title: Functional wiring of the yeast kinome revealed by global analysis of genetic network motifs.
abstract: A combinatorial genetic perturbation strategy was applied to interrogate the yeast kinome on a genome-wide scale. We assessed the global effects of gene overexpression or gene deletion to map an integrated genetic interaction network of synthetic dosage lethal (SDL) and loss-of-function genetic interactions (GIs) for 92 kinases, producing a meta-network of 8700 GIs enriched for pathways known to be regulated by cognate kinases. Kinases most sensitive to dosage perturbations had constitutive cell cycle or cell polarity functions under standard growth conditions. Condition-specific screens confirmed that the spectrum of kinase dosage interactions can be expanded substantially in activating conditions. An integrated network composed of systematic SDL, negative and positive loss-of-function GIs, and literature-curated kinase-substrate interactions revealed kinase-dependent regulatory motifs predictive of novel gene-specific phenotypes. Our study provides a valuable resource to unravel novel functional relationships and pathways regulated by kinases and outlines a general strategy for deciphering mutant phenotypes from large-scale GI networks.
authors.affiliation: Department of Molecular Genetics, The Donnelly Centre, University of Toronto, Toronto, Ontario M5S3E1, Canada.
authors.forename: Sara
authors.initials: S
authors.lastname: Sharifpoor
authors.forename: Dewald
authors.initials: D
authors.lastname: van Dyk
authors.forename: Michael
authors.initials: M
authors.lastname: Costanzo
authors.forename: Anastasia
authors.initials: A
authors.lastname: Baryshnikova
authors.forename: Helena
authors.initials: H
authors.lastname: Friesen
authors.forename: Alison C
authors.initials: AC
authors.lastname: Douglas
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Youn
authors.forename: Benjamin
authors.initials: B
authors.lastname: VanderSluis
authors.forename: Chad L
authors.initials: CL
authors.lastname: Myers
authors.forename: Balázs
authors.initials: B
authors.lastname: Papp
authors.forename: Charles
authors.initials: C
authors.lastname: Boone
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Andrews
mesh_terms: D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D015966:Gene Expression Regulation, Fungal; D053263:Gene Regulatory Networks; D016681:Genome, Fungal / Q000235:genetics; D023281:Genomics / Q000379:methods; D047468:Immunoprecipitation; D008957:Models, Genetic; D009154:Mutation; D059372:Nucleotide Motifs / Q000235:genetics; D010770:Phosphotransferases / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D020543:Proteome / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D020543:Proteome; D029701:Saccharomyces cerevisiae Proteins; D010770:Phosphotransferases