Disturbances in PP2A methylation and one-carbon metabolism compromise Fyn distribution, neuritogenesis, and APP regulation.
Disturbances in PP2A methylation and one-carbon metabolism compromise Fyn distribution, neuritogenesis, and APP regulation.
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DOI：
10.1074/jbc.ra120.016069
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Sontag E
中科院分区：
文献类型：
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作者：
Taleski G;Schuhmacher D;Su H;Sontag JM;Sontag E
非受体蛋白酪氨酸激酶Fyn和蛋白丝氨酸/苏氨酸磷酸酶2A(PP2A)是主要的多功能信号分子。Fyn的放松调控和PP2A甲基化的改变与癌症和阿尔茨海默病(AD)有关。在这里，我们验证了一种假设，即PP2A催化亚基的甲基化状态会影响PP2A亚基的组成和底物专一性，从而影响Fyn的调节和功能。利用Neuro-2a(N2a)神经母细胞瘤细胞模型，我们首次证明了含有Bα亚单位的甲基化PP2A全酶在膜筏中与FYN免疫共沉淀和共分泌。PP2A甲基化状态调节Fyn的分布和Fyn依赖的神经发生，可能部分是通过影响肌动蛋白的动态。甲基化不能的PP2A突变体无法与Fyn相互作用。它扰乱了Fyn和淀粉样前体蛋白(APP)在膜微域的正常分配，而膜微域控制着Fyn的功能和APP的加工。这与APP的淀粉样变性切割增强有关，APP是AD发病的标志。相反，增强的PP2A甲基化以Fyn依赖的方式促进APP的非淀粉样变性切割。控制细胞甲基化的一碳代谢途径的紊乱与阿尔茨海默病和癌症有关。值得注意的是，它们在N2a细胞和急性小鼠脑片中诱导了与膜相关的甲基化PP2A和Fyn酶的平行丢失。一碳代谢也调节依赖Fyn的N2a细胞的生长过程。因此，我们的发现确定了一个新的甲基化依赖的PP2A/Fyn信号模块。他们强调了必要的代谢途径和信号支架之间的交叉对话的重要性被低估了，这些途径参与正常的细胞动态平衡，目前被作为癌症和AD治疗的靶点。
The nonreceptor protein tyrosine kinase Fyn and protein Ser/Thr phosphatase 2A (PP2A) are major multifunctional signaling molecules. Deregulation of Fyn and altered PP2A methylation are implicated in cancer and Alzheimer's disease (AD). Here, we tested the hypothesis that the methylation state of PP2A catalytic subunit, which influences PP2A subunit composition and substrate specificity, can affect Fyn regulation and function. Using Neuro-2a (N2a) neuroblastoma cell models, we first show that methylated PP2A holoenzymes containing the Bα subunit coimmunoprecipitate and copurify with Fyn in membrane rafts. PP2A methylation status regulates Fyn distribution and Fyn-dependent neuritogenesis, likely in part by affecting actin dynamics. A methylation-incompetent PP2A mutant fails to interact with Fyn. It perturbs the normal partitioning of Fyn and amyloid precursor protein (APP) in membrane microdomains, which governs Fyn function and APP processing. This correlates with enhanced amyloidogenic cleavage of APP, a hallmark of AD pathogenesis. Conversely, enhanced PP2A methylation promotes the nonamyloidogenic cleavage of APP in a Fyn-dependent manner. Disturbances in one-carbon metabolic pathways that control cellular methylation are associated with AD and cancer. Notably, they induce a parallel loss of membrane-associated methylated PP2A and Fyn enzymes in N2a cells and acute mouse brain slices. One-carbon metabolism also modulates Fyn-dependent process outgrowth in N2a cells. Thus, our findings identify a novel methylation-dependent PP2A/Fyn signaling module. They highlight the underestimated importance of cross talks between essential metabolic pathways and signaling scaffolds that are involved in normal cell homeostasis and currently being targeted for cancer and AD treatment.