Adam Friedman, Norbert Perrimon  Cell 

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Genetic Screening for Signal Transduction in the Era of Network Biology  Adam Friedman, Norbert Perrimon  Cell  Volume 128, Issue 2, Pages 225-231 (January 2007) DOI: 10.1016/j.cell.2007.01.007 Copyright © 2007 Elsevier Inc. Terms and Conditions

Figure 1 Continuous Distributions of Quantitative Signaling Readouts (A) Quantitative assay for ERK activation in a cell-based Drosophila RNAi screen (Friedman and Perrimon, 2006). Effect of each double-stranded RNA is represented as a Z score relative to control ERK activation. (B) In vivo quantitative P element collection screen in Drosophila assaying deviation of bristle number (Norga et al., 2003). (C) Genome-wide quantitative deletion screen for G protein/MAPK signaling in S. cerevisiae (Chasse et al., 2006). Effect of each deletion on mating factor stimulation relative to an internal wild-type control. Unpublished dataset is courtesy of H. Dohlman. Cell 2007 128, 225-231DOI: (10.1016/j.cell.2007.01.007) Copyright © 2007 Elsevier Inc. Terms and Conditions

Figure 2 Traditional Developmental and Recent Cell-Based Views of Signaling (A) Simplified cell circuit diagram for a signaling pathway depicting a few, compartmentalized components without quantitative information. (B) Network model for signaling. Following a stimulus, information is propagated throughout the network, leading to multiple outputs. Relative contribution, or flow rate, of each protein to the maximal output is represented by line weights (thicker implies larger contribution of that protein or interaction to the output). Canonical components (blue) from genetic screens may make many of the quantitatively significant connections, as measured at a particular protein within the network. Model complexity is magnified when quantitative contributions are considered in the context of multiple signals. (C) Mutant developmental phenotypes may appear only at the extremes of genetic contribution to the signaling pathway due to robustness. Shown is the correlation between extreme positive Z scores (negative regulators) in an RTK/ERK screen (Friedman and Perrimon, 2006) and a gain-of-function (GOF) Torso RTK phenotype (torY9) and extreme negative Z scores (positive regulators) and a loss-of-function (LOF) Torso phenotype (tor−/−). All other gene contributions are buffered by the developmental context and appear as wild-type (WT). (D) Relationship between cell-based quantitative screen output and a network signaling model. In this screen, canonical components have the greatest impact on signaling output and thus are represented at the extreme ends of the distribution. More distant and quantitatively less important proteins appear internally along the distribution. Measuring signaling output at one of these proteins may result in canonical components having weak effects in the assay. (Images in panel C courtesy of Willis Li.) Cell 2007 128, 225-231DOI: (10.1016/j.cell.2007.01.007) Copyright © 2007 Elsevier Inc. Terms and Conditions