Tuning the activation threshold of a kinase network by nested feedback loops.
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.
Justman
Quincey A
QA
Graduate Group in Biophysics, University of California, San Francisco, CA 94158, USA.
Serber
Zach
Z
Ferrell
James E
JE
El-Samad
Hana
H
Shokat
Kevan M
KM
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
D011374:Progesterone; D000071679:Glycogen Synthase Kinase 3 beta; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D007930:Leucine