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Open Access Highly Accessed Research article

Combined logical and data-driven models for linking signalling pathways to cellular response

Ioannis N Melas1, Alexander Mitsos2, Dimitris E Messinis1, Thomas S Weiss3 and Leonidas G Alexopoulos1*

  • * Corresponding author: Leonidas G Alexopoulos leo@mail.ntua.gr

  • † Equal contributors

Author Affiliations

1 Dept of Mechanical Engineering, National Technical University of Athens, 15780 Zografou, Greece

2 Dept of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA

3 Center for Liver Cell Research, Department of Pediatrics and juvenile Medicine, University Medical Center Regensburg, Regensburg, Germany

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BMC Systems Biology 2011, 5:107  doi:10.1186/1752-0509-5-107

Published: 5 July 2011

Abstract

Background

Signalling pathways are the cornerstone on understanding cell function and predicting cell behavior. Recently, logical models of canonical pathways have been optimised with high-throughput phosphoproteomic data to construct cell-type specific pathways. However, less is known on how signalling pathways can be linked to a cellular response such as cell growth, death, cytokine secretion, or transcriptional activity.

Results

In this work, we measure the signalling activity (phosphorylation levels) and phenotypic behavior (cytokine secretion) of normal and cancer hepatocytes treated with a combination of cytokines and inhibitors. Using the two datasets, we construct "extended" pathways that integrate intracellular activity with cellular responses using a hybrid logical/data-driven computational approach. Boolean logic is used whenever a priori knowledge is accessible (i.e., construction of canonical pathways), whereas a data-driven approach is used for linking cellular behavior to signalling activity via non-canonical edges. The extended pathway is subsequently optimised to fit signalling and behavioural data using an Integer Linear Programming formulation. As a result, we are able to construct maps of primary and transformed hepatocytes downstream of 7 receptors that are capable of explaining the secretion of 22 cytokines.

Conclusions

We developed a method for constructing extended pathways that start at the receptor level and via a complex intracellular signalling pathway identify those mechanisms that drive cellular behaviour. Our results constitute a proof-of-principle for construction of "extended pathways" that are capable of linking pathway activity to diverse responses such as growth, death, differentiation, gene expression, or cytokine secretion.