The A2357T substitution in the kinase domain of yeast Tor1 confers growth promoting TORC1 activity independent of Gtr1/2 and Pib2.

The highly conserved Target of Rapamycin Complex 1 (TORC1) plays a central role in controlling eukaryotic cell growth in response to diverse environmental cues, including nitrogen availability. In yeast, TORC1 activity is stimulated through direct interaction with at least two upstream regulators: the Gtr1/2 GTPase complex, homologous to mammalian RagAB/CD and which binds the fungus-specific Tco89 protein, and the FYVE-domain-containing protein Pib2, an amino acid sensor. Here, using a novel genetic approach, we first confirmed that in cells expressing neither Gtr1/2 nor Pib2, no other factor is capable of supporting sufficient TORC1 activity to sustain cell growth, even under 25 different nitrogen supply conditions. We then identified a novel, dominant TOR1 mutation introducing an A2357T substitution into the Tor1 kinase domain and conferring sufficient TORC1 activity to support cell growth despite the loss of both Gtr1/2 and Pib2. Interestingly, previous studies have identified substitutions at the corresponding A2420 residue in human mTOR from multiple cancer cells.