Target of rapamycin (TOR) in nutrient signaling and growth control

TOR (Target Of Rapamycin) is a highly conserved protein kinase that is important in both fundamental and clinical biology. In fundamental biology, TOR is a nutrient-sensitive, central controller of cell growth and aging. In clinical biology, TOR is implicated in many diseases and is the target of the drug rapamycin used in three different therapeutic areas. The yeast Saccharomyces cerevisiae has played a prominent role in both the discovery of TOR and the elucidation of its function. Here we review the TOR signaling network in S. cerevisiae.     

TOR signaling in fission yeast

Fission yeast has two TOR kinases, Tor1 and Tor2. Recent studies have indicated that this microbe has a TSC/Rheb/TOR pathway like higher eukaryotes. Two TOR complexes, namely TORC1 and TORC2, have been identified in this yeast, as in budding yeast and mammals. Fission yeast TORC1, which contains Tor2, and TORC2, which contains Tor1, apparently have opposite functions with regard to the promotion of G1 arrest and sexual development. Rapamycin does not inhibit growth of wild-type fission yeast cells, unlike other eukaryotic cells, but precise analyses have revealed that rapamycin affects certain cellular functions involving TOR in this yeast. It appears that fission yeast has a potential to be an ideal model system to investigate the TOR signaling pathways.     

TOR信号调控真菌细胞的生长与代谢

TOR(target of rapamycin)是一类进化上保守的丝氨酸/苏氨酸(Ser/Thr)蛋白激酶,是真核细胞响应环境信号调控生长和代谢的关键因子。真菌TOR信号途径在营养、压力环境等刺激下,通过核糖体生物合成、营养物质摄入及代谢等过程调节维持胞内稳态。本文主要综述了酵母细胞TOR及TOR复合物的结构,以及近年来真菌TORC1蛋白在不同营养环境、压力等条件下对细胞生长与自噬、代谢以及胁迫生理响应等生命活动的调控机制进展及未来发展方向,为真菌TOR调控生长和代谢产物提供新思路。     

Plant TOR signaling components

Cell growth is a process that needs to be tightly regulated. Cells must be able to sense environmental factors like nutrient abundance, the energy level or stress signals and coordinate growth accordingly. The Target Of Rapamycin (TOR) pathway is a major controller of growth-related processes in all eukaryotes. If environmental conditions are favorable, the TOR pathway promotes cell and organ growth and restrains catabolic processes like autophagy. Rapamycin is a specific inhibitor of the TOR kinase and acts as a potent inhibitor of TOR signaling. As a consequence, interfering with TOR signaling has a strong impact on plant development. This review summarizes the progress in the understanding of the biological significance and the functional analysis of the TOR pathway in plants.     

The expanding TOR signaling network

Cell growth (increase in cell mass or size) is tightly coupled to nutrient availability, growth factors and the energy status of the cell. The target of rapamycin (TOR) integrates all three inputs to control cell growth. The discovery of upstream regulators of TOR (AMPK, the TSC1-TSC2 complex and Rheb) has provided new insights into the mechanism by which TOR integrates its various inputs. A recent finding in flies reveals that TOR controls not only growth of the cell in which it resides (cell-autonomous growth) but also the growth of distant cells, thereby determining organ and organism size in addition to the size of isolated cells. In yeast and mammals, the identification of two structurally and functionally distinct multiprotein TOR complexes (TORC1 and TORC2) has provided a molecular basis for the complexity of TOR signaling. Furthermore, TOR has emerged as a regulator of growth-related processes such as development, aging and the response to hypoxia. Thus, TOR is part of an intra- and inter-cellular signaling network with a remarkably broad role in eukaryotic biology.     

Insulin/TOR signaling in growth and homeostasis: a view from the fly world

The insulin/TOR pathway is a conserved regulator of cell and organism growth in metazoans. Over the last several years, an array of signaling inputs to this pathway has been defined. However the growth-regulatory outputs are less clear. Drosophila has proven to be a powerful genetic model system in which to study insulin/TOR signaling. This review highlights recent studies in Drosophila that have identified essential outputs and key effectors of the pathway. These include the regulation of ribosome synthesis, mRNA translation, autophagy and endocytosis, through downstream effectors such as Myc, FOXO, HIF1-alpha, TIF-IA, 4EBP and Atg1. This network of outputs and effectors can regulate cell and organismal metabolism, and is essential for the control of tissue growth, responses to starvation and stress, and aging. The mechanisms identified in Drosophila likely operate in most metazoans, and are relevent to our understanding of diseases caused by aberrent insulin/TOR signaling such as cancer, diabetes and obesity.     

