Li Hu, Ung Choong Yong, Ma Xiao Hua, Li Bao Wen, Low Boon Chuan, Cao Zhi Wei, Chen Yu Zong
Bioinformatics and Drug Design Group, Department of Pharmacy, National University of Singapore, Blk S16, Level 8, 3 Science Drive 2, Singapore 117543.
Bioinformatics. 2009 Feb 1;25(3):358-64. doi: 10.1093/bioinformatics/btn635. Epub 2008 Dec 11.
Small GTPase RhoA regulates cell-cycle progression via several mechanisms. Apart from its actions via ROCK, RhoA has recently been found to activate a scaffold protein MEKK1 known to promote ERK activation. We examined whether RhoA can substantially affect ERK activity via this MEKK1-mediated crosstalk between RhoA and EGFR-ERK pathway. By extending the published EGFR-ERK simulation models represented by ordinary differential equations, we developed a simulation model that includes this crosstalk, which was validated with a number of experimental findings and published simulation results.
Our simulation suggested that, via this crosstalk, RhoA elevation substantially prolonged duration of ERK activation at both normal and reduced Ras levels. Our model suggests ERK may be activated in the absence of Ras. When Ras is overexpressed, RhoA elevation significantly prolongs duration of ERK activation but reduces the amount of active ERK partly due to competitive binding between ERK and RhoA to MEKK1. Our results indicated possible roles of RhoA in affecting ERK activities via MEKK1-mediated crosstalk, which seems to be supported by indications from several experimental studies that may also implicate the collective regulation of cell fate and progression of cancer and other diseases.
小GTP酶RhoA通过多种机制调节细胞周期进程。除了通过ROCK发挥作用外，最近发现RhoA还能激活一种已知可促进ERK激活的支架蛋白MEKK1。我们研究了RhoA是否能通过这种RhoA与EGFR-ERK途径之间由MEKK1介导的串扰，对ERK活性产生实质性影响。通过扩展已发表的以常微分方程表示的EGFR-ERK模拟模型，我们开发了一个包含这种串扰的模拟模型，该模型通过大量实验结果和已发表的模拟结果进行了验证。
我们的模拟表明，通过这种串扰，在正常和降低的Ras水平下，RhoA升高均能显著延长ERK激活的持续时间。我们的模型表明，在没有Ras的情况下ERK可能被激活。当Ras过表达时，RhoA升高会显著延长ERK激活的持续时间，但会部分降低活性ERK的量，这部分是由于ERK和RhoA与MEKK1之间的竞争性结合。我们的结果表明，RhoA可能通过MEKK1介导的串扰影响ERK活性，这似乎得到了一些实验研究的迹象支持，这些迹象也可能暗示细胞命运以及癌症和其他疾病进展的集体调控。
