File Name: tor signaling in growth and metabolism .zip
Cellular metabolism must ensure that supply of nutrient meets the biosynthetic and bioenergetic needs. Cells have therefore developed sophisticated signaling and regulatory pathways in order to cope with dynamic fluctuations of both resource and demand and to regulate accordingly diverse anabolic and catabolic processes. Intriguingly, these pathways are organized around a relatively small number of regulatory hubs, such as the highly conserved AMPK and TOR kinase families in eukaryotic cells.
Metrics details. The mechanistic target of rapamycin complex 1 mTORC1 is an essential regulator of cell growth and metabolism through the modulation of protein and lipid synthesis, lysosome biogenesis, and autophagy. The activity of mTORC1 is dynamically regulated by several environmental cues, including amino acid availability, growth factors, energy levels, and stresses, to coordinate cellular status with environmental conditions. Dysregulation of mTORC1 activity is closely associated with various diseases, including diabetes, cancer, and neurodegenerative disorders.
Organisms adapt to changing environments by adjusting their development, metabolism, and behavior to improve their chances of survival and reproduction. To achieve such flexibility, organisms must be able to sense and respond to changes in external environmental conditions and their internal state.
Metabolic adaptation in response to altered nutrient availability is key to maintaining energy homeostasis and sustaining developmental growth. Furthermore, environmental variables exert major influences on growth and final adult body size in animals. This developmental plasticity depends on adaptive responses to internal state and external cues that are essential for developmental processes. Genetic studies have shown that the fruit fly Drosophila , similarly to mammals, regulates its metabolism, growth, and behavior in response to the environment through several key hormones including insulin, peptides with glucagon-like function, and steroid hormones.
Here we review emerging evidence showing that various environmental cues and internal conditions are sensed in different organs that, via inter-organ communication, relay information to neuroendocrine centers that control insulin and steroid signaling. This review focuses on endocrine regulation of development, metabolism, and behavior in Drosophila , highlighting recent advances in the role of the neuroendocrine system as a signaling hub that integrates environmental inputs and drives adaptive responses.
Organisms must adapt to changing environments by adjusting their developmental growth, metabolism, and behavior to promote survival and reproduction. This adaptation relies on the ability to sense and respond to changes in internal and external environmental conditions. This involves complex sensing of nutritional conditions, temperature, oxygen, and light. Animals at all developmental stages integrate this information and adjust their metabolism and behavior to take advantage of available resources and to maintain homeostasis.
Furthermore, juvenile animals—those that are still in the non-reproductive growth phase of their development—adjust their growth and development to meet resource availability in such a way that the final adult animal is most likely to be reproductively successful.
The mechanisms that govern developmental, metabolic, and behavioral adaptations frequently make use of systemic endocrine signals to adjust the parameters of underlying genetic programs that control growth, developmental transitions, and physiology. This review explores endocrine mechanisms of environmental adaptation in the fruit fly Drosophila melanogaster , first investigating the modulation of growth and maturation during juvenile larval life and then investigating adult behavioral and metabolic adaptation.
Environmental and internal inputs reflecting temperature, light, nutritional stores, food qualities composition, odor, taste , and oxygen are covered, although others exist beyond the scope of this review such as humidity, CO 2 , and gut microbiota. Drosophila has become an attractive model for understanding the endocrine regulation of growth and metabolic adaptation. Nutrients are digested and absorbed through the intestine, which is also a key endocrine organ that plays a central role in sensing nutritional information and relaying it to other tissues to maintain systemic metabolic homeostasis [ 1 ].
The Drosophila fat body and peripheral oenocytes serve the functions of the mammalian hepatic and adipose tissues [ 2 , 3 ], both of which store energy as glycogen and lipid, respectively but also have endocrine function. In Drosophila , growth is restricted to larval stages called instars, and maturation is induced by reaching a critical size that triggers the onset of metamorphosis, which transforms the juvenile growing larva into the reproductive adult and largely limits any further growth [ 4 , 5 ].
