SIMULATION AND NETWORK ANALYSIS OF MAPK PATHWAY REGULATION

Abstract

Scaffold proteins have been proposed to confine MAPK signaling molecules at certain sub-cellular localizations to realize signal efficiency and specificity. In the first part, exploratory experiments of the endosomal scaffold protein MP1 in MAPK-mediated cell spreading and cytoskeletal trafficking are conducted. In the second part, an ODE model is developed to describe the dynamic activation of EGFR-ERK signaling under a conventional pathway without scaffolds, a KSR-scaffolded pathway, and an MP1-scaffolded pathway. In the third part, a mathematical framework is formulated for investigating resistance evolution in cancer under combined inhibition of the EGFR-ERK pathway. Our calculations suggest that, within the model assumptions, antagonistic drug combination inhibition of MAPK pathway can be more advantageous, especially in cancers with low turnover rate. In conclusion, this thesis shows how a systems biology approach can enhance our understanding of the transmission and propagation of signaling from local immediate effect to system-level and long-term effect.