The small GTPase Rheb plays an important role in cell growth. The tumor suppressor genes Tsc1 and Tsc2, which serves as a GAP, regulate Rheb activity. Rheb in turn regulates TOR, a critical cellular nutrient sensor implicated in many human malignancies from colon to breast to prostate cancer. The mechanism by which Rheb regulates TOR remains elusive and a Rheb activator has yet to be identified. To gain insight into Rheb function, we will focus on three specific aims: 1) Rheb effectors will be identified using a 2urn suppressor screen in yeast, 2) Rheb pull-downs coupled with mass spectrophotometry will be utilized to identify associated proteins in both yeast and mammalian cells and 3) the Rheb regulators and effectors homologous to mammalian genes will be characterized in mammalian cells utilizing RNAi technology, FACS, and cellular biochemistry. A greater understanding of Rheb function and identification of a Rheb activator will have important implications for cancer and may elucidate additional therapeutic drug targets for the fight against cancer.
