title: Tuning the activation threshold of a kinase network by nested feedback loops.
abstract: Determining proper responsiveness to incoming signals is fundamental to all biological systems. We demonstrate that intracellular signaling nodes can tune a signaling network's response threshold away from the basal median effective concentration established by ligand-receptor interactions. Focusing on the bistable kinase network that governs progesterone-induced meiotic entry in Xenopus oocytes, we characterized glycogen synthase kinase-3beta (GSK-3beta) as a dampener of progesterone responsiveness. GSK-3beta engages the meiotic kinase network through a double-negative feedback loop; this specific feedback architecture raises the progesterone threshold in correspondence with the strength of double-negative signaling. We also identified a marker of nutritional status, l-leucine, which lowers the progesterone threshold, indicating that oocytes integrate additional signals into their cell-fate decisions by modulating progesterone responsiveness.
authors.affiliation: Graduate Group in Biophysics, University of California, San Francisco, CA 94158, USA.
authors.forename: Quincey A
authors.initials: QA
authors.lastname: Justman
authors.forename: Zach
authors.initials: Z
authors.lastname: Serber
authors.forename: James E
authors.initials: JE
authors.lastname: Ferrell
authors.forename: Hana
authors.initials: H
authors.lastname: El-Samad
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
mesh_terms: D000818:Animals; D004789:Enzyme Activation; D025461:Feedback, Physiological; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D007930:Leucine / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D008540:Meiosis / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D009865:Oocytes / Q000166:cytology* / Q000378:metabolism*; D009866:Oogenesis / Q000502:physiology*; D010766:Phosphorylation; D011374:Progesterone / Q000502:physiology*; D014981:Xenopus
chemical_list: D011374:Progesterone; D000071679:Glycogen Synthase Kinase 3 beta; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D007930:Leucine