The Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1

TLDR

mTORC1 is a central kinase complex that drives growth in response to insulin, energy, and amino acids and is deregulated in many cancers. The study shows that Rag GTPases bind mTORC1 in an amino‑acid–dependent manner, are required for amino‑acid–induced activation, and that GTP‑bound Rags recruit mTOR to the Rheb‑containing compartment, while GDP‑bound Rags block this activation.

Abstract

The multiprotein mTORC1 protein kinase complex is the central component of a pathway that promotes growth in response to insulin, energy levels, and amino acids and is deregulated in common cancers. We find that the Rag proteins—a family of four related small guanosine triphosphatases (GTPases)—interact with mTORC1 in an amino acid–sensitive manner and are necessary for the activation of the mTORC1 pathway by amino acids. A Rag mutant that is constitutively bound to guanosine triphosphate interacted strongly with mTORC1, and its expression within cells made the mTORC1 pathway resistant to amino acid deprivation. Conversely, expression of a guanosine diphosphate–bound Rag mutant prevented stimulation of mTORC1 by amino acids. The Rag proteins do not directly stimulate the kinase activity of mTORC1, but, like amino acids, promote the intracellular localization of mTOR to a compartment that also contains its activator Rheb.