How do cells sense amino acid availability and regulate mTORC1?

mTORC1 integrates nutrient signals to control cell growth. Amino acid sensing occurs through multiple pathways. Leucine: sensed by Sestrin proteins (cytosolic) and Leucyl-tRNA synthetase (lysosomal), releasing inhibition of GATOR2, which inhibits GATOR1, allowing Rag GTPases to recruit mTORC1 to lysosome where Rheb activates it. Arginine: sensed by CASTOR proteins and SLC38A9 transporter. Glutamine: sensed by Arf1 GTPase, affecting Rag activation. At lysosome, Ragulator anchors Rags; v-ATPase senses lysosomal amino acids. Active mTORC1 promotes: protein synthesis (S6K, 4E-BP phosphorylation), lipid synthesis, nucleotide synthesis, and inhibits autophagy. Sensing pathways are therapeutic targets for metabolic disease and cancer; rapamycin inhibits mTORC1.