Mathematical model of phosphatidylinositol-4,5-bisphosphate hydrolysis mediated by epidermal growth factor receptor generating diacylglycerol.
Phosphatidylinositol-4,5-bisphosphate (PIP2) is hydrolyzed in response to the tyrosine phosphorylation of the epidermal growth factor receptor (EGFR) and plays an important role in regulating cell proliferation and differentiation through the generation of second messengers diacylglycerol (DAG) and trisphosphate inositol (IP3) which lead to the activation of protein kinase C (PKC) and increased levels of intracellular calcium, respectively. In the paper, a mathematical model was established to simulate the accumulation of DAG due to PIP2 hydrolysis mediated by EGFR. Molecular mechanisms between DAG, PIP2, EGFR and phosphatidylinositol transfer protein (PITP) were explained successfully, and positive cooperativity which existed between phospholipase C-gamma1 (PLC-gamma1) and PIP2 was also explained. In the model the effects of parameters on simulation of PIP2 hydrolysis were analyzed and the efficacies of some molecular intervention strategies were predicted. To test the coherence between the model and the biological response to epidermal growth factor (EGF) in cells, the levels of DAG and the tyrosine phosphorylation-EGFRs in NIH3T3 mouse embryonic fibroblast (MEF) were determined by biochemical experiments which showed that the accumulation of DAG was a sigmoidal function of phosphorylation-EGFR concentration, and the consistency between the mathematical model and experimental results was confirmed. In brief, this mathematical model provided a new idea for the further study of the dynamic change of biological characteristics in inositol phospholipid hydrolysis, predicting the efficacy of molecular intervention and the relationship between the metabolisms of inositol phospholipid and other signal transduction pathways.
Su
Yong-chun
YC
Department of Medical Physics, South Medical University, Guangzhou 510515, PR China.
Lu
Di
D
Tan
Xiao-dan
XD
Dong
Ai-rong
AR
Tian
Hui-yong
HY
Luo
Shen-qiu
SQ
Deng
Qin-kai
QK
D000818:Animals; D003198:Computer Simulation; D004075:Diglycerides / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000008:administration & dosage*; D066246:ErbB Receptors / Q000378:metabolism*; D006868:Hydrolysis; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D004075:Diglycerides; D019269:Phosphatidylinositol 4,5-Diphosphate; D004815:Epidermal Growth Factor; D066246:ErbB Receptors