The B55α Subunit of PP2A Drives a p53-Dependent Metabolic Adaptation to Glutamine Deprivation
The B55α Subunit of PP2A Drives a p53-Dependent Metabolic Adaptation to Glutamine Deprivation
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DOI：
10.1016/j.molcel.2013.02.008
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发表时间：
2013-04-25
期刊：
影响因子：
16
通讯作者：
Kong, Mei
中科院分区：
文献类型：
--
作者：
Reid, Michael A.;Wang, Wen-I;Kong, Mei
谷氨酰胺是癌细胞生存和增殖所必需的营养物质，但感知谷氨酰胺水平的信号通路仍未确定。在这里，我们报告了与蛋白磷酸酶2A(PP2A)相关的蛋白，α4，在谷氨酰胺感觉中起着保守的作用。Alpha 4通过在谷氨酰胺剥夺时提供催化亚单位来促进包含B55α调节亚基的适应性PP2A复合体的组装。此外，B55α是在谷氨酰胺缺乏时以ROS依赖的方式特异性诱导的，以激活P53并促进细胞存活。B55α通过与P53负调控因子EDD的直接相互作用和去磷酸化来激活P53。重要的是，B55α-EDD-P53通路在体内外低谷氨酰胺条件下对癌细胞存活和肿瘤生长至关重要。这项研究描绘了一个以前未知的信号通路，它可以感知谷氨酰胺水平，并提供了蛋白质磷酸酶复合体积极参与信号转导的重要证据。
Glutamine is an essential nutrient for cancer cell survival and proliferation, yet the signaling pathways that sense glutamine levels remain uncharacterized. Here, we report that the protein phosphatase 2A (PP2A)-associated protein, alpha 4, plays a conserved role in glutamine sensing. alpha 4 promotes assembly of an adaptive PP2A complex containing the B55 alpha regulatory subunit via providing the catalytic subunit upon glutamine deprivation. Moreover, B55 alpha is specifically induced upon glutamine deprivation in a ROS-dependent manner to activate p53 and promote cell survival. B55 alpha activates p53 through direct interaction and dephosphorylation of EDD, a negative regulator of p53. Importantly, the B55 alpha-EDD-p53 pathway is essential for cancer cell survival and tumor growth under low glutamine conditions in vitro and in vivo. This study delineates a previously unidentified signaling pathway that senses glutamine levels as well as provides important evidence that protein phosphatase complexes are actively involved in signal transduction.