The Rag GTPases-mTORC1-TFE3 Axis in Kidney Cancer and Neurodevelopment: A Mini Review

The MiT/TFE proteins (MITF, TFE3, TFEB, and TFEC) constitute a family of transcription factors that maintain cellular homeostasis by controlling the transcription of genes involved in lysosomal biogenesis, autophagy, oxidative metabolism, and pigmentation. While significant effort has been placed in understanding the downstream function of this family, the upstream regulation has only recently become clearer. It was appreciated that the nutrient-sensing Rag GTPases-mTORC1 pathway attenuates the activity of this family, but how this occurs mechanistically remained unclear. The physiological role of the MiT/TFE family is underscored by the fact that numerous human diseases are caused by their misregulation. The goal of this minireview is to provide a summary of recent findings that have elucidated how this family is regulated upstream and, hence, the molecular basis of a rare kidney cancer and neurodevelopmental syndrome caused by mutations in TFE3. The information presented here may serve as a framework for future studies.