Mathematical Modeling Of Inositol Phospholipid Hydrolyzation Mediated By Epidermal Growth Factor Receptor

Phospholipase C-rl is activated in response to the complex of the epidermal growth factor-receptor by the mechanism of tyrosine phosphorylation, and the second messengers diacylglycerol and trisphosphate inositol are generated through hydrolyzation of phosphatidylinositol-4,5-bisphosphate. Trisphosphate inositol increase the levels of intracellar calcium, and diacylglycerol leads to activation of protein kinase C which phosphorylate many kind of enzyme and protein. Metabolisms of lipid phosphatidylinositol(4,5)-bisphosphate play an important role in regulating cell proliferation and differentitation through the above-mentioned mechanisms. Because of complex and cross-talking of cell signal transduction pathway, it is too difficult to depict dynamically transduction pathway of intracellular signal for traditional biochemistry experiment. Mathematical modeling is one of the important means in researching cell signal transduction, including epicting signal transduction process, analyzing molecular mechanism of intracellular signal expression, enucleating the effect of signal expression on the biological activity in a cell and predicting the efficacy of various molecular intervention strategies, etc.Based on the reported experiment result, the Law of Mass Action and characteristic of biochemistry reaction, a simplified mathematical model was established to simulate generation of IP through hydrolyzation of lipid hosphatidyl-inositol(4,5)-bisphosphate mediated by epidermal growth factor-receptor in phospholipase C-gammal pathway, And a simple arithmetic was applied in estimating concentration of activated protein. Dynamic characteristic of parameters and relations of signal molecule were explained.Under treatment of EGF, the tyrosine phosphorylation-EGFR in NIH3T3 mouse embryonic fibroblast extracts were determined using western blotting, and in the experiments involving DAG kinase inhibitor R59022 and EGF, diacylglycerol from in NIH3T3 cell lipid extraction were determined using thin layer chromatogram. These results indicated that accumulation of DAG is a sigmoidal function of phosphorylation-EGFR concentration. A mathematical model according to experimental data was established tosimulate generation of DAG through hydrolyzation of phosphatidylinositol -4,5-bisphosphate mediated by epidermal growth factor-receptor in phospholipase C-gammal pathway. And the consistency between the mathematical model and experimental results are satisfied. Relations among these signal moleculers, including DAG, PIP2, EGFR and phosphatidylinositol transfer protein(PITP), were depicted successfully. Positive cooperativity between PLC-l and PIP2 was introduced in mathematical model. The effect of parameters on metabolisms of inositol phospholipid was analysed and the efficacy of various molecular intervention strategies was predicted. This mathematical model provided a new idea for further explaining the dynamic change of biological characteristics of inositol phospholipid hydrolysis, predicting efficacy of molecular intervention and relationship between the metabolisms of inositol phospholipid and the other signal transduction pathways.