Studies of amino acid sensing by the mTORC 1 pathway

Abstract

The mTOR complex 1 (mTORC 1) protein kinase is a master growth regulator that responds to multiple cues from the local and systemic environment surrounding the cell. Nutrients and growth factors are both required to activate mTORC 1 and to promote growth. While the mechanisms of growth factor signaling have been reasonably well established, we have only begun to unravel in recent years how amino acids signal to mTORC 1, thanks in large part to the identification of the Rag GTPases, which recruit mTORC 1 to the lysosomal surface for catalytic activation, and of the regulators of Rag function. An ultimate goal is to uncover the biochemical basis of the sensing event that triggers this signaling cascade in the first place: which amino acid(s) are sensed and how? Toward this end, we characterize in detail the amino acids required to fully activate mTORCl signaling in HEK-293T cells and identify SLC38A9 as a Rag-interacting amino acid transporter that may serve as an arginine sensor at the lysosome. Finally, we discuss the many open questions that remain to be studied regarding the mechanisms and logic behind amino acid sensing by the mTORC 1 pathway.