title: Two new competing pathways establish the threshold for cyclin-B-Cdk1 activation at the meiotic G2/M transition.
abstract: Extracellular 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.
authors.affiliation: Science and Education Center, Ochanomizu University, Tokyo 112-8610, Japan hiraoka.daisaku@ocha.ac.jp kishimoto.takeo@ocha.ac.jp.
authors.forename: Daisaku
authors.identifier: 0000-0002-3875-2684
authors.initials: D
authors.lastname: Hiraoka
authors.affiliation: Laboratory of Cell and Developmental Biology, Graduate School of Bioscience, Tokyo Institute of Technology, Yokohama 226-8501, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Aono
authors.affiliation: Laboratory of Cell and Developmental Biology, Graduate School of Bioscience, Tokyo Institute of Technology, Yokohama 226-8501, Japan.
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Hanada
authors.affiliation: Laboratory of Cell and Developmental Biology, Graduate School of Bioscience, Tokyo Institute of Technology, Yokohama 226-8501, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Okumura
authors.affiliation: Science and Education Center, Ochanomizu University, Tokyo 112-8610, Japan Laboratory of Cell and Developmental Biology, Graduate School of Bioscience, Tokyo Institute of Technology, Yokohama 226-8501, Japan hiraoka.daisaku@ocha.ac.jp kishimoto.takeo@ocha.ac.jp.
authors.forename: Takeo
authors.initials: T
authors.lastname: Kishimoto
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D019926:Cyclin B / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D025461:Feedback, Physiological / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism; D006801:Humans; D008540:Meiosis / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013215:Starfish / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D013379:Substrate Specificity / Q000187:drug effects; D020687:cdc25 Phosphatases / Q000378:metabolism
chemical_list: D019926:Cyclin B; D044387:GTP-Binding Protein beta Subunits; D050505:Mutant Proteins; D010768:Phosphoserine; C008407:1-methyladenine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D016203:CDC2 Protein Kinase; D020687:cdc25 Phosphatases; D000225:Adenine
keywords: Akt; Cdk1; Cyclin B; Gβ; Gγ; Meiotic G2/M transition; Oocyte; PI3K; Threshold