The larva can alter its growth rate and the duration of its growth period determined by the timing of metamorphosis to reach a final adult size that maximizes fitness and survival in variable environments. In nutrient-rich conditions, animals grow quickly and soon develop into adults.
On the other hand, when nutrients are limited, the larval growth period is extended to allow additional growth and to ensure an appropriate final adult size under unfavorable growth conditions. The main factors regulating growth and development according to the environment in animals are the conserved insulin and insulin-like growth factors IGFs and steroid hormones [ 6 , 7 , 8 ]. Work has shown that the Drosophila insulin-like peptides DILPs are the main regulators of tissue growth, whereas the steroid hormone ecdysone is the main factor that controls the duration of the growth period, although it also affects growth rate [ 9 , 10 ].
Ecdysone is produced and released from the prothoracic gland PG , a major endocrine organ, in response to DILPs and prothoracicotropic hormone PTTH , another brain-derived neuropeptide [ 5 , 13 ]. Developmental and environmental cues are integrated in the IPCs and PTTH-producing neurons PTTHn as well as by the PG itself to adjust insulin and ecdysone signaling according to intrinsic and extrinsic conditions, in order to adapt growth and development. These systems are all discussed in detail below.
As in mammals, circulating sugar levels and energy storage versus mobilization are regulated by the opposing effects of two hormones in Drosophila , insulin and Adipokinetic hormone Akh, in some ways functionally analogous to mammalian glucagon. Following the intake of dietary sugar, insulin secretion promotes its tissue uptake from the hemolymph insect circulatory fluid , whereas Akh induces mobilization of lipids and breakdown of glycogen to maintain hemolymph levels of lipids and sugars in response to starvation or exertion.
In addition to these metabolic homeostatic circuits, regulation of food intake by modulation of appetite, odor and taste sensation, foraging, and food palatability is a major factor required for adaptation to nutritional conditions.
Following prolonged deprivation of protein in their diet, flies preferentially select amino acid-rich food, based on certain taste neurons whose activity is regulated by the internal nutritional state [ 16 ]. On the other hand, deprivation of dietary sugars specifically increases feeding on sugar-rich foods. Feeding decisions are controlled by neuromodulators such as neuropeptides and hormones that change the motivational state according to the nutritional demand of the animal.
In flies, these include the neuropeptide Diuretic hormone 44 Dh44 , an orthologue of the mammalian corticotropin-releasing hormone CRH , which is involved in detecting the nutritional value of consumed sugars [ 17 ] and amino acids [ 18 ].
The mammalian hormone leptin provides an example of the useful parallels between fly and mammalian developmental endocrinology. Leptin, released from adipose cells in response to their lipid content a reflection of nutritional state , modulates appetite and metabolism by signaling to the brain [ 19 ]. Flies possess a structurally and functionally similar hormone named Unpaired-2 Upd2.
Like leptin, Drosophila Upd2 is a nutrient-dependent adipokine that relays nutritional information to the brain [ 21 ]. Upd2 stimulates insulin secretion, which promotes growth and maturation onset through its effect on the production of the steroid hormone ecdysone [ 9 , 22 ].
Thus, during development in both insects and mammals, endocrine signals related to the amount of body fat provide nutrient-status information to the neuroendocrine signaling system that initiates maturation. Here we will review some of the recent advance to highlight how inter-organ signaling networks allow Drosophila to adjust larval growth and development to variable environments, and we also examine endocrine mechanisms underlying metabolic and behavioral adaptations.
Animals reared in environments differing in temperature, oxygen level, and the availability of food develop at different rates into adults of different sizes. In nutritionally poor or low-oxygen hypoxic environments, Drosophila larvae grow slowly and attain a smaller adult body size, whereas in nutrient- and oxygen-rich environments, larvae develop more quickly into larger adults [ 23 , 24 , 25 , 26 , 27 ].
