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An integrative modeling framework reveals plasticity of TGF-β signaling.

Geoffroy Andrieux 1, 2 Michel Le Borgne 1 Nathalie Théret 2, *
* Corresponding author
1 Dyliss - Dynamics, Logics and Inference for biological Systems and Sequences
Inria Rennes – Bretagne Atlantique , IRISA-D7 - GESTION DES DONNÉES ET DE LA CONNAISSANCE
Abstract : BACKGROUND: The TGF-β transforming growth factor is the most pleiotropic cytokine controlling a broad range of cellular responses that include proliferation, differentiation and apoptosis. The context-dependent multifunctional nature of TGF-β is associated with complex signaling pathways. Differential models describe the dynamics of the TGF-β canonical pathway, but modeling the non-canonical networks constitutes a major challenge. Here, we propose a qualitative approach to explore all TGF-β-dependent signaling pathways. RESULTS: Using a new formalism, CADBIOM, which is based on guarded transitions and includes temporal parameters, we have built the first discrete model of TGF-β signaling networks by automatically integrating the 137 human signaling maps from the Pathway Interaction Database into a single unified dynamic model. Temporal property-checking analyses of 15934 trajectories that regulate 145 TGF-β target genes reveal the association of specific pathways with distinct biological processes. We identify 31 different combinations of TGF-β with other extracellular stimuli involved in non-canonical TGF-β pathways that regulate specific gene networks. Extensive analysis of gene expression data further demonstrates that genes sharing CADBIOM trajectories tend to be co-regulated. CONCLUSIONS: As applied here to TGF-β signaling, CADBIOM allows, for the first time, a full integration of highly complex signaling pathways into dynamic models that permit to explore cell responses to complex microenvironment stimuli.
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https://www.hal.inserm.fr/inserm-00978313
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Submitted on : Monday, April 14, 2014 - 9:49:43 AM
Last modification on : Monday, January 13, 2020 - 10:19:04 AM
Document(s) archivé(s) le : Monday, July 14, 2014 - 10:51:39 AM

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Geoffroy Andrieux, Michel Le Borgne, Nathalie Théret. An integrative modeling framework reveals plasticity of TGF-β signaling.. BMC Systems Biology, BioMed Central, 2014, 8 (1), pp.30. ⟨10.1186/1752-0509-8-30⟩. ⟨inserm-00978313⟩

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