Melas, Ioannis N. and Mitsos, Alexander and Messinis, Dimitris E. and Weiss, Thomas S. and Alexopoulos, Leonidas G. (2011) Combined logical and data-driven models for linking signalling pathways to cellular response. BMC SYSTEMS BIOLOGY, 5: 107. ISSN 1752-0509,
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | GROWTH-FACTOR RECEPTOR; TYROSINE KINASE INHIBITOR; HEPATOCELLULAR-CARCINOMA; TUMOR-CELLS; NETWORKS; TRANSDUCTION; INFLAMMATION; CANCER; HEPATOCYTES; ACTIVATION; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Kinder- und Jugendmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 05 Jun 2020 08:45 |
| Last Modified: | 05 Jun 2020 08:45 |
| URI: | https://pred.uni-regensburg.de/id/eprint/20550 |
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