Linear combinations of docking affinities explain quantitative differences in RTK signaling
Linear combinations of docking affinities explain quantitative differences in RTK signaling
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DOI：
10.1038/msb.2008.72
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发表时间：
2009-01-01
影响因子：
9.9
通讯作者：
MacBeath, Gavin
中科院分区：
文献类型：
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作者：
Gordus, Andrew;Krall, Jordan A.;MacBeath, Gavin
受体酪氨酸激酶 (RTK) 通过激活多种信号蛋白来处理细胞外信号。矛盾的是，他们经常使用相同的蛋白质来引发不同甚至相反的表型反应。因此，二进制“开关”接线图不足以解释它们的差异。在这里，我们表明，当将六种不同的 RTK 置于相同的细胞背景中时，它们会激活许多相同的蛋白质，但数量不同。此外，我们发现上游信号蛋白的相对磷酸化水平可以使用依赖于受体对接亲和力组合的线性模型来准确预测，并且磷酸肌醇3激酶（PI3K）和Shc1的对接位点提供了许多预测信息。相反，我们发现下游蛋白质的磷酸化水平无法使用线性模型预测。总而言之，这些结果表明 RTK 的信息处理可以分为离散的上游和下游步骤，这表明构建 RTK 信号数学模型的挑战性任务可以解析为单独的且更易于管理的层。
Receptor tyrosine kinases (RTKs) process extracellular cues by activating a broad array of signaling proteins. Paradoxically, they often use the same proteins to elicit diverse and even opposing phenotypic responses. Binary, 'on-off' wiring diagrams are therefore inadequate to explain their differences. Here, we show that when six diverse RTKs are placed in the same cellular background, they activate many of the same proteins, but to different quantitative degrees. Additionally, we find that the relative phosphorylation levels of upstream signaling proteins can be accurately predicted using linear models that rely on combinations of receptor-docking affinities and that the docking sites for phosphoinositide 3-kinase (PI3K) and Shc1 provide much of the predictive information. In contrast, we find that the phosphorylation levels of downstream proteins cannot be predicted using linear models. Taken together, these results show that information processing by RTKs can be segmented into discrete upstream and downstream steps, suggesting that the challenging task of constructing mathematical models of RTK signaling can be parsed into separate and more manageable layers.