Rules for PP2A-controlled phosphosignalling and drug responses
Rules for PP2A-controlled phosphosignalling and drug responses
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PP2A 控制的磷酸信号传导和药物反应的规则
DOI：
10.1101/271841
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Tero Aittokal
中科院分区：
文献类型：
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作者：
Otto Kauko;Susumu Y. Imanishi;Evgeny Kulesskiy;Teemu Daniel Laajala;Laxman Yetukuri;Anni Laine;Mikael Jumppanen;Pekka Haapaniemi;Luyao Ruan;Bhagwan Yadav;Veronika Suni;Taru Varila;Garry Corthals;Juri Reimand;Krister Wennerberg;Tero Aittokal
对蛋白磷酸酶 2A (PP2A) 调节的细胞过程的系统理解仍处于起步阶段。在这里，我们提出了受 PP2A 调节调节的磷酸靶标（去磷酸化组）的质谱分析。除了 PP2A 调节的过程和目标之外，数据还揭示了与 PP2A 介导的磷酸调节相关的重要一般概念和规则。这些包括磷酸化调节的单向范式，以及激酶和磷酸酶主导的磷酸靶标的差异空间分布。数据还首次对 PP2A 调节癌蛋白、CIP2A、PME-1 和 SET 靶标进行系统分析；包括 PP2A 可以协调调节癌症驱动因子和肿瘤抑制因子（例如 MYC 或 TP53）活性的靶点。为了验证该数据集的功能实用性，PP2A 去磷酸化组活性与癌细胞对 300 多种药物的反应相关。值得注意的是，我们发现癌症治疗反应可以根据 PP2A 去磷酸化组活性以定量和定性方式进行广泛分类。总之，我们的数据描述了 PP2A 协调癌细胞磷酸信号传导和药物反应的规则。这些结果还可能指导新兴药理学方法在人类疾病中调节 PP2A 活性的应用。
Systemic understanding of protein phosphatase 2A (PP2A)-regulated cellular processes is still at infancy. Here, we present mass-spectrometry analysis of phospho-targets (dephosphorylome) regulated by PP2A modulation. In addition to PP2A-regulated processes and targets, the data reveal important general concepts and rules related to PP2A-mediated phosphoregulation. These include the unidirectionality paradigm of regulation of phosphorylation, and differential spatial distribution of kinase-and phosphatase-dominated phosphotargets. Data also present first systemic analysis of targets of PP2A-modulating oncoproteins, CIP2A, PME-1, and SET; including targets via which PP2A may coordinately regulate activities of cancer drivers and tumor suppressors such as MYC or TP53. To validate functional utility of this dataset, PP2A dephosphorylome activity was correlated with cancer cell responses to over 300 drugs. Notably, we find that cancer therapy responses can be broadly classified based on PP2A dephosphorylome activity, both in quantitative and qualitative manner. In summary, our data characterize rules by which PP2A coordinate cancer cell phosphosignaling and drug responses. The results also may also direct the use of emerging pharmacological approaches for PP2A activity modulation in human diseases.