RHEB and melanoma: Signaling downstream of mTORC1 is partitioned into canonical RHEB-dependent signaling to substrates like S6K and a non-canonical pathway where mTORC1 targeting of TFEB and TFE3 relies instead on RAGC/D and FLCN/FNIP2.93 Paradoxically, activating mTORC1 mutations can trigger a negative feedback loop leading to hypophosphorylated nuclear TFEB/TFE3.94,95 By promoting canonical mTORC1 signaling, it is possible that despite upregulating RRAGD and FNIP2, MITF may suppress non-canonical signaling to promote the largely nuclear TFEB and TFE3 observed in MITFHigh melanoma cells.