Automated ensemble modeling with modelMaGe: analyzing feedback mechanisms in the Sho1 branch of the HOG pathway

PLoS One. 2011 Mar 30;6(3):e14791. doi: 10.1371/journal.pone.0014791.


In systems biology uncertainty about biological processes translates into alternative mathematical model candidates. Here, the goal is to generate, fit and discriminate several candidate models that represent different hypotheses for feedback mechanisms responsible for downregulating the response of the Sho1 branch of the yeast high osmolarity glycerol (HOG) signaling pathway after initial stimulation. Implementing and testing these candidate models by hand is a tedious and error-prone task. Therefore, we automatically generated a set of candidate models of the Sho1 branch with the tool modelMaGe. These candidate models are automatically documented, can readily be simulated and fitted automatically to data. A ranking of the models with respect to parsimonious data representation is provided, enabling discrimination between candidate models and the biological hypotheses underlying them. We conclude that a previously published model fitted spurious effects in the data. Moreover, the discrimination analysis suggests that the reported data does not support the conclusion that a desensitization mechanism leads to the rapid attenuation of Hog1 signaling in the Sho1 branch of the HOG pathway. The data rather supports a model where an integrator feedback shuts down the pathway. This conclusion is also supported by dedicated experiments that can exclusively be predicted by those models including an integrator feedback.modelMaGe is an open source project and is distributed under the Gnu General Public License (GPL) and is available from

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism
  • Models, Theoretical*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Systems Biology


  • Membrane Proteins
  • SHO1 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • HOG1 protein, S cerevisiae
  • Mitogen-Activated Protein Kinases