Pathway sensitivity analysis for detecting pro-proliferation activities of oncogenes and tumor suppressors of epidermal growth factor receptor-extracellular signal-regulated protein kinase pathway at altered protein levels.
BACKGROUND
Mathematic models and sensitivity analyses of biologic pathways have been used for exploring the dynamics and for detecting the key components of signaling pathways.


METHODS
The authors previously developed a mathematic model of the epidermal growth factor receptor-extracellular signal-regulated protein kinase (EGFR-ERK) pathway using ordinary differential equations from existing EGFR-ERK pathway models. By using prolonged ERK activation as an indicator that may lead to cell proliferation under certain circumstances, in the current study, a pathway sensitivity analysis was performed to test its capability of detecting pro-proliferative activities through altered protein levels to examine the effects on ERK activation.


RESULTS
The analysis revealed that 12 of 20 oncoproteins and 4 of 5 tumor suppressors were detected, consistent with reported experimental works. Because pathway dynamics depend on many factors, some of which were not included in the current models, failure to detect all known oncogenes and tumor suppressors can be because of the failure to include relevant crosstalk to other pathway components.


CONCLUSIONS
Overall, the current results indicated that pathway sensitivity analysis is a useful approach for detecting and distinguishing pro-proliferation activities of oncoproteins and suppressed proliferative activities of tumor suppressors at altered protein levels at least in the EGFR-ERK model.
Li
Hu
H
Bioinformatics and Drug Design Group, Department of Pharmacy, National University of Singapore, Singapore.
Ung
Choong Yong
CY
Ma
Xiao Hua
XH
Liu
Xiang Hui
XH
Li
Bao Wen
BW
Low
Boon Chuan
BC
Chen
Yu Zong
YZ
D049109:Cell Proliferation; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D006801:Humans; D008962:Models, Theoretical; D009369:Neoplasms / Q000378:metabolism*; D015513:Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction
D015513:Oncogene Proteins; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases