Artlabeling Activity Catabolic and Anabolic Pathways of Cellular Metabolism
Curr Opin Biotechnol. Author manuscript; available in PMC 2016 Aug ane.
Published in last edited course as:
PMCID: PMC4490161
NIHMSID: NIHMS651163
A nexus for cellular homeostasis: the interplay between metabolic and betoken transduction pathways
Ana P. Gomes
oneMeyer Cancer Center, Weill Cornell Medical College, New York, NY, USA
iiDepartment of Pharmacology, Weill Cornell Medical College, New York, NY, United states
3Department of Jail cell Biology, Harvard Medical School, Boston, MA, U.s.a.
John Blenis
1Meyer Cancer Centre, Weill Cornell Medical College, New York, NY, USA
2Section of Pharmacology, Weill Cornell Medical College, New York, NY, United states
iiiSection of Jail cell Biology, Harvard Medical Schoolhouse, Boston, MA, U.s.a.
Abstract
In multicellular organisms, individual cells have evolved to sense external and internal cues in order to maintain cellular homeostasis and survive under dissimilar environmental atmospheric condition. Cells efficiently adjust their metabolism to reflect the affluence of nutrients, free energy and growth factors. The power to rewire cellular metabolism between anabolic to catabolic processes is critical for cells to thrive. Thus, cells have developed, through evolution, metabolic networks that are highly plastic and tightly regulated to run into the requirements necessary to maintain cellular homeostasis. The plasticity of these cellular systems is tightly regulated past complex signaling networks that integrate the intracellular and extracellular information. The coordination of signal transduction and metabolic pathways is essential in maintaining a good for you and speedily responsive cellular state.
Introduction
Living organisms require a abiding supply of energy to maintain cell and organ function. Thus, an adequate balance between energy production and free energy expenditure is essential to maintain cellular homeostasis. This is achieved past the regulation of the dynamics betwixt the combustion of fuel sources to produce energy (catabolism), and their ability to use energy to synthesize macromolecules (anabolism). The importance of the rest between these two processes becomes apparent when the metabolic differences between growing cells and differentiated/quiescent cells are examined. To back up growth and proliferation, cells rewire their metabolism to promote anabolic processes that synthesize the macromolecules (proteins, carbohydrates, lipids and nucleic acids) required for generating a girl cell. On the other hand, most tissues are comprise of differentiated and non-dividing cells, thus their metabolism is commonly wired towards catabolic processes that provide energy to sustain cellular integrity and function. Maintaining this fragile remainder is 1 of the most important requirements of life. Thus, it comes as no surprise that eukaryotic cells have evolved to constantly and carefully modulate these processes in response to the always-irresolute weather condition.
In multicellular organisms, cells must be responsive to systemic cues of the physiological country to maintain energetic and cellular stability in addition to sensing the immediate environment. This is achieved through the power of the cells to sense secreted factors (e.g. cytokines, growth factors, hormones) that, upon binding to a prison cell surface receptor, initiate signaling cascades that transduce information and regulate metabolism. Moreover, to ensure that balance between both the availability of nutrients and the cellular capacity to use them effectively is maintained, cells can also sense intracellular metabolite concentrations to fine-melody the signaling networks independently of the environs. Many recent findings have highlighted the fact that metabolites serve as indicators of the metabolic state of the cell, that transduce this information through regulation of pro-translational modifications, such as acetylation, methylation and glycosylation, that regulate the activities of several signaling molecules and transcriptional regulators (not discussed further hither, for review on this topic see [1,2]).
Agreement this intricate bidirectional relationship is a challenge due to its complexity, but ane that is vital for understanding the principles of cellular homeostasis. Such knowledge will be of enormous benefit to determining how diseases develop too as how to treat them.
Anabolic rewiring induced by PI3K/Akt and Ras/ERK signaling
Growth factors, hormones and food signals provide the information required to rewire intermediate metabolism towards anabolism, thereby supporting cell growth and proliferation. The signaling framework downstream of these stimuli is primarily defined by two highly conserved and critical pathways, the phosphatidylinositol-3-kinase (PI3K)/Akt and the extracellular signal-regulated kinase - mitogen-activated poly peptide kinase (ERK-MAPK) signaling cascades (Fig.i).
Anabolic rewiring induced past PI3K/Akt, Ras/ERK and mTORC1 signaling
Extracellular signals actuate two major signaling cascades controlled by the activation of PI3K and Ras. PI3K and Ras regulate Akt and ERK, which in plow induce changes in intermediate metabolism to promote anabolic processes. In improver, they also induce the activation of mTORC1, thus further supporting the rewiring of cellular metabolism towards anabolic processes. Through various mechanisms Akt, ERK and mTORC1 stimulate mRNA translation, aerobic glycolysis, glutamine anaplerosis, lipid synthesis, the pentose phosphate and pyrimidine synthesis, thus producing the major components necessary for cell growth and proliferation.
PI3K/Akt signaling-induced Anabolic Reprogramming
Growth factors and other ligands activate PI3K signaling upon bounden and consequent activation of their cell surface receptors, such as receptor tyrosine kinases (RTKs) and Yard poly peptide-coupled receptors (GPCRs). This leads to the phosphorylation of membrane phosphatidylinositiol lipids and the recruitment and activation of several protein kinases, which perpetuate the extracellular signals to modulate intracellular processes [iii,4]. One of the most critical signal propagators regulated by PI3K signaling is protein kinase B/Akt [3,4]. Indeed, Akt rewires metabolism in response to environmental cues by three distinct means; i) past the direct phosphorylation and regulation of metabolic enzymes, ii) past activating/inactivating metabolism altering transcriptional factors, and 3) past modulating other kinases that themselves regulate metabolism [5].
Akt regulates glucose metabolism, inducing both glucose uptake and glycolytic flux by increasing the expression of the glucose transporter genes and regulating the activity of glycolytic enzymes, respectively [6–8]. Morever, the ability of Akt to induce glycolysis is also mediated by the regulation of Hexokinase (HK). HK performs the outset step of glycolysis. Akt has been shown to regulate the power of HK-2 to interact with the mitochondria, and thus promotes glucose carbon to be oxidized through glycolysis [9]. Past regulating glycolysis, Akt might be involved in regulating the tricarboxylic acid (TCA) cycle activity via the malate/aspartate and glycerol-phosphate shuttles. In improver to glucose metabolism, Akt also directly phosphorylates and activates ATP-citrate lyase (ACL) [10]. ACL promotes the product of acetyl-coA in the cytosol from citrate generated in the TCA bicycle [eleven]. Cytosolic acetyl-coA is vital for de novo lipid synthesis, as it can initiate and/or elongate fatty acids chains [11], thus linking Akt signaling to lipid synthesis.
Moreover, Akt also regulates the transcription factor c-Myc, a primal transcriptional gene that promotes anabolic processes, through phosphorylation and inactivation of a negative regulator of c-Myc, glycogen synthase kinase-three (GSK3) [12]. Together these findings demonstrate that upon stimulation, the PI3K/AKT pathway rewires cells from catabolic to anabolic metabolism (Fig.1).
Ras/ERK signaling cascades and its consequences for anabolism
Extracellular cues as well lead to the activation of the small GTPase, Ras. Like PI3K, the Ras family (H-, K- and N-Ras) is activated downstream of prison cell surface receptors. Ras activation involves its transition to a GTP-bound state, which initiates betoken transduction through several pathways, of which the ERK-MAPK signaling cascade is the best characterized [13].
Taking into consideration the primal role of Ras in orchestrating biological responses to stimuli that induce cell growth and proliferation, Ras stands out as a possible primal driver of anabolic reprogramming. In support of this, Ras has been shown to decouple glucose and glutamine metabolism, thus diverting these carbon sources to anabolic pathways to support cell growth and proliferation [xiv]. Ras signaling enhances glucose uptake and glycolytic flux, simply decreases glucose entry into the TCA cycle [14,fifteen]. This increased flux through glycolysis has been shown to fuel anabolic processes past diverting glucose-derived carbon to the not-oxidative arm of the PPP, thus supporting nucleotide biosynthesis [16]. Interestingly, the mechanisms behind these effects of Ras were found to be through ERK stabilization of c-Myc, which increases the expression of enzymes involved in these pathways [sixteen]. In addition, ERK also induces the flux of glucose-derived carbon towards biosynthetic pathways past phosphorylating and inducing nuclear translocation of the anabolism-related version of pyruvate kinase, pyruvate kinase M2 (PKM2) [17]. While Ras signaling diverts the glucose-derived carbon flux away from the TCA wheel, it besides promotes the utilization of glutamine for anaplerosis and the maintenance of redox potential [xiv,18]. Thus, activation of Ras makes the cells more than dependent on glutamine as a source of carbon and nitrogen for anabolic processes [14,xviii].
Together, these reports have shown that activation of Ras/ERK signaling cascade rewires cells towards anabolism, to promote synthesis of building blocks and energy necessary for cell growth and proliferation (Fig.1).
Mechanistic target of rapamycin (mTOR) every bit the primary regulator of anabolic reprogramming
Despite the direct effects of PI3K/AKT and Ras/ERK on metabolism, activation of mTOR by these pathways seems to business relationship for a large proportion of their metabolic contributions. mTOR exists in two functionally and structurally distinct complexes mTOR complex 1 (mTORC1) and 2 (mTORC2). Of the two complexes, mTORC1 seems to accept the most direct influence in the maintenance of energetic residuum [19]. The PI3K-Akt and Ras/ERK pathways are potent activators of mTORC1 activeness, through the negative regulation of tuberous sclerosis circuitous 2 (TSC2), a major inhibitor of mTORC1 activation. Akt direct phosphorylates TSC2 at multiple sites [20]. ERK1/2 induce the phosphorylation of TSC2 through its downstream target p90 ribosomal S6 Kinase (RSK) at some Akt too as at novel sites [21]. These phosphorylation events release TSC2-mediated inhibition of the GTPase Ras homolog enriched in encephalon (RHEB), thus assuasive RHEB to activate mTORC1 [22]. Moreover, both ERK and RSK promote mTORC1 activity by phosphorylating raptor, a key substrate-bounden element of the mTORC1 complex [23,24]. Chiefly, mTORC1 is also considered a major nutrient sensor as its action is regulated by the availability of amino acids and glucose [25,26]. Thus, the ability of mTORC1 to integrate mitogenic signals with the nutritional status of the cell makes it a critical rheostat for the maintenance of metabolic residual and cellular homeostasis [26].
In the presence of nutrients and growth factors, mTORC1 drives ATP-consuming cellular processes necessary for cells to grow and proliferate (Fig. 2). mTORC1 also regulates protein synthesis by inducing mRNA translation and ribosome biogenesis [27,28] through its canonical substrates S6 kinases (S6Ks) and the inhibitory eIF4E-binding proteins (4EBPs) [29]. Interestingly, mTORC1 has been shown to likewise increase the efficiency of proteasome-mediated protein degradation to maintain proteostasis and sustain the increase in protein synthesis [30]. In addition to protein synthesis, mTORC1 has been recently implicated in the regulation of other major metabolic pathways of the jail cell, including lipid and nucleic acrid synthesis, glycolysis, glutaminolysis, TCA cycle and oxidative phosphorylation, further supporting the idea of mTORC1 as a master regulator of metabolism [26,31].
Regulation of intermediate metabolism by nutrient and energy sensors
Nutrient and energy-responsive pathways fine-tune the output of signaling cascades, allowing for the correct balance betwixt the availability of nutrients and the cellular capacity to employ them effectively. AMPK and SIRT1 answer to the free energy status of the cells through sensing of AMP and NAD+ levels respectively. When energy is deficient these sensors are activated inducing a rewiring of intermediate metabolism to catabolic processes in lodge to produce free energy and restore homeostasis. When nutrients (such as glucose and amino acids) and free energy are available, AMPK, SIRT1, SIRT3 and SIRT6 are repressed and mTORC1 is active, thus promoting a shift towards anabolic processes and energy production. These networks of signaling cascades, their interconnection and regulation permit the cells to maintain energetic residuum and let for the physiological accommodation to the ever-irresolute surround.
The ability of mTORC1 to regulate these pathways has been largely attributed to the regulation of key metabolic-related transcription factors. Withal, recent reports have also identified postal service-translational mechanisms [32,33]. Indeed, through regulation of 4EBP1 and S6K1, mTORC1 can promote the translation of hypoxia-inducible gene 1α (HIF1α) and c-Myc, thereby inducing the expression of glycolytic enzymes, glucose transporters and inhibiting the glucose-derived carbon flux through the TCA cycle [34,35]. This diverts the glucose-derived carbon from the TCA bike to biosynthetic pathways, which promote cell growth. Consistent with this notion, mTORC1 signaling induces the oxidative arm of the pentose phosphate pathway (PPP) through increasing the expression of the rate-limiting enzyme, glucose-half dozen-phosphate dehydrogenase (G6PD) thus increasing the generation of ribose (essential for nucleotide synthesis) and NADPH (essential for lipid synthesis) [35]. Moreover, mTORC1 through S6K1, regulates de novo pyrimidine synthesis past phosphorylating and activating the carbamoyl-phosphate synthetase ii, aspartate transcarbamylase, and dihydroorotase (CAD) [33,36]. CAD catalyzes the first iii steps in de novo pyrimidine synthesis, thus providing a direct link betwixt mTORC1 and an increase in the product of nucleotides [33,36].