In contrast, low temperature also slows the growth of larvae and prolongs their development but results in increased adult body size [ 28 ], suggesting that temperature affects developmental growth by different mechanisms than oxygen and nutrients. Furthermore, changes in these environmental conditions affect the proportions of different body parts relative to the whole body [ 26 , 29 ].
This developmental flexibility involves adaptive responses within the boundaries of species-specific genetic developmental frameworks to produce adults of sizes and proportions that suit prevailing environmental conditions.
This developmental plasticity is regulated by nutrition-dependent hormonal signaling pathways that control tissue growth and feed into the endocrine system that determines the timing of metamorphosis and thus the length of the growth period. Steroid-hormone and insulin-like signaling pathways form the core axes of environmentally adaptive systemic regulation of growth and development in metazoans, and these pathways are thus evolutionarily ancient and have been conserved since before the divergence of flies and humans [ 6 , 7 , 8 ].
Finally, we propose a hypothesis that may explain how studying this checkpoint mechanism can potentially contribute to our understanding of human size regulation. Growth-regulating environmental and internal cues are integrated through inter-organ communication in the Drosophila larva.
In the main panel, larval organs communicate with one another via diffusible factors to govern growth and development. Factors that act on growth and development via these various cells are indicated. The bottom-right schematic illustrates the relationships between size, growth rate, and growth duration.
Nutritional availability is a major environmental factor governing growth and development [ 30 , 31 ]. These cells send projections to neurohemal release sites near the esophageal foramen and, in the larva, to the PG, where they contribute to the regulation of ecdysone synthesis [ 9 , 22 ].
Furthermore, after the onset of metamorphosis, when larvae stop feeding, tissue growth is sustained through the secretion of DILP6 by the fat body [ 35 , 36 ]. Thus, the pool of DILPs that mediate tissue growth is diverse in spatial and temporal expression.
One of the primary Akt targets is the transcription factor Forkhead Box class O FoxO , which negatively regulates cellular growth through transcriptional effects on downstream targets, including the translational repressor 4E-binding protein 4EBP, Thor [ 39 , 40 ]. In well-fed animals, in which insulin signaling and thus Akt are active, phosphorylated FoxO is excluded from the nucleus, thereby allowing growth to proceed, whereas under nutrient-restricted conditions, deactivation of Akt allows FoxO to enter the nucleus and act on its target genes, including 4EBP , to suppress cell growth.
Therefore, TOR signaling senses internal nutritional status by two routes: via its diverse cell-autonomous nutrient-sensing mechanisms and through inputs from the insulin pathway via Akt [ 41 , 42 ]. Although TOR has been known mainly for sensing free amino acids, recent work has shown that TOR activity is dependent on internal oxygen concentration as well [ 27 , 43 ], indicating that TOR integrates both amino-acid and oxygen sensing to regulate cell growth in adaptation to changing environmental conditions.
When TOR is active, it phosphorylates 4EBP, suppressing its inhibitory activity, which results in enhanced binding of mRNAs to ribosomes and thus in increased translation [ 44 ]. TOR signaling also promotes translation through the phosphorylation of ribosomal protein S6, mediated by S6 kinase S6K , to enhance ribosomal activity [ 44 ].
Increased ecdysone signaling under these conditions results in the development of small adults not only due to the shortening of the larval growth period but also due to reduced growth rate, since ecdysone negatively regulates systemic growth.
Furthermore, overexpression of DILPs in the IPCs results in similar upregulation of phm and dib [ 47 ], indicating that ecdysone-mediated development can also be considered to be nutrition-dependent through the insulin pathway. Recent studies have shown that a number of humoral factors are secreted from the fat body in an amino-acid-sensitive, TOR-dependent manner to regulate DILP expression in and secretion from the IPCs in the brain Fig.
