Simulation of crosstalk between small GTPase RhoA and EGFR-ERK signaling pathway via MEKK1.
BACKGROUND
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.


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.
Li
Hu
H
Bioinformatics and Drug Design Group, Department of Pharmacy, National University of Singapore, Blk S16, Level 8, 3 Science Drive 2, Singapore 117543.
Ung
Choong Yong
CY
Ma
Xiao Hua
XH
Li
Bao Wen
BW
Low
Boon Chuan
BC
Cao
Zhi Wei
ZW
Chen
Yu Zong
YZ
D000818:Animals; D003198:Computer Simulation; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism*; D008962:Models, Theoretical; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D015203:Reproducibility of Results; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D048728:MAP Kinase Kinase Kinase 1; D020559:Monomeric GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein