Network wiring of pleiotropic kinases yields insight into protective role of diabetes on aneurysm
Network wiring of pleiotropic kinases yields insight into protective role of diabetes on aneurysm
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DOI：
10.1039/c4ib00125g
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发表时间：
2014-11-01
影响因子：
2.5
通讯作者：
Przulj, Natasa
中科院分区：
文献类型：
--
作者：
Sarajlic, Anida;Gligorijevic, Vladimir;Przulj, Natasa
最近的研究表明糖尿病在动脉瘤的发展中具有保护作用，但其背后的生物学机制仍不清楚。这种类型。尽管动脉瘤和动脉粥样硬化的危险因素相似，但糖尿病和动脉粥样硬化之间不存在相关性。我们假设存在破坏糖尿病时动脉瘤发生所需途径的基因。受遗传相互作用在理解疾病关联中的重要性的启发，我们通过整合蛋白质相互作用和遗传相互作用数据来解决这个问题，即，我们检查了与三种疾病相关的生物途径，这些疾病包含参与以下遗传相互作用的基因：遗传相互作用中的一个基因是糖尿病途径的一部分，另一个基因是动脉瘤或动脉粥样硬化途径的一部分。我们创建了一个蛋白质相互作用子网络，其中包含上述疾病途径。然后，我们使用“经纪”测量（一种拓扑测量）来识别该子网络中的蛋白质，这些蛋白质的去除会严重影响其邻近区域的互连性，从而使这些蛋白质能够破坏它们所在的通路。我们识别了一组具有高经纪价值的蛋白质，并发现这组蛋白质富含生物功能，包括细胞基质粘附，这促进了已经被认为是糖尿病动脉瘤关联的可能原因的机制。我们进一步将研究范围缩小到 16 种蛋白质，这些蛋白质涉及动脉瘤或动脉粥样硬化途径，并由参与与糖尿病途径中的基因相互作用的基因编码。该组富含激酶和磷酸化过程，其中两种多效性激酶涉及动脉瘤和动脉粥样硬化途径。激酶可以打开或关闭蛋白质，解释了此类蛋白质的功能变化如何导致通路破坏。因此，如果在与动脉瘤相关的通路中关闭一个基因，就可以预防该疾病的发作。然而，多效性基因的突变可能只对其中一种性状产生影响，这解释了为什么参与动脉瘤和动脉粥样硬化途径的多效性激酶可能会破坏动脉瘤途径，从而降低糖尿病患者患动脉瘤的风险，但不会影响动脉粥样硬化途径。
Recent studies suggest a protective role of diabetes in the development of aneurysm, but the biological mechanisms behind this are still unknown. This type. of association is not present in the case of diabetes and atherosclerosis despite similar risk factors for aneurysm and atherosclerosis. We postulate the existence of genes that disrupt the pathways needed for the onset of aneurysm in the presence of diabetes. Motivated by the significance of genetic interactions in understanding disease disease associations, we tackle this problem by integrating protein protein interaction and genetic interaction data, Le., we examine the biological pathways related to the three diseases that contain genes involved in the following genetic interactions: one gene in a genetic interaction is part of a diabetes pathway, the other gene is part of an aneurysm, or an atherosclerosis pathway. We create a protein protein interaction sub-network that contains disease pathways described above. We then use a "brokerage" measure a topological measure that identifies proteins in this sub-network whose removal severely affects the interconnectedness of their neighbourhood, enabling such proteins to disrupt the pathway they are in. We identify a set of proteins with high brokerage values and find this set to be enriched in biological functions, including cell-matrix adhesion, which facilitates mechanisms that have already been suggested as possible causes of diabetes aneurysm association. We further narrow down our set to 16 proteins that are involved in an aneurysm or an atherosclerosis pathway and are encoded by genes participating in genetic interactions with a gene in a diabetes pathway. This set is enriched in kinases and phosphorylation processes, with two pleiotropic kinases that are involved in both aneurysm and atherosclerosis pathways. Kinases can turn on or off proteins, explaining how functional changes of such proteins could result in the disruption of pathways. So if in an aneurysm-related pathway a gene is turned off, the onset of the disease could be prevented. However, mutations of pleiotropic genes could have effects only on one of the traits, which explains why pleiotropic kinases that are involved in both aneurysm and atherosclerosis pathways could disrupt aneurysm pathways explaining the reduced risk of aneurysm in diabetes patients, but not affect the atherosclerosis pathways.