Identification and characterization of novel positive regulators of the Target of Rapamycin (TOR) pathway in Drosophila melanogaster

Abstract

Target of Rapamycin (TOR) is an evolutionary conserved pathway in eukaryotes for growth and proliferation. TOR pathway plays an important role for growth homeostasis by coupling nutritional and growth factor availability and cellular stress levels to both temporal and spatial aspects of growth. Aberrant TOR signaling results in dysregulation of growth leading to a number of human pathologies such as Tuberous Sclerosis, Peutz-Jegher's syndrome, cancers and neurological diseases such as Alzeihmer's. Inspite of the importance of TOR-mediated growth, there are a number of unanswered questions in the pathway such as unknown regulators and effectors of TOR and how exactly amino acids are sensed by TOR pathway. In order to understand the complexity of the TOR pathway and gain answers to some of the questions in the pathway, we undertook forward and reverse genetic approaches to identify novel positive regulators in the TOR pathway using Drosophila as a model. Our studies identify Rag GTPases to be important for amino acid sensing and upregulating TOR activity. We also present a possible mechanistic model for how Rag-GTPase mediated amino acid sensing may activate TOR pathway. The positive regulators identified in this study have aided our understanding of the important process of amino acid sensing at a cellular level and have contributed to furthering our knowledge of the TOR pathway.