Recently, we demonstrated that the 36 kDa catalytic subunit of protein phosphatase 2A (PP2Ac) undergoes methylation at its C-terminal leucine in normal rat islets, human islets and isolated β cells; this modification increases the catalytic activity of PP2A [Kowluru et al. Endocrinology. 137:2315–2323, 1996]. Previous studies have suggested that adenine and guanine nucleotides or glycolytic intermediates [which are critical mediators in β cell function] also modulate phosphatase activity in the pancreatic β cell. Therefore, we examined whether these phosphorylated molecules specifically regulate the carboxyl methylation and the catalytic activity of PP2A in β cells. Micromolar concentrations of ATP, ADP, GTP or GDP each inhibited the carboxyl methylation of PP2Ac and, to a lesser degree, the catalytic activity of PP2A. Likewise, the carboxyl methylation of PP2Ac and its catalytic activity were inhibited by [mono- or di-] phosphates of glucose or fructose. Additionally, however, the carboxyl methylation of PP2Ac was significantly stimulated by divalent metal ions (Mn2+ > Mg2+ > Ca2+ > control). The nucleotide or sugar phosphate-mediated inhibition of carboxyl methylation of PP2Ac and the catalytic activity of PP2A were completely prevented by Mn2+ or Mg2+. These data indicate that divalent metal ions protect against the inhibition by purine nucleotides or sugar phosphates of the carboxyl methylation of PP2Ac perhaps permitting PP2A to function under physiologic conditions. Therefore, these data warrant caution in interpretation of extant data on the regulation of phosphatase function by purine nucleotides.

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