title: Functional overlap and regulatory links shape genetic interactions between signaling pathways.
abstract: To understand relationships between phosphorylation-based signaling pathways, we analyzed 150 deletion mutants of protein kinases and phosphatases in S. cerevisiae using DNA microarrays. Downstream changes in gene expression were treated as a phenotypic readout. Double mutants with synthetic genetic interactions were included to investigate genetic buffering relationships such as redundancy. Three types of genetic buffering relationships are identified: mixed epistasis, complete redundancy, and quantitative redundancy. In mixed epistasis, the most common buffering relationship, different gene sets respond in different epistatic ways. Mixed epistasis arises from pairs of regulators that have only partial overlap in function and that are coupled by additional regulatory links such as repression of one by the other. Such regulatory modules confer the ability to control different combinations of processes depending on condition or context. These properties likely contribute to the evolutionary maintenance of paralogs and indicate a way in which signaling pathways connect for multiprocess control.
authors.affiliation: University Medical Centre Utrecht, The Netherlands. f.c.p.holstege@umcutrecht.nl
authors.forename: Sake
authors.initials: S
authors.lastname: van Wageningen
authors.forename: Patrick
authors.initials: P
authors.lastname: Kemmeren
authors.forename: Philip
authors.initials: P
authors.lastname: Lijnzaad
authors.forename: Thanasis
authors.initials: T
authors.lastname: Margaritis
authors.forename: Joris J
authors.initials: JJ
authors.lastname: Benschop
authors.forename: Inês J
authors.initials: IJ
authors.lastname: de Castro
authors.forename: Dik
authors.initials: D
authors.lastname: van Leenen
authors.forename: Marian J A
authors.initials: MJ
authors.lastname: Groot Koerkamp
authors.forename: Cheuk W
authors.initials: CW
authors.lastname: Ko
authors.forename: Antony J
authors.initials: AJ
authors.lastname: Miles
authors.forename: Nathalie
authors.initials: N
authors.lastname: Brabers
authors.forename: Mariel O
authors.initials: MO
authors.lastname: Brok
authors.forename: Tineke L
authors.initials: TL
authors.lastname: Lenstra
authors.forename: Dorothea
authors.initials: D
authors.lastname: Fiedler
authors.forename: Like
authors.initials: L
authors.lastname: Fokkens
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Aldecoa
authors.forename: Eva
authors.initials: E
authors.lastname: Apweiler
authors.forename: Virginia
authors.initials: V
authors.lastname: Taliadouros
authors.forename: Katrin
authors.initials: K
authors.lastname: Sameith
authors.forename: Loes A L
authors.initials: LA
authors.lastname: van de Pasch
authors.forename: Sander R
authors.initials: SR
authors.lastname: van Hooff
authors.forename: Linda V
authors.initials: LV
authors.lastname: Bakker
authors.forename: Nevan J
authors.initials: NJ
authors.lastname: Krogan
authors.forename: Berend
authors.initials: B
authors.lastname: Snel
authors.forename: Frank C P
authors.initials: FC
authors.lastname: Holstege
mesh_terms: D004843:Epistasis, Genetic; D020869:Gene Expression Profiling; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D010770:Phosphotransferases / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D010770:Phosphotransferases; D010744:Phosphoric Monoester Hydrolases