Phosphoproteomic analyses reveal novel cross‐modulation mechanisms between two signaling pathways in yeast |
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Authors: | Stefania Vaga Marti Bernardo‐Faura Thomas Cokelaer Alessio Maiolica Christopher A Barnes Ludovic C Gillet Björn Hegemann Frank van Drogen Hoda Sharifian Edda Klipp Matthias Peter Julio Saez‐Rodriguez Ruedi Aebersold |
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Institution: | 1.Department of Biology, Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland;2.European Molecular Biology Laboratory (EMBL), European Bioinformatics Institute (EBI), Cambridge, UK;3.Department of Biology, Institute of Biochemistry, ETH Zürich, Zürich, Switzerland;4.Department of Biology, Theoretical Biophysics, Humboldt-Universität zu Berlin, Berlin, Germany;5.Faculty of Science, University of Zurich, Zurich, Switzerland |
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Abstract: | Cells respond to environmental stimuli via specialized signaling pathways. Concurrent stimuli trigger multiple pathways that integrate information, predominantly via protein phosphorylation. Budding yeast responds to NaCl and pheromone via two mitogen‐activated protein kinase cascades, the high osmolarity, and the mating pathways, respectively. To investigate signal integration between these pathways, we quantified the time‐resolved phosphorylation site dynamics after pathway co‐stimulation. Using shotgun mass spectrometry, we quantified 2,536 phosphopeptides across 36 conditions. Our data indicate that NaCl and pheromone affect phosphorylation events within both pathways, which thus affect each other at more levels than anticipated, allowing for information exchange and signal integration. We observed a pheromone‐induced down‐regulation of Hog1 phosphorylation due to Gpd1, Ste20, Ptp2, Pbs2, and Ptc1. Distinct Ste20 and Pbs2 phosphosites responded differently to the two stimuli, suggesting these proteins as key mediators of the information exchange. A set of logic models was then used to assess the role of measured phosphopeptides in the crosstalk. Our results show that the integration of the response to different stimuli requires complex interconnections between signaling pathways. |
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Keywords: | cell signaling network crosstalk HOG pathway pheromone pathway phosphoproteomics |
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