title: Post-translational regulation of the Drosophila circadian clock requires protein phosphatase 1 (PP1).
abstract: Phosphorylation is an important timekeeping mechanism in the circadian clock that has been closely studied at the level of the kinases involved but may also be tightly controlled by phosphatase action. Here we demonstrate a role for protein phosphatase 1 (PP1) in the regulation of the major timekeeping molecules in the Drosophila clock, TIMELESS (TIM) and PERIOD (PER). Flies with reduced PP1 activity exhibit a lengthened circadian period, reduced amplitude of behavioral rhythms, and an altered response to light that suggests a defect in the rising phase of clock protein expression. On a molecular level, PP1 directly dephosphorylates TIM and stabilizes it in both S2R(+) cells and clock neurons. However, PP1 does not act in a simple antagonistic manner to SHAGGY (SGG), the kinase that phosphorylates TIM, because the behavioral phenotypes produced by inhibiting PP1 in flies are different from those achieved by overexpressing SGG. PP1 also acts on PER, and TIM regulates the control of PER by PP1, although it does not affect PP2A action on PER. We propose a modified model for post-translational regulation of the Drosophila clock, in which PP1 is critical for the rhythmic abundance of TIM/PER while PP2A also regulates the nuclear translocation of TIM/PER.
authors.affiliation: Howard Hughes Medical Institute, Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Yanshan
authors.initials: Y
authors.lastname: Fang
authors.forename: Sriram
authors.initials: S
authors.lastname: Sathyanarayanan
authors.forename: Amita
authors.initials: A
authors.lastname: Sehgal
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D004330:Drosophila / Q000235:genetics / Q000502:physiology*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D017344:Genes, Insect; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D056950:Period Circadian Proteins; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D011499:Protein Processing, Post-Translational
chemical_list: D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C539040:PER protein, Drosophila; D056950:Period Circadian Proteins; C021042:protein phosphatase inhibitor-1; C096445:tim protein, Drosophila; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1