An Integrative Analysis of Tumor Proteomic and Phosphoproteomic Profiles to Examine the Relationships Between Kinase Activity and Phosphorylation
An Integrative Analysis of Tumor Proteomic and Phosphoproteomic Profiles to Examine the Relationships Between Kinase Activity and Phosphorylation
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DOI：
10.1074/mcp.ra119.001540
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发表时间：
2019-08-09
影响因子：
7
通讯作者：
McDermott, Jason E.
中科院分区：
文献类型：
--
作者：
Arshad, Osama A.;Danna, Vincent;McDermott, Jason E.
蛋白质磷酸化是细胞调节功能的关键方式，无论是在单个蛋白质水平还是在信号通路水平。激酶负责底物的磷酸化，通常是丝氨酸、苏氨酸或酪氨酸残基的磷酸化。尽管可以鉴定决定残基是否会被特定激酶磷酸化的特定序列模式，但这些模式不能高度预测磷酸化。使用基于质谱的方法生成的大规模蛋白质组和磷酸化蛋白质组数据集的可用性提供了研究激酶活性、底物特异性和磷酸化之间的重要关系的机会。在这项研究中，我们分析了 150 多个肿瘤样本中蛋白质丰度和磷酸肽丰度之间的关系，结果表明特定磷酸位点的磷酸化与总体激酶丰度没有很好的相关性。然而，各个激酶在该激酶的已知磷酸位点靶标和随机选择的磷酸位点之间的相关性显示出明显且统计学上显着的差异。我们进一步研究激酶上已知激活或抑制位点的磷酸化与其目标磷酸位点的磷酸化之间的关系。与基于基序的分析相结合，这种方法可以预测新的激酶靶标，并显示激酶靶标库的哪些子集在一种条件下与另一种条件下特别活跃。
Phosphorylation of proteins is a key way cells regulate function, both at the individual protein level and at the level of signaling pathways. Kinases are responsible for phosphorylation of substrates, generally on serine, threonine, or tyrosine residues. Though particular sequence patterns can be identified that dictate whether a residue will be phosphorylated by a specific kinase, these patterns are not highly predictive of phosphorylation. The availability of large scale proteomic and phosphoproteomic data sets generated using mass-spectrometrybased approaches provides an opportunity to study the important relationship between kinase activity, substrate specificity, and phosphorylation. In this study, we analyze relationships between protein abundance and phosphopeptide abundance across more than 150 tumor samples and show that phosphorylation at specific phosphosites is not well correlated with overall kinase abundance. However, individual kinases show a clear and statistically significant difference in correlation among known phosphosite targets for that kinase and randomly selected phosphosites. We further investigate relationships between phosphorylation of known activating or inhibitory sites on kinases and phosphorylation of their target phosphosites. Combined with motif-based analysis, this approach can predict novel kinase targets and show which subsets of a kinase's target repertoire are specifically active in one condition versus another.