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Tuning the Activation Threshold of a Kinase Network by Nested Feedback Loops

Science  24 Apr 2009:
Vol. 324, Issue 5926, pp. 509-512
DOI: 10.1126/science.1169498

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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–3β (GSK-3β) as a dampener of progesterone responsiveness. GSK-3β 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.

  • * Present address: Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.

  • Present address: Amyris Biotechnologies, Incorporated, Emeryville, CA 94608, USA.

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