Identifying novel regulatory roles of RagC GTPase and rapamycin on mTOR complex1 pathway — ASN Events
  1. Schedule
  2. Session 12: Poster Talks
  3. Identifying novel regulatory roles of RagC GTPase and rapamycin on mTOR complex1 pathway

Identifying novel regulatory roles of RagC GTPase and rapamycin on mTOR complex1 pathway (#105)

Guang Yang 1 2 , Danielle Murashige 2 3 , Deanne Francis 1 , Sean Humphrey 1 2 , David James 1 2
  1. The Charles Perkins Centre, The School of Life & Environmental Sciences, The University of Sydney, Sydney, NSW, Australia
  2. Diabetes and Obesity Program, Garvan Institute of Medical Research, Sydney, NSW, Australia
  3. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

The mechanistic target of rapamycin complex1 (mTORC1) is a central player in the control of cell growth, proliferation and metabolism in response to a vast range of internal and external stimuli. Two major parallel pathways are implicated in mTORC regulation and these include the growth factor (GF) pathway mediated via TSC2/Rheb and the amino acid pathway mediated via the Rag GTPases. In this study, we identify three insulin responsive phosphorylation sites on RagC, a component of Rag heterodimer, implicating an additional role of Rag GTPases in the GF pathway. RagC phosphorylation is associated with destabilization of mTORC1 and is essential for both insulin and amino acid-induced mTORC1 activation. Genetic studies in Drosophila show that RagC phosphorylation plays an essential role in cell growth regulation. Phosphorylation of Ser21 in RagC is catalysed by mTORC1 itself and surprisingly phosphorylation at this site by mTORC1 is potentiated by rapamycin, a mTORC1 specific inhibitor, while other mTORC1 substrates are blocked.  This rapamycin-potentiating phosphorylation depends on mTORC1 kinase activity rather than inhibition of the negative feedback loop. This work suggests that there is unforeseen convergence between amino acid and GF pathways at the level of the RagC GTPase and that phosphorylation of this protein unveils a completely novel behaviour of mTORC1 that results in its hyperactivation toward this particular substrate in the presence of rapamycin.  These findings have intriguing implications for the role of rapamycin as a therapeutic.