The PP2A regulatory subunit Tap46, a component of the TOR signaling pathway, modulates growth and metabolism in plants

Tap42/α4, a regulatory subunit of protein phosphatase 2A, is a downstream effector of the target of rapamycin (TOR) protein kinase, which regulates cell growth in coordination with nutrient and environmental conditions in yeast and mammals. In this study, we characterized the functions and phosphatase regulation of plant Tap46. Depletion of Tap46 resulted in growth arrest and acute plant death with morphological markers of programmed cell death. Tap46 interacted with PP2A and PP2A-like phosphatases PP4 and PP6. Tap46 silencing modulated cellular PP2A activities in a time-dependent fashion similar to TOR silencing. Immunoprecipitated full-length and deletion forms of Arabidopsis thaliana TOR phosphorylated recombinant Tap46 protein in vitro, supporting a functional link between Tap46 and TOR. Tap46 depletion reproduced the signature phenotypes of TOR inactivation, such as dramatic repression of global translation and activation of autophagy and nitrogen mobilization, indicating that Tap46 may act as a positive effector of TOR signaling in controlling those processes. Additionally, Tap46 silencing in tobacco (Nicotiana tabacum) BY-2 cells caused chromatin bridge formation at anaphase, indicating its role in sister chromatid segregation. These findings suggest that Tap46, in conjunction with associated phosphatases, plays an essential role in plant growth and development as a component of the TOR signaling pathway.     

Nutrient sensing and TOR signaling in yeast and mammals

Coordinating cell growth with nutrient availability is critical for cell survival. The evolutionarily conserved TOR (target of rapamycin) controls cell growth in response to nutrients, in particular amino acids. As a central controller of cell growth, mTOR (mammalian TOR) is implicated in several disorders, including cancer, obesity, and diabetes. Here, we review how nutrient availability is sensed and transduced to TOR in budding yeast and mammals. A better understanding of how nutrient availability is transduced to TOR may allow novel strategies in the treatment for mTOR‐related diseases.     

RAG GTPases in nutrient-mediated TOR signaling pathway

Amino acids are key nutrients for protein synthesis and many metabolic processes. There is compelling evidence that amino acids themselves regulate protein synthesis, degradation, and cell growth. Mammalian target of rapamycin complex 1 (mTORC1) plays a central role in cellular growth regulation. Amino acids potently activate mTORC1, however, the mechanism of amino acid signaling is largely unknown. Recent studies have identified Rag small GTPases as key components mediating amino acid signals to mTORC1 activation.     

TOR signaling regulates microtubule structure and function

The functional diversity and structural heterogeneity of microtubules are largely determined by microtubule-associated proteins (MAPs) [1] [2]. Bik1p (bilateral karyogamy defect protein) is one of the MAPs required for microtubule assembly, stability and function in cell processes such as karyogamy and nuclear migration and positioning in the yeast Saccharomyces cerevisiae [3]. The macrocyclic immunosuppressive antibiotic rapamycin, complexed with its binding protein FKBP12, binds to and inhibits the target of rapamycin protein (TOR) in yeast [4] [5]. We report here that TOR physically interacts with Bik1p, the yeast homolog of human CLIP-170/Restin [6] [7]. Inhibition of TOR by rapamycin significantly affects microtubule assembly, elongation and stability. This function of TOR is independent of new protein synthesis. Rapamycin also causes defects in spindle orientation, nuclear movement and positioning, karyogamy and chromosomal stability, defects also found in the bikDelta mutant. Our data suggest a role for TOR signaling in regulating microtubule stability and function, possibly through Bik1p.     

Complexity of the TOR signaling network

The target of rapamycin (TOR) is a serine/threonine kinase of the phosphatidylinositol kinase-related kinase family and is highly conserved from yeast to mammals. TOR functions as a central regulator of cell growth and is itself regulated by a wide range of signals, including growth factors, nutrients and stress conditions. Recent studies in eukaryotic cells have identified two distinct TOR complexes, TORC1 and TORC2, which phosphorylate different substrates and have distinct physiological functions. Here, we discuss new findings that have extended the complexity of TOR signaling and the different roles of the TORC complexes in yeast, flies and mammals.     

