The Spectrum of "TFEopathies" - Flipping the mTOR Switch in Renal Tumorigenesis.

ABSTRACT

The Mammalian Target of Rapamycin Complex 1 (mTORC1) is a serine threonine kinase that couples nutrient and growth factor signaling to the cellular control of metabolism and plays a fundamental role in aberrant proliferation in cancer. mTORC1 has previously been considered an "on/off" switch, capable of phosphorylating the entire pool of its substrates when activated. However recent studies have indicated that mTORC1 may be active towards its canonical substrates, 4EBP1 and S6K, involved in mRNA translation and protein synthesis, and inactive towards TFEB and TFE3, transcription factors involved in the regulation of lysosome biogenesis, in several pathological contexts. Among these conditions are Birt Hogg Dube (BHD) and recently, Tuberous Sclerosis Complex (TSC). Furthermore, TFEB and TFE3 hyperactivation in these syndromes, and in translocation Renal Cell Carcinomas (tRCC), drives mTORC1 activity towards the canonical substrates, through the transcriptional activation of the Rag GTPases, thereby positioning TFEB and TFE3 upstream of mTORC1 activity towards 4EBP1 and S6K. The expanding importance of TFEB and TFE3 in the pathogenesis of these renal diseases warrants a novel clinical grouping that we term "TFEopathies". Currently, there no therapeutic options directly targeting TFEB and TFE3, which represents a challenging and critically required avenue for cancer research.