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Science 324 (5926): 509-512

Copyright © 2009 by the American Association for the Advancement of Science

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

Quincey A. Justman,1,2,* Zach Serber,3,{dagger} James E. Ferrell, Jr.,3 Hana El-Samad,4,{ddagger} Kevan M. Shokat2,{ddagger}

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.

1 Graduate Group in Biophysics, University of California, San Francisco, CA 94158, USA.
2 Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.
3 Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305–5174, USA.
4 Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA.

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

{dagger} Present address: Amyris Biotechnologies, Incorporated, Emeryville, CA 94608, USA.

{ddagger} To whom correspondence should be addressed. E-mail: helsamad{at}biochem.ucsf.edu (H.E.); shokat{at}cmp.ucsf.edu (K.M.S.)

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