TOR signaling: an odyssey from cellular stress to the cell growth machinery

The target of rapamycin (TOR) protein kinase is centrally involved in the coordination of cell growth and proliferation with the availability of growth factors and nutrients. Two recent reports have illuminated a mechanism whereby hypoxic stress dampens TOR signaling in metazoan cells.     

Identification of TOR signaling complexes: more TORC for the cell growth engine

The eukaryotic cytoskeleton is a dynamic filamentous network with various cellular and developmental functions. Plant cells display a singular architecture, necessitating a structurally and functionally unique cytoskeleton and plant specific control mechanisms.     

Insulin/IGF and target of rapamycin signaling: a TOR de force in growth control

'They come in all sizes.' Apart from its origin and use in the clothing industry, this saying reflects the fact that the size of organisms spans an enormous range. Whether destined to be large or small, species grow in an organized fashion to reach their final specified size. For growth to proceed, food must be metabolized to liberate energy in the form of adenosine triphosphate (ATP) and protein building blocks in the form of amino acids. One major orchestrator of this complex growth process in diverse metazoan species is the insulin/insulin-like growth factor (IGF) system. This review summarizes current studies primarily from Drosophila regarding the function of the insulin/IGF system in the control of growth.     

Mitochondrial signaling, TOR, and life span

Growing evidence supports the concept that mitochondrial metabolism and reactive oxygen species (ROS) play a major role in aging and determination of an organism's life span. Cellular signaling pathways regulating mitochondrial activity, and hence the generation of ROS and retrograde signaling events originating in mitochondria, have recently moved into the spotlight in aging research. Involvement of the energy-sensing TOR pathway in both mitochondrial signaling and determination of life span has been shown in several studies. This brief review summarizes the recent progress on how mitochondrial signaling might contribute to the aging process with a particular emphasis on TOR signaling from invertebrates to humans.     

Mammalian TOR signaling to the AGC kinases

The mechanistic (or mammalian) target of rapamycin (mTOR), an evolutionarily conserved protein kinase, orchestrates cellular responses to growth, metabolic and stress signals. mTOR processes various extracellular and intracellular inputs as part of two mTOR protein complexes, mTORC1 or mTORC2. The mTORCs have numerous cellular targets but members of a family of protein kinases, the protein kinase (PK)A/PKG/PKC (AGC) family are the best characterized direct mTOR substrates. The AGC kinases control multiple cellular functions and deregulation of many members of this family underlies numerous pathological conditions. mTOR phosphorylates conserved motifs in these kinases to allosterically augment their activity, influence substrate specificity, and promote protein maturation and stability. Activation of AGC kinases in turn triggers the phosphorylation of diverse, often overlapping, targets that ultimately control cellular response to a wide spectrum of stimuli. This review will highlight recent findings on how mTOR regulates AGC kinases and how mTOR activity is feedback regulated by these kinases. We will discuss how this regulation can modulate downstream targets in the mTOR pathway that could account for the varied cellular functions of mTOR.     

Mammalian TOR signaling to the AGC kinases

The mechanistic (or mammalian) target of rapamycin (mTOR), an evolutionarily conserved protein kinase, orchestrates cellular responses to growth, metabolic and stress signals. mTOR processes various extracellular and intracellular inputs as part of two mTOR protein complexes, mTORC1 or mTORC2. The mTORCs have numerous cellular targets but members of a family of protein kinases, the protein kinase (PK)A/PKG/PKC (AGC) family are the best characterized direct mTOR substrates. The AGC kinases control multiple cellular functions and deregulation of many members of this family underlies numerous pathological conditions. mTOR phosphorylates conserved motifs in these kinases to allosterically augment their activity, influence substrate specificity, and promote protein maturation and stability. Activation of AGC kinases in turn triggers the phosphorylation of diverse, often overlapping, targets that ultimately control cellular response to a wide spectrum of stimuli. This review will highlight recent findings on how mTOR regulates AGC kinases and how mTOR activity is feedback regulated by these kinases. We will discuss how this regulation can modulate downstream targets in the mTOR pathway that could account for the varied cellular functions of mTOR.