Molecular Mechanisms Underlying Cardiac Protein Phosphatase 2A Regulation in Heart
Molecular Mechanisms Underlying Cardiac Protein Phosphatase 2A Regulation in Heart
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DOI：
10.1074/jbc.m112.426957
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发表时间：
2013-01-11
影响因子：
4.8
通讯作者：
Mohler, Peter J.
中科院分区：
文献类型：
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作者：
DeGrande, Sean T.;Little, Sean C.;Mohler, Peter J.
在健康和疾病中，激酶/磷酸酶平衡控制心脏的兴奋性。虽然已经建立了详细的心肌激酶调节机制，但对心肌蛋白磷酸酶2A(PP2A)的调节知之甚少。这在很大程度上是由于PP2A全酶结构的复杂性(来自17个亚基基因的三个亚基酶的组合组装)，以及无法将PP2A的“全局”功能与多个“局部”全酶种群的活动分开。在这里，我们报告了PP2A催化、调节和支架亚基在转录、翻译和翻译后水平受到严格调控，以调节基线和疾病中的心肌细胞功能。我们发现，过去对细胞PP2A活性的全局读出更合适地代表了许多单个PP2A全酶的集体活性，每个酶都显示了特定的亚细胞定位(由特定的PP2A调节亚基决定)以及局部特定的翻译后催化亚基甲基化和磷酸化事件，这些事件调节局部和快速的全酶组装/拆卸(通过亮氨酸羧甲基转移酶1/磷酸酶甲基酯酶1(LCMT-1/PME-1)。我们报道，PP2A亚单位在人和动物模型之间、跨心腔、甚至在特定的心肌细胞类型中被选择性地调节。此外，这种调节可以快速调整，以响应细胞激活。最后，我们报告说，在人类和心脏病的实验模型中，全局PP2A发生了改变，但每种病理都通过特定的PP2A亚单位调节事件显示了自己独特的分子特征。这些新数据提供了控制心脏中PP2A功能的信号通路的初步观点，也为确定健康和疾病中特定的PP2A调控目标奠定了第一步。
Kinase/phosphatase balance governs cardiac excitability in health and disease. Although detailed mechanisms for cardiac kinase regulation are established, far less is known regarding cardiac protein phosphatase 2A (PP2A) regulation. This is largely due to the complexity of the PP2A holoenzyme structure (combinatorial assembly of three subunit enzyme from >17 subunit genes) and the inability to segregate "global" PP2A function from the activities of multiple "local" holoenzyme populations. Here we report that PP2A catalytic, regulatory, and scaffolding subunits are tightly regulated at transcriptional, translational, and post-translational levels to tune myocyte function at base line and in disease. We show that past global read-outs of cellular PP2A activity more appropriately represent the collective activity of numerous individual PP2A holoenzymes, each displaying a specific subcellular localization (dictated by select PP2A regulatory subunits) as well as local specific post-translational catalytic subunit methylation and phosphorylation events that regulate local and rapid holoenzyme assembly/disassembly (via leucine carboxymethyltransferase 1/phosphatase methylesterase 1 (LCMT-1/PME-1). We report that PP2A subunits are selectively regulated between human and animal models, across cardiac chambers, and even within specific cardiac cell types. Moreover, this regulation can be rapidly tuned in response to cellular activation. Finally, we report that global PP2A is altered in human and experimental models of heart disease, yet each pathology displays its own distinct molecular signature though specific PP2A subunit modulatory events. These new data provide an initial view into the signaling pathways that govern PP2A function in heart but also establish the first step in defining specific PP2A regulatory targets in health and disease.