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Metabolic Flux Regulates Cell Signaling Downloaded from genesdev.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press PERSPECTIVE Metabolism strikes back: metabolic flux regulates cell signaling Christian M. Metallo1 and Matthew G. Vander Heiden2,3,4 1Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; 2Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; 3Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA Mammalian cells depend on growth factor signaling to feedback control on signal transduction networks so that take up nutrients; however, coordination of glucose and metabolic activity is coordinated with cell growth and glutamine uptake has been a mystery. In this issue of proliferation. Genes & Development, Wellen and colleagues (pp. In this issue of Genes & Development, Wellen et al. 2784–2799) show that glucose flux through the hexos- (2010) demonstrate that flux through the hexosamine amine biosynthesis pathway regulates growth factor re- biosynthesis pathway coordinates glucose and glutamine ceptor glycosylation and enables glutamine consumption. metabolism by regulating surface expression of growth This mechanism ensures that cells do not engage in ana- factor receptors. Using a cellular system that decouples bolic metabolism when nutrients are limiting, and high- apoptosis from nutrient deprivation, Thompson and col- lights how substrate availability for protein modifications leagues (Wellen et al. 2010) observed that glucose-deprived can modulate cell signaling. hematopoietic cells do not switch to glutamine metabolism despite the presence of the growth factor IL-3 and a plentiful extracellular supply of the amino acid. Interestingly, glu- cose-dependent glutamine uptake is restored in growth Throughout the 20th century, biochemists systemati- factor-replete cells by supplying N-acetylglucosamine cally worked to outline the pathways cells use to capture (GlcNAc). GlcNAc is unable to enter glycolysis or other energy as ATP and transform organic molecules to syn- pathways of central carbon metabolism and is therefore thesize biomass from various substrates. Often working not available to cells as a fuel source. Rather, GlcNAc enzyme by enzyme, these studies provided the foundation supplementation replenishes the supply of precursors nec- for our mechanistic understanding of metabolism, or ‘‘bio- essary for glycosylation of the IL-3 receptor a subunit (IL- chemical networks,’’ in prokaryotes and higher organisms. 3Ra), leading to proper receptor folding and trafficking to More recently, analogous efforts by molecular biologists the cell surface. Thus, GlcNAc-mediated rescue of glu- have elucidated signal transduction pathways, or ‘‘protein cose-deprived cells restores surface expression of IL-3Ra networks,’’ which control a multitude of cellular functions and allows growth factor-dependent signal transduction, related to growth, differentiation, cell death, and metabo- leading to glutamine consumption and cell growth. lism. Recent work has found that many of the same The finding that cells are unable to consume a readily signaling pathways that control growth also influence available supply of extracellular nutrients when glucose cellular metabolism (Kim and Dang 2006). For example, is absent is surprising. The Thompson group (Rathmell receptor-mediated signaling cascades initiated by growth et al. 2000; Lum et al. 2005) has reported previously that factors stimulate nutrient uptake, cell growth, and cell the ability to initiate glucose uptake is a critical function of cycle progression (DeBerardinis et al. 2008). In mammals, growth factor signaling to promote cell survival (Rathmell the two major nutrients taken up to supply carbon and et al. 2000), and that apoptosis-resistant cells survive by nitrogen for cell proliferation are glucose and glutamine. autophagy in the absence of growth factor (Lum et al. Because glucose and glutamine provide biosynthetic pre- 2005). Wellen et al. (2010) show that pools of metabolites cursors through distinct metabolic pathways, their con- involved in central carbon metabolism drop following sumption must be coordinated by cells. Nevertheless, glucose withdrawal. Nevertheless, these cells still require despite a growing understanding of how signaling path- ATP generation to maintain cellular homeostasis irrespec- ways regulate metabolism, much less is known about how tive of their inability to undergo programmed cell death. In flux through specific pathways is ‘‘sensed’’ to provide the absence of glutamine or other amino acid uptake to support bioenergetics, it is likely that these cells generate [Keywords: Metabolism; glucose; glutamine; hexosamine; growth factor ATP by autophagy. This suggests that the signals used by signaling; glycosylation] cells to initiate catabolism of endogenous cellular compo- 4Corresponding author. E-MAIL [email protected]; FAX (617) 253-3189. nents to maintain survival are distinct from those used to Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.2010510. metabolize nutrients in the extracellular environment. GENES & DEVELOPMENT 24:2717–2722 Ó 2010 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/10; www.genesdev.org 2717 Downloaded from genesdev.