Fig. 4

Ca²⁺-mediated pathways of mTORC1 activation. a Leucine triggers the increase of intracellular Ca²⁺ concentrations ([Ca²⁺]_i) and stimulates the kinase activity of hVps34. The rise in [Ca²⁺]_i may be sensed by CaM. Leucine may also activate hVps34 via hVps15 and LRS. PI3P production by activated hVps34 results in recruitment of PLD1, producing PA, b Leucine may be sensed by GPCRs, which elevate [Ca²⁺]_i through Ca²⁺ fluxes from the ER via SHP-2-PLCβ4-IP3R signaling, leading to mTORC1 activation. c The umami receptor, T1R1/T1R3, senses amino acids and increases [Ca²⁺]_i in a VDCC-dependent manner via unknown mechanisms, leading to lysosomal translocation and activation of mTORC1. d TRPML1 mediates lysosomal Ca²⁺ release into the cytosol, resulting in a local and transient increase in [Ca²⁺]_i, which might be sensed by CaM to activate mTORC1. In turn mTORC1 phosphorylates TRPML1 to negatively regulate its Ca²⁺ release activity. Such feedback loop possibly maintains lysosomal and cellular homeostasis during nutrient starvation