Thus, the fat body regulates DILP secretion in response to a number of dietary macronutrients, thereby coupling growth to nutrient intake, which is an important adaptive growth response of the organism to environmental conditions.
In addition to its role in nutrition sensing, the fat body is also the main sensor of internal oxygen levels, which allows organisms to adapt their growth to environmental oxygen conditions through the regulation of DILP secretion [ 27 ]. Similar to low-amino-acid conditions that reduce growth via down-regulation of TOR, tissue hypoxia induced either by low environmental oxygen levels or by undergrowth of the tracheal airways also slows larval growth and development.
This adaptive response requires oxygen sensing via the transcription factor Hypoxia-inducible factor 1 alpha HIF-1a in the fat body [ 27 ]. Fat-body hypoxia disinhibits HIF-1a activity, which in turn leads to the release of one or more unidentified fat-derived humoral factors that act on the IPCs to inhibit DILP expression and secretion. This HIF-1a-dependent fat-body oxygen-sensing mechanism strongly inhibits systemic insulin-dependent growth in response to tissue-hypoxia conditions.
These conditions, at the same time, increase fibroblast growth factor FGF -like signaling, promoting the growth of the tracheal airway system to permit greater oxygen delivery to tissues. This adaptive growth and metabolic response promotes survival under environmental conditions with low oxygen. Furthermore, DILP secretion is also regulated by temperature, through a neuronal circuit involving a group of larval cold-sensing neurons that sense temperature fluctuation [ 28 ].
Furthermore, developing organisms also need enough time to complete the growth of their organs, as well as the adaptive plasticity to adjust their growth to compensate for impaired tissue growth or injury, to ensure developmental stability. These adaptive responses, which maximize survival and reproductive success, require the integration of photoperiod and organ-growth status with developmental programs.
Photoperiodic inputs and tissue-damage signals are integrated by the PTTHn, two pairs of neurosecretory cells in the larval brain that produce PTTH and directly innervate the PG [ 55 ].
PTTH controls developmental timing through its effects on the PG, where it activates its receptor tyrosine kinase Torso, leading to the pulse of ecdysone production that initiates metamorphosis [ 56 ]. The PTTHn integrate developmental and environmental cues to adjust the length of the growth period during larval development by changing the timing of PTTH secretion. For instance, photoperiod strongly affects PTTH secretion in a broad range of insect species, although Drosophila shows weak responses compared to other insects [ 62 , 63 ].
Furthermore, beyond controlling the developmental growth period by determining the timing of metamorphosis, PTTH also coordinates larval behavior with this developmental transition to maximize survival. The PTTH neurons themselves may be regulated by transitions in light intensity, forming a feedback loop between development, environment, and the nervous system [ 65 ].
When insect larvae face abnormality in tissue development, such as injury, accidental asymmetric growth of a paired organ, tissue overgrowth, or tumorigenesis, they slow their development to allow time for healing or regeneration [ 66 , 67 , 68 ].
In response to abnormal growth, the tissue primordia that give rise to adult appendages—the imaginal discs—secrete DILP8 [ 69 , 70 ], which delays metamorphosis by changing the timing of ecdysone peaks. DILP8 secreted by abnormally growing organs is sensed by the receptor Lgr3 in a pair of neurons that synapse upon the PTTHn [ 71 , 72 , 73 ], suggesting that abnormal organ growth delays developmental timing primarily by affecting the timing of PTTH secretion.
Developmental coordination between growth and maturation is also mediated by the neuropeptide Allatostatin A AstA and its receptor AstA receptor 1 AstA-R1 , which regulate developmental timing by controlling PTTH and insulin signaling [ 74 , commentary in 75 ].
Interestingly, AstA and AstA-R1 are homologous to human kisspeptin KISS and its receptor GPR54 [ 76 ], which are known to be required for human puberty through their control of gonadotropin-releasing hormone GnRH secretion from the brain, which initiates maturation by inducing sex-steroid production [ 77 ]. This suggests that the neuroendocrine architecture that controls the initiation of maturation has been evolutionarily conserved and that this system in Drosophila coordinates developmental growth with the juvenile-to-adult transition to achieve an appropriate size under different environmental conditions to maximize adult fitness.
