Schematic presentation of the regulation of metabolic signaling and lysosomal movement by the lysosome-associated Ragulator complex that consists of five LAMTOR subunits (LT1–5). (Top) In the absence of nutrients and growth factors, Ragulator activates the catabolic liver kinase B1 (LKB1)–AMPK signaling pathway via Axin scaffold protein and retains lysosomes in the perinuclear area by binding to the Lyspersin subunit of BORC, thereby inhibiting the Arl8/SKIP-mediated association of BORC and kinesin motors. (Bottom) In the presence of nutrients and growth factors, Axin and BORC dissociate from the Ragulator, which leads to the inactivation of AMPK and activation of BORC/Arl8/SKIP/Kinesin-mediated antegrade movement of lysosomes away from the microtubule organizing center (MTOC). Subsequently, Ragulator is more efficient in promoting Rag GTPase-dependent mTORC1 activation and Mek1-dependent Erk1 activation. In nutrient-rich conditions, mTORC1 is further stimulated by amino acid sensed by the V-H⁺-ATPase and SLC38A9.