title: Systematic identification of signal integration by protein kinase A.
abstract: Cellular processes and homeostasis control in eukaryotic cells is achieved by the action of regulatory proteins such as protein kinase A (PKA). Although the outbound signals from PKA directed to processes such as metabolism, growth, and aging have been well charted, what regulates this conserved regulator remains to be systematically identified to understand how it coordinates biological processes. Using a yeast PKA reporter assay, we identified genes that influence PKA activity by measuring protein-protein interactions between the regulatory and the two catalytic subunits of the PKA complex in 3,726 yeast genetic-deletion backgrounds grown on two carbon sources. Overall, nearly 500 genes were found to be connected directly or indirectly to PKA regulation, including 80 core regulators, denoting a wide diversity of signals regulating PKA, within and beyond the described upstream linear pathways. PKA regulators span multiple processes, including the antagonistic autophagy and methionine biosynthesis pathways. Our results converge toward mechanisms of PKA posttranslational regulation by lysine acetylation, which is conserved between yeast and humans and that, we show, regulates protein complex formation in mammals and carbohydrate storage and aging in yeast. Taken together, these results show that the extent of PKA input matches with its output, because this kinase receives information from upstream and downstream processes, and highlight how biological processes are interconnected and coordinated by PKA.
authors.affiliation: Département de Biologie, The Quebec Network for Research on Protein Function, Structure, and Engineering, Institut de Biologie Intégrative et des Systèmes.
authors.forename: Marie
authors.initials: M
authors.lastname: Filteau
authors.affiliation: Département de Biologie, The Quebec Network for Research on Protein Function, Structure, and Engineering, Institut de Biologie Intégrative et des Systèmes.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Diss
authors.affiliation: Département de Biologie, The Quebec Network for Research on Protein Function, Structure, and Engineering, Institut de Biologie Intégrative et des Systèmes.
authors.forename: Francisco
authors.identifier: http://orcid.org/0000-0002-3073-8546
authors.initials: F
authors.lastname: Torres-Quiroz
authors.affiliation: Département de Biologie, The Quebec Network for Research on Protein Function, Structure, and Engineering, Institut de Biologie Intégrative et des Systèmes.
authors.forename: Alexandre K
authors.initials: AK
authors.lastname: Dubé
authors.affiliation: Institute of Biochemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, A-6020 Innsbruck, Austria; and.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schraffl
authors.affiliation: Institute of Biochemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, A-6020 Innsbruck, Austria; and.
authors.forename: Verena A
authors.initials: VA
authors.lastname: Bachmann
authors.affiliation: Département de Biologie, The Quebec Network for Research on Protein Function, Structure, and Engineering, Institut de Biologie Intégrative et des Systèmes.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gagnon-Arsenault
authors.affiliation: Département de Biologie, The Quebec Network for Research on Protein Function, Structure, and Engineering, Institut de Biologie Intégrative et des Systèmes.
authors.forename: Andrée-Ève
authors.initials: AÈ
authors.lastname: Chrétien
authors.affiliation: Département de Biologie Moléculaire, Biochimie Médicale et Pathologie, and Centre de Recherche sur le Cancer, Université Laval, Québec, QC, G1V 0A6, Canada; Centre de Recherche du Centre Hospitalier Universitaire de Québec, Québec, QC, G1R 2J6, Canada.
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Steunou
authors.affiliation: Département de Biologie Moléculaire, Biochimie Médicale et Pathologie, and Centre de Recherche sur le Cancer, Université Laval, Québec, QC, G1V 0A6, Canada; Centre de Recherche du Centre Hospitalier Universitaire de Québec, Québec, QC, G1R 2J6, Canada.
authors.forename: Ugo
authors.initials: U
authors.lastname: Dionne
authors.affiliation: Département de Biologie Moléculaire, Biochimie Médicale et Pathologie, and Centre de Recherche sur le Cancer, Université Laval, Québec, QC, G1V 0A6, Canada; Centre de Recherche du Centre Hospitalier Universitaire de Québec, Québec, QC, G1R 2J6, Canada.
authors.forename: Jacques
authors.identifier: http://orcid.org/0000-0001-6751-555X
authors.initials: J
authors.lastname: Côté
authors.affiliation: The Quebec Network for Research on Protein Function, Structure, and Engineering, Département de Biologie Moléculaire, Biochimie Médicale et Pathologie, and Centre de Recherche sur le Cancer, Université Laval, Québec, QC, G1V 0A6, Canada; Centre de Recherche du Centre Hospitalier Universitaire de Québec, Québec, QC, G1R 2J6, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bisson
authors.affiliation: Institute of Biochemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, A-6020 Innsbruck, Austria; and.
authors.forename: Eduard
authors.initials: E
authors.lastname: Stefan
authors.affiliation: Département de Biologie, The Quebec Network for Research on Protein Function, Structure, and Engineering, Institut de Biologie Intégrative et des Systèmes, Christian.landry@bio.ulaval.ca.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Landry
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D001343:Autophagy; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005690:Galactose / Q000737:chemistry; D005947:Glucose / Q000737:chemistry; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D049410:Luciferases, Renilla / Q000378:metabolism; D008715:Methionine / Q000737:chemistry; D008969:Molecular Sequence Data; D010802:Phylogeny; D011499:Protein Processing, Post-Translational; D051381:Rats; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D029701:Saccharomyces cerevisiae Proteins; D008715:Methionine; D000242:Cyclic AMP; D049410:Luciferases, Renilla; D058570:TOR Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose; D005690:Galactose
keywords: Ras/cAMP/PKA pathway; TOR; acetylation; autophagy; methionine
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