Tumor cells often display fundamental changes in metabolism and increase their uptake of nutrients to meet the increased bioenergetic demands of proliferation. Glucose and glutamine are two main nutrients whose uptake is directly controlled by oncogenic mutations and are essential for tumor cell survival and proliferation. During tumor growth, increased uptake of nutrients and rapid accumulation of cells can outstrip the supply of essential nutrients, including glucose and glutamine. How tumor cells survive these temporary periods of nutrient deprivation is unclear, but is necessary for tumorigenesis to persist. The major goal of our laboratory is to delineate the strategies used by tumor cells to survive periods of nutrient deprivation and then to develop novel therapies targeting nutrient-sensing pathways of neoplastic cells. We recently discovered that protein phosphatase 2A (PP2A)-associated protein, α4, plays a conserved role in glutamine sensing. α4 promotes assembly of an adaptive PP2A complex containing the B55α regulatory subunit via providing the catalytic subunit upon glutamine deprivation. Moreover, B55α is specifically induced upon glutamine deprivation in a ROS-dependent manner to activate p53 and promote cell survival. B55α activates p53 through direct interaction and dephosphorylation of EDD, a negative regulator of p53. Importantly, the B55α-EDD-p53 pathway is essential for cancer cell survival and tumor growth under low glutamine conditions in vitro and in vivo. Our studies provided not only deeper understanding of the survival pathway used by cancer cells when glutamine metabolism is blocked, but also provides important evidence that protein phosphatase complexes are actively involved in signal transduction.