c-Myc and mTORC1 are potent regulators of glutamine-mediated anabolic processes. c-Myc induces the expression of several proteins essential for glutamine anaplerosis, such as glutaminase (GLS) and the glutamine transporters [37]. Cells with mTORC1 agile have been reported to be fond to glutamine [38], indicating that glutamine is a cardinal carbon source for mTORC1-related metabolic rewiring. Interestingly, mTORC1 has been recently shown to enhance c-Myc translation efficiency through S6K1, and consequently increase GLS action [39] and many other c-Myc targets. mTORC1 likewise induces the activity of the mitochondrial glutamate dehydrogenase (GDH) through inhibition of SIRT4 transcription, a known regulator of GDH activity [40], supporting the part of mTORC1 in inducing glutamine anaplerosis to replenish the TCA cycle and anabolic processes.
In addition to increasing the activeness of HIF1α and c-Myc, mTORC1 activation also leads to increased sterol regulatory element bounden proteins (SREBP) activity [35]. SREBPs orchestrate the power of the cells to synthesize lipids, every bit they induce the global expression of enzymes involved in de novo fatty acid synthesis [41]. In add-on, mTORC1 likewise regulates SREBPs activity past inducing the phosphorylation and inhibition of LIPIN1, a phosphatase that inhibits SREBPs activity [42], thus straight linking mTORC1 to lipid synthesis.
mTORC1 signaling, therefore, is a critical regulator of anabolic processes that fuel jail cell growth and proliferation (Fig.i).
Fine-tuning signaling networks and catabolic rewiring through energetic sensors
Energetic homeostasis is regulated by both nutrient availability and energy demand, which are constantly changing. Therefore, cells accept evolved multiple nutrient- and energy-sensing pathways to recognize the level of intracellular nutrients (such as mTORC1, described above) and energetic status (AMP/ATP ratio, NAD+/NADH). In times of nutrient deprivation or energetic arrears, nonessential ATP consumption is inhibited and energy stores are mobilized for catabolic processes. The all-time known regulators of these processes are AMP-activated protein kinase (AMPK), and Silent information regulator 1 (SIRT1) [43–45]. Under low-energy conditions, AMPK and SIRT1 are activated by increases in intracellular AMP and NAD+ levels, respectively. Once activated AMPK and SIRT1 switch on catabolic pathways that generate ATP while switching off anabolic pathways and other ATP-consuming processes, thus restoring the energy balance [43–45]. The complementary furnishings of AMPK and SIRT1 propose that cells evolved both enzymes to piece of work in a coordinated fashion. Thus, AMPK and SIRT1 are able to regulate each other [46] and are both frequently required to stimulate major pathways [47,48].
AMPK and SIRT1 coordinate the increase in the ability of the cells to oxidize fatty acids, thus fueling mitochondrial oxidative phosphorylation and the generation of ATP in an efficient manner [49]. AMPK promotes fat acids oxidation (FAO) past regulation and activation of the peroxisome proliferator-activated receptor alpha (PPARα), a key transcriptional regulator of FAO [50]. AMPK too phosphorylates and inactivates acetyl- coenzyme A (CoA) carboxylase (ACC)-two, thus releasing the inhibitory pressure of malonyl-CoA from the uptake of fatty acids by the mitochondria for β-oxidation [51]. Importantly, in add-on to increasing FAO, both AMPK and SIRT1 repress the ability of cells to synthesize fat acids, by inhibiting the actions of SREBP1c [52,53].
