Pant Dhruv K, Ghosh Avijit
Drexel University, 3141 Chestnut St, Philadelphia, PA, 19104 United States.
Biophys Chem. 2006 Jan 1;119(1):49-60. doi: 10.1016/j.bpc.2005.09.001. Epub 2005 Sep 26.
The Extracellular signal Regulated Kinase (ERK) pathway is one of the most well-studied signaling pathways in cell cycle regulation. Disruption in the normal functioning of this pathway is linked to many forms of cancer. In a previous study [D.K. Pant, A. Ghosh, Automated oncogene detection in complex protein networks, with applications to the MAPK signal transduction pathway, Biophys. Chem. 113 (2005) 275-288.], we developed a novel approach to predict single point mutations that are likely to cause cellular transformation in signaling transduction networks. We have extended this method to study disparate pair mutation in enzyme/protein interactions and in expression levels in signal transduction pathway and have applied it to the MAPK signaling pathway to study how synergistic or cooperative mutation within signaling networks acts in unison to cause malignant transformation. The method provides a quantitative ranking of the modifier pair of ERK activation. It is seen that the highest ranking single point mutations comprise the highest ranking pair mutations. We validate some of our results with experimental literature on multiple mutations. A second order sensitivity analysis scheme is additionally used to determine the effect of correlations among mutations at different sites in the pathways.
细胞外信号调节激酶（ERK）通路是细胞周期调控中研究最为深入的信号通路之一。该通路正常功能的破坏与多种癌症形式相关。在先前的一项研究[D.K.潘特、A.戈什，复杂蛋白质网络中的自动癌基因检测及其在MAPK信号转导通路中的应用，生物物理化学杂志113（2005）275 - 288。]中，我们开发了一种新方法来预测可能导致信号转导网络中细胞转化的单点突变。我们将此方法扩展到研究酶/蛋白质相互作用以及信号转导通路中表达水平的不同对突变，并将其应用于MAPK信号通路，以研究信号网络内的协同或合作突变如何共同作用导致恶性转化。该方法提供了ERK激活修饰对的定量排名。可以看出，排名最高的单点突变包含排名最高的对突变。我们用关于多个突变的实验文献验证了我们的一些结果。此外，还使用二阶敏感性分析方案来确定通路中不同位点突变之间相关性的影响。
