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Bioinformatics Advance Access published online on December 11, 2008
Bioinformatics, doi:10.1093/bioinformatics/btn635
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Simulation of Crosstalk between Small GTPase RhoA and EGFR-ERK Signaling Pathway via MEKK1

Hu Li 1,6, Choong Yong Ung 1,4,6, Xiao Hua Ma 1,4,6, Bao Wen Li 3,6, Boon Chuan Low 2, Zhi Wei Cao 5 and Yu Zong Chen *,1,5,6

1Bioinformatics and Drug Design Group, Department of Pharmacy, National University of Singapore, Blk S16, Level 8, 3 Science Drive 2, Singapore 117543
2Cell Signaling and Developmental Biology Laboratory, Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543
3Department of Physics, National University of Singapore, 2 Science Drive 3, Singapore 117542
4Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543
5Shanghai Center for Bioinformation Technology, Shanghai, 201203, P. R. China.
6Center of Computational Science and Engineering, National University of Singapore, Blk S16, Level 8, 3 Science Drive 2, Singapore 117543

*To whom correspondence should be addressed. Prof. Yu Zong Chen, E-mail: phacyz{at}nus.edu.sg


  Abstract

Motivation: 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 activ-ity via this MEKK1-mediated crosstalk between RhoA and EGFR-ERK pathway. By extending the published EGFR-ERK simulation models repre-sented by ordinary differential equations, we developed a simulation model that includes this crosstalk, which was validated with a number of experi-mental findings and published simulation results.

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 ab-sence of Ras. When Ras is over-expressed, 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.

Contact: Y.Z. Chen. Tel.: 65-6874-6877. Fax: 65-6774-6756. E-mail: phacyz{at}nus.edu.sg

Associate Editor: Dr. Olga Troyanskaya

Received on August 22, 2008; revised on November 4, 2008; accepted on December 7, 2008

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