TOR Complex 2-Ypk1 Signaling Maintains Sphingolipid Homeostasis by Sensing and Regulating ROS Accumulation

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Aging in the post-genomic era: simple or complex?

A report on the Third Genetic Effects on Aging Meeting, The Jackson Laboratory, Bar Harbor, Maine, August 4-8, 2000.     

TOR regulation: sorting out the answers

Components involved in vesicle trafficking processes such as secretion, endocytosis, and autophagy are gaining recognition as important regulators and effectors of target of rapamycin (TOR) signaling. A recent report by now implicates Pmr1, a secretory pathway Ca(2+)/Mn(2+) ATPase located in the Golgi apparatus, as a novel regulator of TOR and its downstream targets in yeast.     

TOR and aging: less is more

Metabolism and mitochondrial activity are thought to be important determinants of life span. A new study in this issue of Cell Metabolism (Bonawitz et al., 2007) suggests that the TOR pathway controls mitochondrial respiration in yeast and that the harder mitochondria work, the longer yeast live.     

TOR1 and TOR2 have distinct locations in live cells

TOR is a structurally and functionally conserved Ser/Thr kinase found in two multiprotein complexes that regulate many cellular processes to control cell growth. Although extensively studied, the localization of TOR is still ambiguous, possibly because endogenous TOR in live cells has not been examined. Here, we examined the localization of green fluorescent protein (GFP) tagged, endogenous TOR1 and TOR2 in live S. cerevisiae cells. A DNA cassette encoding three copies of green fluorescent protein (3XGFP) was inserted in the TOR1 gene (at codon D330) or the TOR2 gene (at codon N321). The TORs were tagged internally because TOR1 or TOR2 tagged at the N or C terminus was not functional. The TOR1^D330-3XGFP strain was not hypersensitive to rapamycin, was not cold sensitive, and was not resistant to manganese toxicity caused by the loss of Pmr1, all indications that TOR1-3XGFP was expressed and functional. TOR2-3XGFP was functional, as TOR2 is an essential gene and TOR2^N321-3XGFP haploid cells were viable. Thus, TOR1 and TOR2 retain function after the insertion of 748 amino acids in a variable region of their noncatalytic domain. The localization patterns of TOR1-3XGFP and TOR2-3XGFP were documented by imaging of live cells. TOR1-3XGFP was diffusely cytoplasmic and concentrated near the vacuolar membrane. The TOR2-3XGFP signal was cytoplasmic but predominately in dots at the plasma membrane. Thus, TOR1 and TOR2 have distinct localization patterns, consistent with the regulation of cellular processes as part of two different complexes.     

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.     

ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis

Reactive oxygen species (ROS) have been shown to be toxic but also function as signalling molecules. This biological paradox underlies mechanisms that are important for the integrity and fitness of living organisms and their ageing. The pathways that regulate ROS homeostasis are crucial for mitigating the toxicity of ROS and provide strong evidence about specificity in ROS signalling. By taking advantage of the chemistry of ROS, highly specific mechanisms have evolved that form the basis of oxidant scavenging and ROS signalling systems.     

More chores for TOR: de novo ceramide synthesis

In this issue of Cell Metabolism, Aronova et al. (2008) show that target of rapamycin complex 2 (TORC2) controls de novo ceramide synthesis in yeast by regulating the activity of ceramide synthase. This work may provide insight into how chemotherapeutic drugs increase de novo ceramide synthesis and promote cell death in humans.     

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.     

Bending the path to TOR

Cells sense and respond to physical stresses through mechanotransduction, a process that converts mechanical stimuli into biochemical signals. The bending of primary cilia has now been shown to modulate TOR signalling to negatively regulate cell size.     

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.     

Review series: TOR kinase complexes and cell migration

Cell migration is a fundamental process in a wide array of biological and pathological responses. It is regulated by complex signal transduction pathways in response to external cues that couple to growth factor and chemokine receptors. In recent years, the target of rapamycin (TOR) kinase, as part of either TOR complex 1 (TORC1) or TOR complex 2 (TORC2), has been shown to be an important signaling component linking external signals to the cytoskeletal machinery in a variety of cell types and organisms. Thus, these complexes have emerged as key regulators of cell migration and chemotaxis.