Regulation of the TSC/mTOR pathway in human disease and cellular stress

A fundamental question in cell biology is how various extracellular cues can cause changes in translational output and hence the growth of the cell. The mammalian target of rapamycin (mTOR) is a key regulator of translation that acts to stimulate protein synthesis by phosphorylating the ribosomal translation regulators p70 ribosomal S6 kinase (56K) and eukaryote initiation factor 4E binding protein 1 (4EBP1). mTOR is known to receive inputs from multiple signaling pathways and responds by increasing or decreasing protein synthesis appropriately. A prominent example of this phenomenon is how mTOR is stimulated by growth factors and the availability of nutrients, while it is inhibited by conditions such as low ATP levels, the absence of nutrients, or cellular stressors such as DNA damage or hypoxia. Regulation of protein synthesis by mTOR is responsible for controlling cell size and proliferation, and dysregulation of the mTOR pathway in vivo has been implicated in the pathogenesis of several hypertrophic and hamartoma (benign tumor) syndromes, including tuberous sclerosis complex and the pten-hamartoma tumor syndromes. Here we show that LKB1, the gene mutated in another hamartoma syndrome -- the Peutz-Jeghers hamartoma syndrome -- directly affects signaling through mTOR. We show that loss of LKB1 causes increased signaling through mTOR targets S6K and 4EBP1, and LKB1 over-expression causes physiological markers of mTOR signaling to decrease. Our results indicate that LKB1 plays a role in cell growth regulation in response to cellular energy levels; and they also suggest that rapamycin or rapamycin analogs might be of therapeutic benefit in Peutz-Jeghers syndrome. We also propose a provisional system to classify hamartoma and hypertrophic syndromes according to their potential or proven role in the mTOR pathway.; Another area of investigation relates to how mTOR is regulated by stress conditions such as energy starvation, DNA damage, hypoxia, or glucocorticoid treatment. We observed that two stress-induced proteins, RTP801/Redd1 and RTP801L/Redd2, potently inhibit signaling through mTOR. Our data support the hypothesis that RTP801 functions downstream of AKT and upstream of TSC2 -- two known constituents of the mTOR pathway -- to inhibit mTOR functions. RTP801 and RTP801L are homologous, yet show little sequence similarity to known protein domains other than a coiled-coil domain. We also present evidence for a mechanism as to how these proteins may function to regulate the mTOR pathway. Taken together, these results add a new dimension to mTOR pathway regulation and provide a possible molecular mechanism of how cellular stress conditions may regulate mTOR function.