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Mol Syst Biol

Title:		Single-cell profiling screen identifies microtubule-dependent reduction of variability in signaling
Author(s):		Pesce CG; Zdraljevic S; Peria WJ; Bush A; Repetto MV; Rockwell D; Yu RC; Colman-Lerner A; Brent R;
Address:		"Abalone Bio, Inc., Richmond, CA, USA. Department of Molecular Biosciences, Northwestern University, Evanston, IL, USA. Fred Hutchinson Cancer Research Center, Seattle, WA, USA. IFIBYNE-UBA-CONICET and Departamento de Fisiologia, Biologia Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina. Fred Hutchinson Cancer Research Center, Seattle, WA, USA rbrent@fhcrc.org"
Journal Title:		Mol Syst Biol
Year:		2018
Volume:		20180404
Issue:		4
Page Number:		e7390 -
DOI:		10.15252/msb.20167390
ISSN/ISBN:		1744-4292 (Electronic) 1744-4292 (Linking)
Abstract:		"Populations of isogenic cells often respond coherently to signals, despite differences in protein abundance and cell state. Previously, we uncovered processes in the Saccharomyces cerevisiae pheromone response system (PRS) that reduced cell-to-cell variability in signal strength and cellular response. Here, we screened 1,141 non-essential genes to identify 50 'variability genes'. Most had distinct, separable effects on strength and variability of the PRS, defining these quantities as genetically distinct 'axes' of system behavior. Three genes affected cytoplasmic microtubule function: BIM1, GIM2, and GIM4 We used genetic and chemical perturbations to show that, without microtubules, PRS output is reduced but variability is unaffected, while, when microtubules are present but their function is perturbed, output is sometimes lowered, but its variability is always high. The increased variability caused by microtubule perturbations required the PRS MAP kinase Fus3 and a process at or upstream of Ste5, the membrane-localized scaffold to which Fus3 must bind to be activated. Visualization of Ste5 localization dynamics demonstrated that perturbing microtubules destabilized Ste5 at the membrane signaling site. The fact that such microtubule perturbations cause aberrant fate and polarity decisions in mammals suggests that microtubule-dependent signal stabilization might also operate throughout metazoans"
Keywords:		"Adaptor Proteins, Signal Transducing/genetics Cell Cycle Proteins/genetics MAP Kinase Signaling System/*genetics Microtubule Proteins/*genetics Microtubules/*genetics/metabolism Mitogen-Activated Protein Kinases/genetics Pheromones/genetics Saccharomyces;"
Notes:		"MedlinePesce, C Gustavo Zdraljevic, Stefan Peria, William J Bush, Alan Repetto, Maria Victoria Rockwell, Daniel Yu, Richard C Colman-Lerner, Alejandro Brent, Roger eng P50 HG002370/HG/NHGRI NIH HHS/ R01 GM086615/GM/NIGMS NIH HHS/ R01 GM097479/GM/NIGMS NIH HHS/ T32 GM008061/GM/NIGMS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England 2018/04/06 Mol Syst Biol. 2018 Apr 4; 14(4):e7390. doi: 10.15252/msb.20167390"