AstA is regulated by nutrition, at least in adults [ 78 ], suggesting that in addition to photoperiod and organ-growth status, nutrition may modulate PTTH secretion. This is in line with a recent report showing that PTTH secretion is regulated by amino-acid levels [ 79 ]. Furthermore, studies in lepidopterans have indicated that PTTH secretion is gated not only by the photoperiod but also by JH, which represses ecdysone biosynthesis and metamorphic development [ 30 ].
One of the functions of JH is to change the duration of the growth period by modulating the timing of PTTH and ecdysone release [ 62 ].
Although it is not clear whether JH regulates PTTH in Drosophila , removing the corpora allata CA , which comprises the JH-producing cells, induces developmental delay [ 80 ], suggesting a potential interaction with ecdysone production.
This may occur through PTTH signaling, as seen in other species. Taken together, recent advances have shown that the PTTHn integrate several intrinsic and extrinsic cues to modulate the timing of steroid-hormone production and secretion, and thus developmental maturation, by modulating the timing of PTTH secretion. PTTH, therefore, seems to be the key factor in the adaptive plasticity that allows animals to adjust development to variable environmental conditions. To achieve such flexibility, the neuroendocrine network controlling PTTH, the principal regulator of maturation in Drosophila , likely integrates a wide range of inputs to control PTTH secretion.
In all eukaryotes, the mechanistic target of rapamycin mTOR signaling emerges as a master regulator of homeostasis, which integrates environmental inputs, including nutrients, energy, and growth factors, to regulate many fundamental cellular processes such as cell growth and metabolism. While mTORC1 is well characterized for its structure, regulation, and function in the last decade, information of mTORC2 signaling is only rapidly expanding in recent years, from structural biology, signaling network, to functional impact. Here we review the recent advances in many aspects of the mTORC2 signaling, with particular focus on its involvement in the control of cell metabolism and its physiological implications in metabolic diseases and aging. In addition to this compositional difference, the two complexes also differ in their response to rapamycin with mTORC1 activity being acutely inhibited by rapamycin while mTORC2 only responding to long-term treatments [ 3 ]. This is especially well established in mTORC1 signaling through its regulation of anabolic process.
The mechanistic target of rapamycin mTOR ,  previously referred to as the mammalian target of rapamycin , and sometimes called FKbinding protein rapamycin-associated protein 1 FRAP1 , is a kinase that in humans is encoded by the MTOR gene. The study of TOR originated in the s with an expedition to Easter Island known by the island inhabitants as Rapa Nui , with the goal of identifying natural products from plants and soil with possible therapeutic potential. In , Suren Sehgal identified a small molecule, from a soil bacterium Streptomyces hygroscopicus , that he purified and initially reported to possess potent antifungal activity. He appropriately named it rapamycin, noting its original source and activity Sehgal et al. However, early testing revealed that rapamycin also had potent immunosuppressive and cytostatic anti-cancer activity. Unfortunately, rapamycin did not initially receive significant interest from the pharmaceutical industry until the s, when Wyeth-Ayerst supported Sehgal's efforts to further investigate rapamycin's effect on the immune system. This eventually led to its FDA approval as an immunosuppressant following kidney transplantation.
