Abstract
ABSTRACTExtracellular ligands control biological phenomena. Cells distinguish physiological stimuli from weak noise stimuli by establishing a ligand-concentration threshold. Hormonal control of the meiotic G2/M transition in oocytes is essential for reproduction. However, the mechanism for threshold establishment is unclear. In starfish oocytes, maturation-inducing hormones activate the PI3K–Akt pathway through the Gβγ complex of heterotrimeric G-proteins. Akt directly phosphorylates both Cdc25 phosphatase and Myt1 kinase, resulting in activation of cyclin-B–Cdk1, which then induces meiotic G2/M transition. Here, we show that cyclin-B–Cdk1 is partially activated after subthreshold hormonal stimuli, but this triggers negative feedback, resulting in dephosphorylation of Akt sites on Cdc25 and Myt1, thereby canceling the signal. We also identified phosphatase activity towards Akt substrates that exists independent of stimuli. In contrast to these negative regulatory activities, an atypical Gβγ-dependent pathway enhances PI3K–Akt-dependent phosphorylation. Based on these findings, we propose a model for threshold establishment in which hormonal dose-dependent competition between these new pathways establishes a threshold; the atypical Gβγ-pathway becomes predominant over Cdk-dependent negative feedback when the stimulus exceeds this threshold. Our findings provide a regulatory connection between cell cycle and signal transduction machineries.
Highlights
Cells must respond to extracellular stimuli, such as hormones and environmental stresses, in order to adapt to changing environments
Ser188 on Cdc25 is phosphorylated by Akt To monitor signaling dynamics, we performed immunoblotting with phosphorylation-specific antibodies against residue Ser477 on Akt (Hiraoka et al, 2011) and residue Tyr15 on Cdk1 to monitor the activity of cyclin-B– Cdk1
In this study, we identified two new pathways that regulate PI3K– Akt-pathway-dependent phosphorylation of Akt substrates in an opposing manner – the cyclin-B–Cdk1-dependent negativefeedback pathway, which induces dephosphorylation of Akt substrates and thereby prevents subthreshold stimulus-induced noise signaling, and an atypical Gβγ-pathway, which is distinct from the PI3K–Akt pathway and enhances Akt-catalyzed phosphorylation
Summary
Cells must respond to extracellular stimuli, such as hormones and environmental stresses, in order to adapt to changing environments. By establishing a stimulus threshold, cells are able to discriminate physiologically relevant stimuli from noise stimuli. Supra-threshold but not subthreshold doses of stimuli elicit cellular responses. Such stimulus-intensity-dependent responses can control progression of the cell cycle. An important example is hormonal control of meiosis in oocytes. Immature oocytes, which have a large nucleus, called the germinal vesicle, arrest at prophase of meiosis I (meiotic prophase I) (Masui, 1985), which is equivalent to the
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