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

Interacting negative feedback loops control the sensitivity of amphibian oocytes to the hormone progesterone. Model Progesterone Response The hormone progesterone stimulates maturation of oocytes in the toad Xenopus laevis by binding to its receptor. Although receptor number and affinity for the hormone stay relatively constant, the dose of hormone required to stimulate meiotic maturation varies according to the environmental stimuli to which the animal is exposed, but little is known about how this is regulated. Justman et al. (p. 509; see the Perspective by Skotheim) combined experimental analysis and mathematical modeling to explore the role of glycogen synthase kinase—3β in desensitization, and a natural, sensitizing co-stimulus, the amino acid L-leucine. The results help to explain the layered complexity seen in signal transduction networks: If multiple stimuli act upon components of linked feedback loops, cells can tune their sensitivities dynamically to match their environment. 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.