Specificity and function of PP2A carboxymethylation

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DESCRIPTION (provided by applicant): PP2A, a multifunctional Ser/Thr phosphatase, has been implicated in the regulation of cell growth and proliferation, including the G2/M transition, and in the development of human cancers. PP2A is methylated on its catalytic subunit C-terminal leucine alpha-carboxy group by LCMT-1 and is demethylated by PME-1. Together, these two proteins regulate the methylation of the C subunit, indirectly regulating PP2A by altering ts holoenzyme formation, and thus its subcellular targeting and substrate specificity. Reversible methylation s the most specific cellular mechanism for regulating PP2A, and thus may have promise as a mechanism- based therapeutic target. The level of PP2A C subunit methylation changes in a cell cycle-dependent manner and a methylation-dependent form of PP2A regulates several key proteins at the G2/M transition, suggesting PP2A methylation may regulate entry into mitosis. PP4 and PPG phosphatases exhibit a high degree of sequence homology to PP2A and PP4 is also reversibly methylated. Although PP6 has the same hree carboxy-terminal amino acids as PP2A and PP4, it has not been determined whether PP6 can also be reversibly methylated. In addition, the methyltransferase that catalyzes the methyl esterification of PP4's C- terminal leucine has not been identified. My interrelated yet independent aims of this fellowship are (1) to determine the substrate specificities of LCMT-1, LCMT-2, and PME-1 towards PP2A, PP4, and PP6 and (2) :to determine if PP2A catalytic subunit methylation plays a role the G2/M transition.