Rictor is a component of the target of rapamycin complex 2 TORC2. While TORC2 has been implicated in insulin and other growth factor signaling pathways, the key inputs and outputs of this kinase complex remain unknown. We identified mutations in the Caenorhabditis elegans homolog of rictor in a forward genetic screen for increased body fat. Despite high body fat, rictor mutants are developmentally delayed, small in body size, lay an attenuated brood, and are short-lived, indicating that Rictor plays a critical role in appropriately partitioning calories between long-term energy stores and vital organismal processes. Rictor is also necessary to maintain normal feeding on nutrient-rich food sources. In contrast to wild-type animals, which grow more rapidly on nutrient-rich bacterial strains, rictor mutants display even slower growth, a further reduced body size, decreased energy expenditure, and a dramatically extended life span, apparently through inappropriate, decreased consumption of nutrient-rich food. Rictor acts directly in the intestine to regulate fat mass and whole-animal growth.
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B Corresponding author. Email: wangxqbj The target of rapamycin TOR signalling network plays a pivotal role in regulating sugar metabolism and life-span in yeast, plants and mammals, in which TOR functions as a crucial protein. Factors like light, auxin, glucose, sucrose and amino acid can activate TOR protein as upstream signals to further phosphorylate downstream factors of TOR which promote cell proliferation and growth in plants. In this review, we analyse the TOR signalling network in plants and discuss the relationship between glucose and TOR, as well as the dynamic balance between TOR and sucrose-non-fermenting-related protein kinases SnRKs. Given that 63 novel TOR-regulated proteins have been identified in previous studies, we also believe there are many unknown functions of TOR that need to be further investigated. Additional keywords: glucose, signalling network, sucrose-non-fermenting-related protein kinases, sugar metabolism, target of rapamycin.
В руке красная туристская сумка фирмы Л. Белл. Светлые волосы тщательно уложены. - Прошу меня извинить, - пробормотал Беккер, застегивая пряжку на ремне. - Мужская комната оказалась закрыта… но я уже ухожу. - Ну и проваливай, пидор.
While mTORC1 regulates cell growth and metabolism, mTORC2 instead One remarkable feature of the TOR pathway is its conservation as a major growth Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been.
- Голос послышался совсем. - Ни за. Ты же меня прихлопнешь. - Я никого не собираюсь убивать. - Что ты говоришь. Расскажи это Чатрукьяну.
- Хейл сильнее сжал горло Сьюзан. - Если лифт обесточен, я отключу ТРАНСТЕКСТ и восстановлю подачу тока в лифт. - У дверцы лифта есть код, - злорадно сказала Сьюзан. - Ну и проблема! - засмеялся Хейл. - Думаю, коммандер мне его откроет.
Слева и справа от алтаря в поперечном нефе расположены исповедальни, священные надгробия и дополнительные места для прихожан. Беккер оказался в центре длинной скамьи в задней части собора. Над головой, в головокружительном пустом пространстве, на потрепанной веревке раскачивалась серебряная курильница размером с холодильник, описывая громадную дугу и источая едва уловимый аромат. Колокола Гиральды по-прежнему звонили, заставляя содрогаться каменные своды. Беккер перевел взгляд на позолоченную стену под потолком.
Дэвид! - крикнула. - Что… Но было уже поздно.
Быть может, вы могли бы… - Право же, без фамилии я ничего не могу поделать. - И все-таки, - прервал ее Беккер. Ему в голову пришла другая мысль. - Вы дежурили все это время. - Моя смена от семи до семи, - кивнула женщина.
Нисколько. - Беккер взял подушку с соседней койки и помог Клушару устроиться поудобнее. Старик умиротворенно вздохнул. - Так гораздо лучше… спасибо. - Pas du tout, - отозвался Беккер.
Беккер прижал дуло к виску убийцы и осторожно наклонился. Одно движение, и он выстрелит. Но стрелять не понадобилось. Халохот был мертв. Беккер отшвырнул пистолет и без сил опустился на ступеньку.
К ней снова вернулись страхи, связанные с новой попыткой найти ключ Хейла в Третьем узле. Коммандер был абсолютно убежден в том, что у Хейла не хватит духу на них напасть, но Сьюзан не была так уж уверена в. Хейл теряет самообладание, и у него всего два выхода: выбраться из шифровалки или сесть за решетку.
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