Receptor differential activation and cooperativity better explain cellular preference for different chemoattractant gradient shapes in an EGFR system

Abstract

This manuscript describes mathematical models that apply an aggregating receptor scheme to the epidermal growth factor receptor (EGFR) system to interpret and predict directed cell migration behaviors in differently-shaped chemoattractant gradients. This method incorporates the latest biochemical insights on ligand–receptor activation kinetics and receptor cooperativity into the commonly used difference in the fractional receptor occupancy (DFRO) model for explaining chemotaxis. The enhanced model derives the functionally more relevant value of difference in fractional receptor activation (DFRA). This DFRA analysis encompasses all features and predictions of the DFRO analyses. Importantly, DFRA analysis can additionally explain in vitro microfluidic chemotaxis experiments that are difficult to explain using only DFRO concepts such as why some cells may migrate well only in a higher concentration regime of exponential chemoattractant gradients. The DFRA analysis also suggests receptor activation strategies that cells may use to tune their responsiveness to differently-shaped in vivo gradients. DFRA analysis is conceptually and computationally straightforward. The results it provides are envisioned to serve as quick semi-quantitative guides to design chemotaxis experiments and to develop hypotheses for interpretation of results from directed cell migration experiments.