Function and post-translational regulation of the PP2A methylesterase PME-1 in the cellular response to stress conditions

Cells have developed diverse mechanisms to protect themselves from acute damage by environmental stresses, such as nutrient or growth factor deprivation, oxidative stress and DNAdamage. In all these responses, stress-regulated protein kinases and phosphatases are commonly involved. Protein Phosphatase 2A (PP2A) is a major cellular phosphatase with pleiotropic functions, including in stress signaling. Here, we aim to investigate how cellular stressors regulate PP2A function through its methylesterase, PME-1. PME-1 regulates PP2A in diverse ways, most notably by demethylating the PP2A catalytic subunit, by stabilizing an inactive pool of PP2A and by preventing PP2A degradation. Sustained by preliminary data, we hypothesize that PME-1, through regulation of PP2A, affects cell survival in response to cellular stresses, and that stress-induced PME-1 phosphorylation plays a major role in this.

Our specific aims are: (1) To identify stress-induced PME-1 phosphorylation sites and (2) upstream kinases; (3) to analyze the consequences of PME-1 phosphorylation on PME-1 and PP2A function in vitro and in stressed cells; (4) to establish how PME-1 (phosphorylation) affects stress responses in glioma and uterine cancer cells; (5) to determine whether pharmacologic inhibition of PME-1 or stress-induced PME-1 kinases might sensitize these cancer cells to the applied stresses. Hence, this project may reveal novel mechanisms to exploit PP2A and PME-1 as potential cancer therapy targets.