title: Plasticity of the MAPK signaling network in response to mechanical stress.
abstract: Cells display versatile responses to mechanical inputs and recent studies have identified the mitogen-activated protein kinase (MAPK) cascades mediating the biological effects observed upon mechanical stimulation. Although, MAPK pathways can act insulated from each other, several mechanisms facilitate the crosstalk between the components of these cascades. Yet, the combinatorial complexity of potential molecular interactions between these elements have prevented the understanding of their concerted functions. To analyze the plasticity of the MAPK signaling network in response to mechanical stress we performed a non-saturating epistatic screen in resting and stretched conditions employing as readout a JNK responsive dJun-FRET biosensor. By knocking down MAPKs, and JNK pathway regulators, singly or in pairs in Drosophila S2R+ cells, we have uncovered unexpected regulatory links between JNK cascade kinases, Rho GTPases, MAPKs and the JNK phosphatase Puc. These relationships have been integrated in a system network model at equilibrium accounting for all experimentally validated interactions. This model allows predicting the global reaction of the network to its modulation in response to mechanical stress. It also highlights its context-dependent sensitivity.
authors.affiliation: Instituto de Biología Molecular de Barcelona (CSIC), Parc Cientific de Barcelona, Baldiri Reixac 10-12, Barcelona, Spain.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Pereira
authors.affiliation: Nanobiophysics, MESA+ Institute for Nanotechnology & MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands.
authors.forename: Cicerone
authors.initials: C
authors.lastname: Tudor
authors.affiliation: Instituto de Biología Molecular de Barcelona (CSIC), Parc Cientific de Barcelona, Baldiri Reixac 10-12, Barcelona, Spain.
authors.forename: Philippe-Alexandre
authors.initials: PA
authors.lastname: Pouille
authors.affiliation: Nanobiophysics, MESA+ Institute for Nanotechnology & MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands.
authors.forename: Shashank
authors.initials: S
authors.lastname: Shekhar
authors.affiliation: Nanobiophysics, MESA+ Institute for Nanotechnology & MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands.
authors.forename: Johannes S
authors.initials: JS
authors.lastname: Kanger
authors.affiliation: Nanobiophysics, MESA+ Institute for Nanotechnology & MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands.
authors.forename: Vinod
authors.initials: V
authors.lastname: Subramaniam
authors.affiliation: Instituto de Biología Molecular de Barcelona (CSIC), Parc Cientific de Barcelona, Baldiri Reixac 10-12, Barcelona, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Martín-Blanco
mesh_terms: D000818:Animals; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism; D004789:Enzyme Activation; D004843:Epistasis, Genetic; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D013314:Stress, Mechanical; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C110854:puc protein, Drosophila; D010749:Phosphoprotein Phosphatases; D020741:rho GTP-Binding Proteins