Comparative Analysis Reveals Conserved Protein Phosphorylation Networks Implicated in Multiple Diseases
Comparative Analysis Reveals Conserved Protein Phosphorylation Networks Implicated in Multiple Diseases
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DOI：
10.1126/scisignal.2000316
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发表时间：
2009-07-28
影响因子：
7.3
通讯作者：
Linding, Rune
中科院分区：
文献类型：
--
作者：
Tan, Chris Soon Heng;Bodenmiller, Bernd;Linding, Rune
蛋白激酶使细胞信息处理成为可能。虽然已经确定了大量的人类磷酸化位点及其动力学特征，但许多信号事件的进化历史和生理重要性仍不清楚。使用通过相似的实验和计算管道确定的目标磷酸蛋白质组，我们研究了远缘关系模式生物(苍蝇、蠕虫和酵母)中人类磷酸化事件的保守性。通过序列比对的方法，我们在344个人类蛋白质中发现了479个磷酸化事件，这些事件似乎在6亿年的进化过程中位置保守，因此很可能参与基本的细胞过程。这一序列比对分析表明，许多磷酸化位点进化迅速，因此在远亲生物中的序列位置并不表现出很强的进化保守性。因此，我们设计了一种网络对齐方法来重建保守的激酶-底物网络，该方法在698个人类蛋白质中识别了778个磷酸化事件。这两种方法都确定了由磷酸化和信号整合中心严格调控的蛋白质，两种类型的磷蛋白都富含由疾病相关基因编码的蛋白质。我们分析了这些保守信号事件的细胞功能和结构关系，注意到当前磷酸蛋白质组的不完整性质。事实证明，在位点和网络水平上评估磷酸化保守对于探索快速进化和古老的信号事件都是有用的。我们发现，多种复杂的疾病似乎汇聚在保守的网络中，这表明疾病的发展可能依赖于共同的分子网络。
Protein kinases enable cellular information processing. Although numerous human phosphorylation sites and their dynamics have been characterized, the evolutionary history and physiological importance of many signaling events remain unknown. Using target phosphoproteomes determined with a similar experimental and computational pipeline, we investigated the conservation of human phosphorylation events in distantly related model organisms (fly, worm, and yeast). With a sequence-alignment approach, we identified 479 phosphorylation events in 344 human proteins that appear to be positionally conserved over similar to 600 million years of evolution and hence are likely to be involved in fundamental cellular processes. This sequence alignment analysis suggested that many phosphorylation sites evolve rapidly and therefore do not display strong evolutionary conservation in terms of sequence position in distantly related organisms. Thus, we devised a network-alignment approach to reconstruct conserved kinase-substrate networks, which identified 778 phosphorylation events in 698 human proteins. Both methods identified proteins tightly regulated by phosphorylation as well as signal integration hubs, and both types of phosphoproteins were enriched in proteins encoded by disease-associated genes. We analyzed the cellular functions and structural relationships for these conserved signaling events, noting the incomplete nature of current phosphoproteomes. Assessing phosphorylation conservation at both site and network levels proved useful for exploring both fast-evolving and ancient signaling events. We reveal that multiple complex diseases seem to converge within the conserved networks, suggesting that disease development might rely on common molecular networks.