Richard A. Cerione | Searcharxiv

arXiv2006

Optimal experimental design in an EGFR signaling and down-regulation model

We apply the methods of optimal experimental design to a differential equation model for epidermal growth factor receptor (EGFR) signaling, trafficking, and down-regulation. The model incorporates the role of a recently discovered protein complex made up of the E3 ubiquitin ligase, Cbl, the guanine exchange factor (GEF), Cool-1 (Beta-Pix), and the Rho family G protein Cdc42. The complex has been suggested to be important in disrupting receptor down-regulation. We demonstrate that the model interactions can accurately reproduce the experimental observations, that they can be used to make predictions with accompanying uncertainties, and that we can apply ideas of optimal experimental design to suggest new experiments that reduce the uncertainty on unmeasurable components of the system.

q-bio.MN↗

arXiv2004

The statistical mechanics of complex signaling networks : nerve growth factor signaling

It is becoming increasingly appreciated that the signal transduction systems used by eukaryotic cells to achieve a variety of essential responses represent highly complex networks rather than simple linear pathways. While significant effort is being made to experimentally measure the rate constants for individual steps in these signaling networks, many of the parameters required to describe the behavior of these systems remain unknown, or at best, estimates. With these goals and caveats in mind, we use methods of statistical mechanics to extract useful predictions for complex cellular signaling networks. To establish the usefulness of our approach, we have applied our methods towards modeling the nerve growth factor (NGF)-induced differentiation of neuronal cells. Using our approach, we are able to extract predictions that are highly specific and accurate, thereby enabling us to predict the influence of specific signaling modules in determining the integrated cellular response to the two growth factors. We show that extracting biologically relevant predictions from complex signaling models appears to be possible even in the absence of measurements of all the individual rate constants. Our methods also raise some interesting insights into the design and possible evolution of cellular systems, highlighting an inherent property of these systems wherein particular ''soft'' combinations of parameters can be varied over wide ranges without impacting the final output and demonstrating that a few ''stiff'' parameter combinations center around the paramount regulatory steps of the network. We refer to this property -- which is distinct from robustness -- as ''sloppiness.''

q-bio.MN↗