Protein Phosphatase Methyl-Esterase PME-1 Protects Protein Phosphatase 2A from Ubiquitin/Proteasome Degradation.
Protein Phosphatase Methyl-Esterase PME-1 Protects Protein Phosphatase 2A from Ubiquitin/Proteasome Degradation.
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DOI：
10.1371/journal.pone.0145226
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Sato K
中科院分区：
文献类型：
--
作者：
Yabe R;Miura A;Usui T;Mudrak I;Ogris E;Ohama T;Sato K
蛋白磷酸酶2A（PP 2A）是一种保守的必需酶，基于其在磷酸化依赖性信号通路中的中心作用而被认为是肿瘤抑制剂。蛋白磷酸酶甲基酯酶（PME-1）特异性催化PP 2A催化亚基（PP 2Ac）C-末端Leu 309残基的去甲基化。已经显示PME-1通过使PP 2Ac脱甲基化，而且还通过直接结合到磷酸酶活性位点来影响PP 2A的活性，这表明细胞中PME-1的损失将增强PP 2A活性。然而，在这里我们表明PME-1敲除小鼠胚胎成纤维细胞（MEF）表现出比野生型MEF更低的PP 2A活性。PME-1的缺失增强了PP 2Ac的多聚泛素化，缩短了PP 2Ac蛋白的半衰期，导致PP 2Ac水平降低。PME-1的化学抑制和救援实验与野生型和突变的PME-1显示甲基酯酶活性是必要的，以保持PP 2Ac蛋白水平。我们的数据表明，PME-1甲基酯酶活性保护PP 2Ac从泛素/蛋白酶体降解。
Protein phosphatase 2A (PP2A) is a conserved essential enzyme that is implicated as a tumor suppressor based on its central role in phosphorylation-dependent signaling pathways. Protein phosphatase methyl esterase (PME-1) catalyzes specifically the demethylation of the C-terminal Leu309 residue of PP2A catalytic subunit (PP2Ac). It has been shown that PME-1 affects the activity of PP2A by demethylating PP2Ac, but also by directly binding to the phosphatase active site, suggesting loss of PME-1 in cells would enhance PP2A activity. However, here we show that PME-1 knockout mouse embryonic fibroblasts (MEFs) exhibit lower PP2A activity than wild type MEFs. Loss of PME-1 enhanced poly-ubiquitination of PP2Ac and shortened the half-life of PP2Ac protein resulting in reduced PP2Ac levels. Chemical inhibition of PME-1 and rescue experiments with wild type and mutated PME-1 revealed methyl-esterase activity was necessary to maintain PP2Ac protein levels. Our data demonstrate that PME-1 methyl-esterase activity protects PP2Ac from ubiquitin/proteasome degradation.