Study On Computational Model Of MAPK/ERK Signal Transduction Pathway

Mitogen activated protein kinase (MAPK) referring to the family name for a still growing number of related kinases, especially including the extra-cellular signal regulated kinase (ERK), are the most important signal transduction pathways from membrane to the nucleus. MAPK/ERK signal transduction pathway is not only involved in the regulation of a multitude of cellular process including the fundamental functions such as gene expression, cell proliferation, survival, differentiation and apoptosis, but also correlated to a multitude of diseases, especially, tumor or cancer. It is important to investigate the inner mechanism of signal transduction pathway. This paper presents the computational models to study the inner mechanism of ERK signal transduction pathway. Through dynamic simulating, the function of crucial proteins in the signal transduction pathway is analyzed. It is helpful to find the targeted molecules of medicament for disease therapy. Our work includes:1. We realize protein kinases of ERK signal transduction pathway and the response processes firstly. Then a computional model of integrated ERK signal transduction pathway is constructed for the first time. The model is validated by contrasting to the experiment results.2. The effect of EGFR (epidemal growth factor receptor) is analyzed by dynamic simulating. The obtained results show that over-express or high concentration of EGFR will change the pattern of ERK signal transduction from transient activation to sustained activation. It may strength the cell proliferation which brings normal cell pathological changes. So EGFR is the pivotal molecule in the ERK signal transduction pathway.3. Adaptor proteins perform different influences on the ERK signal transduction pathway. Especially, Grb2 and She can affect ERK activation dramatically. They might be new target molecules in ERK signal transduction pathway for tumor therapy. However, PLCγaffect little to the ERK activation.4. Coupling and dynamic effects of the two Ras activated pathway are ayalyzed. The obtained results indicate that EGFR_G_S can weaken the sustained activation, but EGFR_Sh_G_S can bring the sustained activation of ERK. Therefore, EGFR_Sh_G_S and EGFR_G_S are also the target molecules to regulate the ERK activation, which control the normal processes of cell. 5. A computational model that offers an integrated quantitative and dynamic simulation of ERK signal transduction network is established, which contains the feedback loops from ERKPP. The different influences of positive and negative feedback loops of the ERK signal transduction pathway are mainly analyzed. The obtain results indicate that feedback loops are the main impacting factor to the oscillation of ERK signal transduction pathway. The predictions of the oscillation to the downstream ERK activation agree well with the literature. Influence of feedback loops of ERK signal network can lead to different signal patterns of the downstream substrates and induce corresponding biological behaviors which may relate with various diseases.In summary, former investigations and analyses are helpful to understand the inner mechanism of ERK signal transduction pathway and the relationship with diseases, which will give new insight to the targeted therapy of tumor. Study of models can guide the design and research of biology experiment.