Functional wiring of the yeast kinome revealed by global analysis of genetic network motifs
- Sara Sharifpoor1,
- Dewald van Dyk1,
- Michael Costanzo1,
- Anastasia Baryshnikova1,
- Helena Friesen1,
- Alison C Douglas1,
- Ji-Young Youn1,
- Benjamin VanderSluis2,
- Chad L Myers2,
- Balázs Papp3,
- Charles Boone1 and
- Brenda J Andrews1,4
- 1 University of Toronto, Centre for Cellular and Biomolecular Research;
- 2 3. Department of Computer Science & Engineering, University of Minnesota-Twin Cities;
- 3 Institute of Biochemistry, Biological Research Center
- ↵* Corresponding author; email: brenda.andrews{at}utoronto.ca
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 8,700 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 genetic interaction networks.
- Received July 18, 2011.
- Accepted January 26, 2012.
- Copyright © 2012, Cold Spring Harbor Laboratory Press
