Institute of Biotechnology, University of Helsinki, Helsinki 00014, Finland.
Institute of Molecular Systems Biology, ETH Zurich, Zurich 8093, Switzerland.
Cell Syst. 2017 Apr 26;4(4):430-444.e5. doi: 10.1016/j.cels.2017.02.011. Epub 2017 Mar 18.
Coordinated activities of protein kinases and phosphatases ensure phosphorylation homeostasis, which, when perturbed, can instigate diseases, including cancer. Yet, in contrast to kinases, much less is known about protein phosphatase functions and their interactions and complexes. Here, we used quantitative affinity proteomics to assay protein-protein interactions for 54 phosphatases distributed across the three major protein phosphatase families, with additional analysis of their 12 co-factors. We identified 838 high-confidence interactions, of which 631, to our knowledge, have not been reported before. We show that inhibiting the activity of phosphatases PP1 and PP2A by okadaic acid disrupts their specific interactions, supporting the potential of therapeutics that target these proteins. Additional analyses revealed candidate physical and functional interaction links to phosphatase-based regulation of several signaling pathways and to human cancer. Our study provides an initial glimpse of the protein interaction landscape of phosphatases and their functions in cellular regulation.
蛋白激酶和磷酸酶的协调活动确保了磷酸化的平衡，当这种平衡被打破时，可能会引发疾病，包括癌症。然而，与激酶相比，人们对磷酸酶的功能及其相互作用和复合物知之甚少。在这里，我们使用定量亲和蛋白质组学来检测分布在三大蛋白磷酸酶家族中的 54 种磷酸酶的蛋白-蛋白相互作用，同时还分析了它们的 12 种共因子。我们鉴定了 838 个高可信度的相互作用，其中 631 个相互作用据我们所知以前尚未报道过。我们表明，通过冈田酸抑制磷酸酶 PP1 和 PP2A 的活性会破坏它们的特异性相互作用，这支持了以这些蛋白质为靶点的治疗药物的潜力。进一步的分析揭示了磷酸酶调节几种信号通路和人类癌症的候选物理和功能相互作用的联系。我们的研究提供了磷酸酶及其在细胞调节中的功能的蛋白质相互作用图谱的初步概览。
