METABOLIC SIGNALS DRIVING CELL GROWTH & PROLIFERATION

 描述（由申请人提供）：主要细胞磷酸酶蛋白磷酸酶2A（PP2A）受其催化亚基羧基末端的非常规但保守的甲基化修饰调控。然而，这种甲基化的功能作用仍然不完全清楚。在当前的资助期内，研究表明PP2A上的这种甲基化修饰对细胞内甲硫氨酸和SAM水平有反应。因此，氨基酸甲硫氨酸及其下游代谢物SAM能够促进PP2A的甲基化，从而影响磷酸酶针对细胞信号传导和生长控制中的特定底物的活性。该更新申请提出使用遗传学、化学和蛋白质组学相结合的方法全面研究PP2A甲基化的体内功能。值得注意的是，PP2A上的这种修饰使其能够作为氨基酸响应性的代谢调节磷酸酶发挥作用，这可以影响许多重要信号蛋白的磷酸化状态，与细胞的代谢状态相协调。

 DESCRIPTION (provided by applicant): The major cellular phosphatase Protein Phosphatase 2A (PP2A) is regulated by an unconventional but conserved methylation modification on the very carboxy terminus of its catalytic subunit. However, the functional role of this methylation remains incompletely understood. In the current funding period, it was shown that this methylation modification on PP2A is responsive to intracellular methionine and SAM levels. As such, the amino acid methionine and its downstream metabolite SAM are able to promote the methylation of PP2A and thereby influence the activity of the phosphatase against particular substrates in cellular signaling and growth control. This renewal application proposes to comprehensively investigate the in vivo functions of the methylation of PP2A using a combined genetic, chemical, and proteomic approach. It is notable that this modification on PP2A enables it to function as an amino acid-responsive, metabolically-regulated phosphatase which could impact the phosphorylation status of many important signaling proteins in tune with the metabolic state of the cell.