Stochastic Spatial and Non-Spatial Simulations of the Erbb Signaling Pathways Demonstrate the Importance of Spatial Organization In Signal Transduction

Overexpression of the ErbB family of receptors leads to an activation of intracellular signaling pathways that are responsible for controlling cellular proliferation, growth, differentiation, and apoptosis. Therefore, overexpression of the ErbB receptors is often associated with cancer, and extensive efforts have been made to understand the signaling events associated with ErbB activation. In recent years, several different research groups have used a systems biology perspective to study ErbB signaling. Although the systems biology computational models have grown in complexity, little work has been done to uncover the spatial-temporal dynamics of receptor interactions and how it affects downstream signaling within this pathway. Herein, we have developed an algorithm which couples a spatial stochastic model of receptor reaction and diffusion on the cell membrane with a nonspatial stochastic model of intercellular reactions and interactions in the cytosol. This framework allowed us to elucidate the effects of downstream signaling due to receptor clustering and spatial heterogeneity on the membrane.