SIRT1 and AMPK besides accept an important office in the regulation of glucose metabolism. AMPK induces glucose uptake and its oxidation through the glycolytic pathway, through regulation of glucose transporters and 6-phosphofructo-2-kinase/fructose-two,6-biphosphate [54,55]. Moreover, AMPK blocks glucose uptake through inducing a thioredoxin-interacting protein-dependent regulation of GLUT1 [56]. SIRT1 promotes the carbon flux from glucose to enter the TCA wheel by repressing HIF-1α, thus feeding oxidative phosphorylation (OXPHOS) in the mitochondria [57,58]. This suggests that SIRT1 and AMPKs deportment complement each other, ensuring that the glucose that enters cells is used to produce ATP through oxidative phosphorylation and preventing information technology from entering biosynthetic pathways, such as the PPP. In improver, AMPK and SIRT1 regulate the CREB-regulated transcription co-activator2 (CRTC2), thus repressing gluconeogenesis [59,60].
SIRT1 and AMPK are too both necessary for the activation of the peroxisome proliferator-activated receptor gamma coactivator i-alpha (PGC-1α) [49]. Following phosphorylation by AMPK, SIRT1 deacetylates PGC-1α and leads to its total activation, thus inducing the expression of genes related with FAO and mitochondrial biogenesis [48,61]. Chiefly, this ability to activate mitochondrial biogenesis is fundamental to the metabolic rewiring induced by AMPK and SIRT1 as information technology generates increased capacity for the oxidative catabolism of both glucose and fatty acids.
In add-on to SIRT1, other sirtuin family members also play a role in regulation of metabolism. Particularly SIRT3 and SIRT6 accept been shown to regulate glycolysis and TCA bike through HIF-1α and c-Myc [62–64]. SIRT3 too contributes for catabolic processes by promoting oxidative phosphorylation through direct deacetylation of OXPHOS components [65,66]. On the other hand, SIRT4 has been shown to negatively regulate FAO [67,68], too as to promote glutamine anaplerosis [40], suggesting a potential role for this sirtuin in promoting anabolic processes.
As a major regulator of anabolic processes, mTORC1's activity is also indirectly regulated by the energetic country of the cells. AMPK phosphorylates and stimulates the activity of TSC2, thus repressing mTORC1 signaling [69]. AMPK too directly phosphorylates raptor, a critical component of mTORC1, to suppress mTORC1 signaling [70]. Moreover, free energy depletion too inhibits mTORC1 function in an AMPK-independent fashion. The AAA+ ATPase-containing complex Tel2-Tti-Tti2-RUVBL1/2 (TTT-RUVBL1/2) responds to cellular energy land and directly regulates the functional assembly of mTORC1 [71], notwithstanding the mechanism of energy sensing for this process remains to be elucidated. Thus, AMPK, SIRT1 and the TTT-RUVBL complex fine-melody signaling transduction in accord to the energetic state of the cell, regulating the residual between anabolic and catabolic processes, thereby maintaining cellular homeostasis (Fig.2).
Conclusions
Cellular homeostasis is maintained in coordination with extracellular cues (such as growth factors and nutrients) and intracellular metabolite concentrations. The interplay among all these factors coordinate complex point transduction networks that perpetuate the information and rewire the metabolism of the cells. Taking into consideration the fact that cells are highly plastic and constantly exposed to a multitude of signals, an important question emerges. How are these pathways coordinated past the small number of upstream signaling regulators in response to the various intra and extra-cellular signals? The response is even so largely unknown, only surely part of the answer must be based on how these conserved pathways integrate their actions, their crosstalk and how they are regulated. Importantly, the notion that intracellular metabolite levels are potent regulators of signaling pathways should also be taken into account. This is an important expanse of inquiry that has emerged recently, with numerous metabolites existence described to regulate signaling cascades, thus contributing to the maintenance of energetic residuum. Therefore, the understanding of these signaling cascades and their power to fine-tune the residue between catabolism and anabolism is extremely of import for understanding the evolution of metabolic-related diseases. An in depth written report of these signal integration mechanisms is therefore an attractive area for further investigation. Furthermore, the cognition gained may yield important therapeutic targets for drug evolution for use in a multitude of metabolic diseases.
Acknowledgments
Nosotros repent to those whose piece of work was not discussed and cited in this review due to limitations in space and scope. Nosotros thank Dr. Michal Nagiec, Dr. Eric Bell, Dr. Sang Gyun Kim and Gwen Buel for kindly providing helpful discussions and comments on this manuscript. J.B. is an Established Investigator of the LAM Foundation. NIH Grants GM51405, CA46595 and HL121266 provide research support for the Blenis laboratory.
Footnotes
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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4490161/
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