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Metallo and Vander Heiden These findings also suggest that cells are wired to avoid in excess (Fang et al. 2010). Together, these studies consuming extracellular resources unless all the metabolic demonstrate that cells require both ATP and biosynthetic components are present along with a growth signal to precursors for proper folding and surface expression of support biosynthesis and cell proliferation. growth factor receptors. The failure to effectively trans- Wellen et al. (2010) found that surface expression of the duce cell growth signals when nutrients are limited may IL-3Ra chain was dependent on the availability of UDP- ensure that cells do not activate the cell growth machinery GlcNAc for receptor N-glycosylation (Fig. 1). Production unless adequate substrates are present. of UDP-GlcNAc under standard growth conditions re- Remarkably, cells that are supplemented with GlcNAc quires glucose flux into the hexosamime biosynthesis in the absence of glucose are able to grow by consuming pathway, glutamine availability to supply the nitrogen for glutamine and other amino acids. Under these condi- the amino sugar, and acetyl-coenzyme A (AcCoA) to donate tions, glutamine serves as an anaplerotic substrate to the acetyl moiety. Numerous surface proteins and growth replenish tricarboxylic acid (TCA) cycle intermediates factor receptors are modified by N-linked glycosylation. and drive oxidative ATP generation, provide carbon for Indeed, receptors important for growth regulation—such lipid synthesis, and facilitate leucine uptake. Two key as CTLA-4, GLUT4, IGFR, EGFR, HER2/ErbB2, and observations were made upon GlcNAc-mediated rescue FGFR—are glycosylated, and the extent of glycosylation of IL-3-dependent cell growth. First, glutamine and other influences surface expression as well as cell growth or dif- amino acids did not allow cell division in the absence of ferentiation (Lau et al. 2007; Fang et al. 2010). This glucose. The finding that cells grow but do not divide in suggests that the availability of UDP-GlcNAc for protein the absence of glucose suggests another mechanism is glycosylation is a means by which cells detect glucose present to sense glucose or a downstream metabolite. Do availability. Notably, physiologically relevant changes in cells use unique metabolic checkpoints to advance through glucose concentration increased IL-3Ra surface expression different stages of the cell cycle? Second, glutamine must in a dose-dependent manner, indicating the sensitivity of have the ability to contribute to multiple metabolic path- this feedback regulation to glucose supply. Because gluta- ways in order to mediate cell growth. Through what path- mine and AcCoA are also needed to make UDP-GlcNAc, ways is glutamine preferentially metabolized within cells, glutamine withdrawal or AcCoA limitation may result in and under what physiological conditions is glutamine used decreased growth factor receptor expression via the same as a carbon source to build biomass? mechanism. Indeed, glucose uptake is also dependent on Glutamine enters the cell through amino acid trans- glutamine metabolism, as both glutamine and cell-perme- porters and acts as a critical source of nitrogen for cells. able a-ketoglutarate (aKG) can repress the MondoA tran- The amido-nitrogen of glutamine (rather than the nitro- scription factor, stimulating glucose consumption and cell gen that remains on glutamate) is essential for synthesis proliferation (Kaadige et al. 2009). Another recent study of nucleotides and hexosamines, and glutamine can also identified an energetic checkpoint that only allowed ef- be deaminated by glutaminase to generate free ammonia fective receptor glycosylation and folding when ATP was in cells. Each of these reactions produces glutamate, one Figure 1. Metabolic pathways provide sub- strates for post-translational modifications (PTMs) that influence cell signaling. Growth factor signaling induces uptake of nutrients such as glucose and glutamine that fuel bio- energetic and biosynthetic pathways in cells. In turn, the availability of UDP-GlcNAc gen- erated
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