response to nutrient and energy deprivation, at least in part, through the inhibition of mTORC1 signaling. The process of autophagy serves to recycle cytosolic components, such as proteins and organelles, into their nutrient components through engulfment in a membranous structure called the autophagosome, which subsequently fuses with the lysosome for degradation of its components. The autophagy pathway is made up of several

Conclusions and impact on human diseases

It is now evident that mTORC1 serves as a key molecular link between signals that control cell growth and the metabolic processes that underlie growth (Figure 2). It should be emphasized that, while mTORC1 is essential for the survival of organisms from yeast to mammals [104, 105], it is not generally required for the basal activity of the metabolic pathways it controls. As such, inhibition of mTORC1 is not equal to direct inhibition of a metabolic enzyme in the given pathway. However, the

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank Gerta Hoxhaj and Alexander Valvezan for discussions and critical comments. Studies in the Manning laboratory on this topic were supported by grants from the LAM Foundation (I.B.-S.), Tuberous Sclerosis Alliance (B.D.M.), Ellison Medical Foundation (B.D.M.), and NIH grants K99/R00-CA194192 (I.B.-S.) and P01-CA120964 and R35-CA197459 (B.D.M.).

References (119)

  • V. Iadevaia et al.

    mTORC1 signaling controls multiple steps in ribosome biogenesis

    Semin. Cell Dev. Biol.

    (2014)
  • D.N. Roberts et al.

    Dephosphorylation and genome-wide association of Maf1 with Pol III-transcribed genes during repression

    Mol. Cell

    (2006)
  • A.A. Michels et al.

    mTORC1 directly phosphorylates and regulates human MAF1

    Mol. Cell Biol.

    (2010)
  • T.W. Traut

    Physiological concentrations of purines and pyrimidines

    Mol. Cell Biochem.

    (1994)
  • A.M. Robitaille et al.

    Quantitative phosphoproteomics reveal mTORC1 activates de novo pyrimidine synthesis

    Science

    (2013)
  • I. Ben-Sahra et al.

    mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle

    Science

    (2016)
  • J.B. French et al.

    Spatial colocalization and functional link of purinosomes with mitochondria

    Science

    (2016)
  • T.R. Peterson et al.

    mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway

    Cell

    (2011)
  • S.J. Ricoult et al.

    Oncogenic PI3K and K-Ras stimulate de novo lipid synthesis through mTORC1 and SREBP

    Oncogene

    (2016)
  • T.E. Harris et al.

    Dual function lipin proteins and glycerolipid metabolism

    Trends Endocrinol. Metab.

    (2011)
  • R.M. Young et al.

    Dysregulated mTORC1 renders cells critically dependent on desaturated lipids for survival under tumor-like stress

    Genes Dev.

    (2013)
  • S.Y. Lunt et al.

    Aerobic glycolysis: meeting the metabolic requirements of cell proliferation

    Annu. Rev. Cell Dev. Biol.

    (2011)
  • E. Laughner et al.

    HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression

    Mol. Cell Biol.

    (2001)
  • H. Nakamura et al.

    TCR engagement increases hypoxia-inducible factor-1 alpha protein synthesis via rapamycin-sensitive pathway under hypoxic conditions in human peripheral T cells

    J. Immunol.

    (2005)
  • J.W. Lee et al.

    The association of AMPK with ULK1 regulates autophagy

    PLoS One

    (2010)
  • A.S. Loffler et al.

    Ulk1-mediated phosphorylation of AMPK constitutes a negative regulatory feedback loop

    Autophagy

    (2011)
  • L. Shang et al.

    Nutrient starvation elicits an acute autophagic response mediated by Ulk1 dephosphorylation and its subsequent dissociation from AMPK

    Proc. Natl. Acad. Sci. U. S. A.

    (2011)
  • Y.M. Kim et al.

    mTORC1 phosphorylates UVRAG to negatively regulate autophagosome and endosome maturation

    Mol. Cell

    (2015)
  • R.M. Perera et al.

    The lysosome as a regulatory hub

    Annu. Rev. Cell Dev. Biol.

    (2016)
  • W. Palm et al.

    The Utilization of extracellular proteins as nutrients is suppressed by mTORC1

    Cell

    (2015)
  • C.C. Dibble et al.

    Signal integration by mTORC1 coordinates nutrient input with biosynthetic output

    Nat. Cell Biol.

    (2013)
  • Y. Sancak et al.

    The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1

    Science

    (2008)
  • E. Kim et al.

    Regulation of TORC1 by Rag GTPases in nutrient response

    Nat. Cell Biol.

    (2008)
  • L. Bar-Peled et al.

    A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1

    Science

    (2013)
  • R.L. Wolfson et al.

    Sestrin2 is a leucine sensor for the mTORC1 pathway

    Science

    (2016)
  • L. Chantranupong et al.

    The CASTOR proteins are arginine sensors for the mTORC1 pathway

    Cell

    (2016)
  • S. Menon et al.

    Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome

    Cell

    (2014)
  • S. Menon et al.

    Common corruption of the mTOR signaling network in human tumors

    Oncogene

    (2008)
  • A.C. Gingras et al.

    Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism

    Genes Dev.

    (1999)
  • P.E. Burnett et al.

    RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1

    Proc. Natl. Acad. Sci. U. S. A.

    (1998)
  • N. Sonenberg et al.

    Regulation of translation initiation in eukaryotes: mechanisms and biological targets

    Cell

    (2009)
  • H.B. Jefferies et al.

    Rapamycin selectively represses translation of the polypyrimidine tract mRNA family

    Proc. Natl. Acad. Sci. U. S. A.

    (1994)
  • A.C. Hsieh et al.

    The translational landscape of mTOR signalling steers cancer initiation and metastasis

    Nature

    (2012)
  • K. Aoki et al.

    LARP1 specifically recognizes the 3′ terminus of poly(A) mRNA

    FEBS Lett.

    (2013)
  • J. Tcherkezian et al.

    Proteomic analysis of cap-dependent translation identifies LARP1 as a key regulator of 5′TOP mRNA translation

    Genes Dev.

    (2014)
  • B.D. Fonseca et al.

    La-related protein 1 (LARP1) represses terminal oligopyrimidine (TOP) mRNA translation downstream of mTOR complex 1 (mTORC1)

    J. Biol. Chem.

    (2015)
  • N.V. Dorrello et al.

    S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth

    Science

    (2006)
  • D. Shahbazian et al.

    The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity

    EMBO J.

    (2006)
  • X. Wang et al.

    Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase

    EMBO J.

    (2001)
  • W.J. Faller et al.

    mTORC1-mediated translational elongation limits intestinal tumour initiation and growth

    Nature

    (2015)
  • Cited by (425)

    View all citing articles on Scopus
    *

    Current address: Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

    View full text