The mTORC1 kinase promotes growth in response to growth factors, energy levels, and
amino acids, and its activity is often deregulated in disease. The Rag GTPases interact
with mTORC1 and are proposed to activate it in response to amino acids by promoting
mTORC1 translocation to a membrane-bound compartment that contains the mTORC1 activator,
Rheb. We show that amino acids induce the movement of mTORC1 to lysosomal membranes,
where the Rag proteins reside. A complex encoded by the MAPKSP1, ROBLD3, and c11orf59
genes, which we term Ragulator, interacts with the Rag GTPases, recruits them to lysosomes,
and is essential for mTORC1 activation. Constitutive targeting of mTORC1 to the lysosomal
surface is sufficient to render the mTORC1 pathway amino acid insensitive and independent
of Rag and Ragulator, but not Rheb, function. Thus, Rag-Ragulator-mediated translocation
of mTORC1 to lysosomal membranes is the key event in amino acid signaling to mTORC1.
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