Mammalian target of rapamycin complex 1: signalling inputs, substrates and feedback mechanisms.

The mammalian target of rapamycin (mTOR) signalling pathway is implicated in the pathogenesis of a number of cancers and inherited hamartoma syndromes which have led to mTOR inhibitors, such as rapamycin, being tested in clinical trials. Knowledge of the mTOR pathway is rapidly expanding. This review provides an update on the most recent additions to the mTOR pathway with particular emphasis on mTORC1 signalling. mTORC1 signalling is classically known for its role in regulating cell growth and proliferation through modulation of protein synthesis. Recent research has identified novel mTORC1 cell signalling mechanisms that modulate mitochondrial biogenesis, hypoxia signalling and cell cycle progression and uncovered novel mTORC1 targets; YY1, HIF and SGK1. It is unsurprising that regulation of mTORC1 is multifaceted with many positive and negative signalling inputs. We discuss the recent advances that have been made to determine the upstream mechanisms that control mTORC1 through hypoxia, energy sensing and nutrient signalling. Also discussed are current findings that have unravelled a series of novel mTORC1-associated proteins that directly control the activity of mTORC1 and include PRAS40, FKBP38, Rag GTPases and RalA.