Protein phosphatase 2A (PP2A) is a major Ser/Thr protein phosphatase in mammalian cells that is involved in multiple processes. Deregulation of PP2A activity often leads to oncogenic transformation, which has led to the notion that PP2A is an important tumor suppressor. Due to its multi-subunit composition and its ability to interact with numerous regulatory proteins, the structure and regulation of PP2A remains poorly understood. The long-term goal of the applicant is to deduce the mechanism of PP2A regulation using a structural approach and to refine our knowledge of its roles in cell function using proteomic methods. This information will facilitate the development of potential PP2A based strategies for cancer therapy. The immediate goals of this research are i) to solve the structure of PP2A methyltransferase (PMT) and methylesterase (PME) in complex with the PP2A A-C core dimer and thereby elucidate the mechanism of reversible methylation of the catalytic subunit, a process that is essential for PP2A regulation, and to provide the long-awaited structural information for A-C complex; ii) to elucidate the mechanism of cellular inhibitory proteins I1PP2A and I2PP2A to inhibit the phosphatase activity of PP2A using structural and biochemical approach, and to investigate the roles of the common poly-acidic motif existed in PME, alpha4 protein, I1PP2A and I2PP2A; and iii) to resolve the protein phosphorylation profiles in cells affected by small molecule inhibitors such as okadaic acid, and by the methylation process, by alpha4 protein, I1PP2A, I2PP2A and some of the regulatory B-subunits. Their effects on cell growth, proliferation will also be tested on carcinoma cell lines. The activity of PP2A is often down regulated in cancer cells. The inhibitory proteins that down regulate PP2A function, such as PME, alpha4 protein, 11PP2A and I2PP2A are excellent targets for therapeutic intervention of cancer. The proteomic data should facilitate the identification of the regulatory element of PP2A that has the greatest promise for use as a target, and the structural data should provide ultimate clarity to PP2A regulation and function, and facilitate the design of therapeutic compounds that have the greatest potential therapeutic use for slowing or halting the growth, proliferation, and metastasis of oncogenic cells. ? ? ?
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