title: 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.
authors.affiliation: Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), INF 280, Heidelberg, Germany.
authors.forename: Lorenza A
authors.initials: LA
authors.lastname: D'Alessandro
authors.affiliation: Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Samaga
authors.affiliation: Institute of Physics, University of Freiburg, Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Maiwald
authors.affiliation: Institute of Physics, University of Freiburg, Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
authors.forename: Seong-Hwan
authors.initials: SH
authors.lastname: Rho
authors.affiliation: Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), INF 280, Heidelberg, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Bonefas
authors.affiliation: Institute of Physics, University of Freiburg, Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany; Merrimack Pharmaceuticals, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Andreas
authors.initials: A
authors.lastname: Raue
authors.affiliation: Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), INF 280, Heidelberg, Germany.
authors.forename: Nao
authors.initials: N
authors.lastname: Iwamoto
authors.affiliation: Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), INF 280, Heidelberg, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kienast
authors.affiliation: Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), INF 280, Heidelberg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Waldow
authors.affiliation: Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), INF 280, Heidelberg, Germany.
authors.forename: Rene
authors.initials: R
authors.lastname: Meyer
authors.affiliation: Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), INF 280, Heidelberg, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Schilling
authors.affiliation: Institute of Physics, University of Freiburg, Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Timmer
authors.affiliation: Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Klamt
authors.affiliation: Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), INF 280, Heidelberg, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Klingmüller
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003198:Computer Simulation; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D008115:Liver Regeneration / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D017228:Hepatocyte Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt