Introduction: Signaling pathways are not isolated from their surroundings. They are also intervened by other signaling pathways; known as “crosstalk mechanism”. One of the most important crosstalk mechanisms is the insulin-EGF networks. In this study, we used the analytical tools of the systems biology workbench for elucidating of some ambiguities of the insulin-EGF crosstalk. Materials and methods: The construction and further analysis of the model was carried out by Matlab simbiology toolbox. This toolbox can perform time-dependent sensitivity analysis. Results: Based on sensitivity analysis, we reconstructed an elucidated model with 51 chemical reactions in comparison with the previous model with 111 chemical reactions. We noticed two controlling pathways with direct participation of phosphorylated insulin and EGF receptors that involve insulin receptor substrate (IRS) and Src kinase modules. Also, insulin pathway by producing phosphatidylinositol-3, 4, 5-triphosphate (PIP3), and EGF pathway by activation of GAB1, control the downstream events and lead to potentialities in the mitogenic signal. Surprisingly, Shc and phosphatase SHP2-dependent reactions have no significant roles in the synergy conditions and are not involved in the reduced model. Conclusion: The main aims of current study are to reproduce an elucidated model of insulin-EGF networks and reliably determine the controlling and synergy nods of this crosstalk. Interestingly this reduced model (with 51 chemical reactions) reproduces the results of the original model (with 111 chemical reactions) in synergy conditions.

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