%0 Journal Article
%T Combined logical and data-driven models for linking signalling pathways to cellular response
%A Ioannis N Melas
%A Alexander Mitsos
%A Dimitris E Messinis
%A Thomas S Weiss
%A Leonidas G Alexopoulos
%J BMC Systems Biology
%D 2011
%I BioMed Central
%R 10.1186/1752-0509-5-107
%X 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.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.Construction of signalling pathways is a major endeavour in biology. Signalling cascades, starting at the receptor level, orchestrate a variety of normal or pathological responses via a complex network of kinases, adaptor molecules, and other signalling proteins [1]. Several gene- and protein-based approaches have emerged for elucidating the complex intracellular signalling activity. Gene-based analysis has the advantage of whole genome exploration [2-4] whereas proteomic approaches are applicable on small pathways but with a more reliable view of pathway function, since proteins are the ultimate reporters of cellular activity [5,6]. Both approaches
%U http://www.biomedcentral.com/1752-0509/5/107