In mechanistic models of complex systems, understanding input-output relationships must often contend with identifying sensitive parameters in a high dimensional parameter space. For cell signaling systems, this challenge has been tackled by global sensitivity analysis or Sloppiness analysis; however, the relationship between the two methods has not previously been explored. Understanding this relationship is integral to obtaining accurate predictions of parameter sensitivities and system behaviors. This study utilizes a dimensionality reduction-based sensitivity analysis and Sloppiness analysis to distill model sensitivity information from a multidimensional parameter space and explain unresolved biological observations about the epidermal growth factor receptor (EGFR)-mitogen activated protein kinase (MAPK) pathway. While it is well-understood that EGF-EGFR binding initiates signaling events that lead to activation of the RAS-RAF-MEK-ERK cascade, much remains to be learned about RAS-mediated activation of RAF and the signaling consequences of recently discovered low RAF abundance at the membrane. First, we identified regions in parameter space that unexpectedly lead to stochastic behavior of model-predicted membrane RAF1 dynamics, which is consistent with large variances in membrane RAF1 concentrations previously measured by others. Second, using parameter estimates from Sloppiness analysis as the baseline parameters for simulations of KRAS mutant signaling, we found that RAF1 acts as a bottleneck in the induction of ERK activity and thereby dampens the effects of constitutively active RAS mutations that arise in numerous cancers. Third, from both sensitivity and Sloppiness analyses, we found that the parameters upstream of RAF exert strong control on RAS-GTP, RAF1, MEK, and ERK dynamics, implying that control of those species’ dynamics preferentially occurs downstream of RAF1 when membrane bound RAF1 is no longer limiting. Our results illustrate how sensitivity and Sloppiness analyses can be integrated to gain more complete understanding of EGFR-ERK signaling than when either method is used alone and are intended to guide practitioners on using sensitivity analysis for hypothesis generation and efficient model calibration.

Distillation of global sensitivity and sloppiness analysis results explains consequences of low plasma membrane RAF abundance in EGFR-ERK signaling

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.