Godfrey Molly, Touati Sandra A, Kataria Meghna, Jones Andrew, Snijders Ambrosius P, Uhlmann Frank
Chromosome Segregation Laboratory, The Francis Crick Institute, London NW1 1AT, UK.
Mass Spectrometry Proteomics Science Technology Platform, The Francis Crick Institute, London NW1 1AT, UK.
Mol Cell. 2017 Feb 2;65(3):393-402.e3. doi: 10.1016/j.molcel.2016.12.018. Epub 2017 Jan 26.
In the quantitative model of cell-cycle control, progression from G1 through S phase and into mitosis is ordered by thresholds of increasing cyclin-dependent kinase (Cdk) activity. How such thresholds are read out by substrates that respond with the correct phosphorylation timing is not known. Here, using the budding yeast model, we show that the abundant PP2A phosphatase counteracts Cdk phosphorylation during interphase and delays phosphorylation of late Cdk substrates. PP2A specifically counteracts phosphorylation on threonine residues, and consequently, we find that threonine-directed phosphorylation occurs late in the cell cycle. Furthermore, the late phosphorylation of a model substrate, Ndd1, depends on threonine identity of its Cdk target sites. Our results support a model in which Cdk-counteracting phosphatases contribute to cell-cycle ordering by imposing Cdk thresholds. They also unveil a regulatory principle based on the phosphoacceptor amino acid, which is likely to apply to signaling pathways beyond cell-cycle control.
在细胞周期调控的定量模型中，细胞从G1期经过S期进入有丝分裂的进程是由细胞周期蛋白依赖性激酶（Cdk）活性的递增阈值所调控的。目前尚不清楚底物如何通过正确的磷酸化时间来响应这些阈值。在此，我们利用芽殖酵母模型表明，大量的PP2A磷酸酶在间期抵消Cdk磷酸化，并延迟晚期Cdk底物的磷酸化。PP2A特异性地抵消苏氨酸残基上的磷酸化，因此，我们发现苏氨酸定向磷酸化发生在细胞周期后期。此外，模型底物Ndd1的晚期磷酸化取决于其Cdk靶位点的苏氨酸特性。我们的结果支持一种模型，即Cdk拮抗磷酸酶通过设定Cdk阈值来促进细胞周期排序。它们还揭示了一种基于磷酸化氨基酸的调控原则，这可能适用于细胞周期调控以外的信号通路。
