A systems biology study to delineate the T cell receptor-activated Erk-MAPK signaling pathway

Utilization of mathematical modeling and computer simulation to extract embedded quantitative information from experimental data promotes a systems level understanding of complex biological networks. Thus a Systems Biology approach is formulated and implemented to investigate the antigen receptor-mediated Erk-MAPK signaling pathway in T lymphocytes. An initial model of the early signaling events was developed based on ordinary differential equations and revealed nonlinear system behaviors within the pathway that arise from multiple feedback loops. Immunoblotting experiments acquired quantitative data of T cell signaling responses in Jurkat cells that were utilized for extending, refining and evaluating the model. This integrated modeling and experimental approach discovered a previously unknown Erk-mediated feedback control of T cell receptor down-regulation that was subsequently supported experimentally by flow cytometry data. A comparative study of parameter sensitivities on the model using a novel parameter identification-embedded method and different existing global and local sensitivity analysis methods identified critical reactions in the TCR-activated Erk-MAPK signaling pathway and revealed their impact on the signaling dynamics. These findings provided insights into the regulatory regime of the signaling pathway and its functions within the immune system. This research demonstrated the power of a Systems Biology approach to streamline the discovery of biological knowledge, and recommended a general sensitivity analysis-based strategy that may be used to efficiently and reliably infer quantitative, dynamic as well as topological properties from Systems Biology models.