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Disentangling the Complexity of HGF Signaling by Combining Qualitative and Quantitative Modeling

Abstract:

Signaling pathways are characterized by crosstalk, feedback and feedforward mechanisms giving rise to highly complex and cell-context specific signaling networks. Dissecting the underlying relations is crucial to predict the impact of targeted perturbations. However, a major challenge in identifying cell-context specific signaling networks is the enormous number of potentially possible interactions. Here, we report a novel hybrid mathematical modeling strategy to systematically unravel hepatocyte growth factor (HGF) stimulated phosphoinositide-3-kinase (PI3K) and mitogen activated protein kinase (MAPK) signaling, which critically contribute to liver regeneration. By combining time-resolved quantitative experimental data generated in primary mouse hepatocytes with interaction graph and ordinary differential equation modeling, we identify and experimentally validate a network structure that represents the experimental data best and indicates specific crosstalk mechanisms. Whereas the identified network is robust against single perturbations, combinatorial inhibition strategies are predicted that result in strong reduction of Akt and ERK activation. Thus, by capitalizing on the advantages of the two modeling approaches, we reduce the high combinatorial complexity and identify cell-context specific signaling networks.

10.1371/journal.pcbi.1004192

Projects: A2.1: Multi-level regulation of signalling pathways important for primin..., A2.3: Cross-talk and distinct properties of growth factor signalling reg..., A2.4: Linking signalling pathways regulating liver regeneration and orga..., A2: Integration of Signalling Pathways in Hepatocellular Response, A3.2: Cross-talk of signaling pathways and endocytic machinery in hepato..., A3.4: Linking signalling to metabolic functions, E1: Integration on the cellular level, Showcase HGF and Regeneration

PLoS Comput Biol
PLoS Comput Biol 11(4) : e1004192
23rd Apr 2015

Lorenza A. D’Alessandro, Regina Samaga, Tim Maiwald, Seong-Hwan Rho, Sandra Bonefas, Andreas Raue, Nao Iwamoto, Alexandra Kienast, Katharina Waldow, Rene Meyer, Marcel Schilling, Jens Timmer, Steffen Klamt, Ursula Klingmüller

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[Lorenza D'Alessandro] [Regina Samaga] [Thomas Maiwald] [Seong-Hwan Rho] [Andreas Raue]
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Views: 1322
  • Created: 5th May 2015 at 13:29
  • Last updated: 22nd May 2015 at 08:57

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