Abstract
The target of rapamycin (TOR) kinase coordinately regulates fundamental metabolic and cellular processes to support growth, proliferation, survival, and differentiation, and consequently it has been proposed as a therapeutic target for the treatment of cancer, metabolic disease, and aging. The TOR kinase is found in two biochemically and functionally distinct complexes, termed TORC1 and TORC2. Aided by the compound rapamycin, which specifically inhibits TORC1, the role of TORC1 in regulating translation and cellular growth has been extensively studied. The physiological roles of TORC2 have remained largely elusive due to the lack of pharmacological inhibitors and its genetic lethality in mammals. Among potential targets of TORC2, the pro-survival kinase AKT has garnered much attention. Within the context of intact animals, however, the physiological consequences of phosphorylation of AKT by TORC2 remain poorly understood. Here we describe viable loss-of-function mutants in the Caenorhabditis elegans homolog of the TORC2-specific component, Rictor (CeRictor). These mutants display a mild developmental delay and decreased body size, but have increased lipid storage. These functions of CeRictor are not mediated through the regulation of AKT kinases or their major downstream target, the insulin-regulated FOXO transcription factor DAF-16. We found that loss of sgk-1, a homolog of the serum- and glucocorticoid-induced kinase, mimics the developmental, growth, and metabolic phenotypes of CeRictor mutants, while a novel, gain-of-function mutation in sgk-1 suppresses these phenotypes, indicating that SGK-1 is a mediator of CeRictor activity. These findings identify new physiological roles for TORC2, mediated by SGK, in regulation of C. elegans lipid accumulation and growth, and they challenge the notion that AKT is the primary effector of TORC2 function.
Highlights
Target of rapamycin (TOR), a serine/threonine kinase of the phosphatidylinositol kinase-related family, is broadly conserved in eukaryotes, and in all systems examined, it is required for normal growth [1]
The target of rapamycin (TOR) kinase acts as a conserved sensor of energy status and governs diverse functions such as metabolism, growth, and cell size via two separate multiprotein complexes
TOR complex 1 (TORC1), which is sensitive to the immunosuppressant drug rapamycin, is well understood but the physiological roles and molecular mechanisms of action of the second TOR complex (TORC2) are not so clear
Summary
Target of rapamycin (TOR), a serine/threonine kinase of the phosphatidylinositol kinase-related family, is broadly conserved in eukaryotes, and in all systems examined, it is required for normal growth [1]. One reason for the immense diversity of TOR-regulated processes is that the kinase operates in two complexes, each with its own unique set of components and subsequent substrates [3]. TORC1 can be distinguished from TORC2 functionally, because only TORC1 is inhibited by the compound rapamycin [3,4,5]. The use of this drug has been the major driving force in the study of the TOR kinase—it enabled the identification of key TORC1 targets [6,7,8], and the TOR kinase itself was first discovered by genetic analysis in yeast aimed at determining the mechanism of rapamycin’s growth-inhibitory action [9]
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