Removal of Centrosomal PP1 by NIMA Kinase Unlocks the MPF Feedback Loop to Promote Mitotic Commitment in S. pombe
Removal of Centrosomal PP1 by NIMA Kinase Unlocks the MPF Feedback Loop to Promote Mitotic Commitment in S. pombe
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DOI：
10.1016/j.cub.2012.12.039
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发表时间：
2013-02-04
期刊：
影响因子：
9.2
通讯作者：
Hagan, Iain M.
中科院分区：
文献类型：
--
作者：
Grallert, Agnes;Chan, Kuan Yoow;Hagan, Iain M.
背景：细胞周期蛋白依赖性激酶1（Cdk1）/细胞周期蛋白B复合物的激活，也称为有丝分裂促进因子（MPF），推动细胞进入有丝分裂。间期的MPF通过Wee1相关激酶对Cdk1的磷酸化作用而受到抑制。由于Cdc25磷酸酶可去除此磷酸基团，Cdc25的活性是促使细胞进入有丝分裂的转换过程的关键部分。活性MPF关键“触发因素”的产生促进了一个正反馈回路，该回路利用波罗激酶（Polo kinase）提高Cdc25活性并抑制Wee1，从而确保有丝分裂启动是一个双稳态开关。纺锤体极体（SPB）成分Cut12的突变可抑制Cdc25原本致命的缺陷。
结果：Cut12具有一个二分的蛋白磷酸酶1（PP1）对接结构域。单独突变其中任何一个元件都可抑制cdc25.22的温度依赖性致死性，而同时去除这两个元件则可使细胞在完全没有Cdc25的情况下进行分裂。在G2期晚期，MPF和NIMA激酶Fin1对这两个元件之间的磷酸化作用阻止了PP1（Dis2）的募集，从而促进了波罗激酶向Cut12和SPB的募集，并提高了整个细胞内的波罗激酶总体活性。
结论：PP1向Cut12的募集为波罗激酶的反馈回路活性设定了一个阈值，该阈值将细胞锁定在间期，直到Cdc25推动MPF活性突破这一障碍以启动有丝分裂。我们提出，SPB（以及据推测的中心体）上发生的事件整合了来自不同信号网络的输入，以产生一个适合每个细胞特定环境背景的协调一致的分裂决定。PP1的募集为这个开关内的单个或多个局部事件设定了一个或多个关键阈值。
Background: Activation of the Cdk1/cyclin B complex, also known as mitosis-promoting factor (MPF), drives commitment to mitosis. Interphase MPF is inhibited through phosphorylation of Cdk1 by Wee1-related kinases. Because Cdc25 phosphatases remove this phosphate, Cdc25 activity is an essential part of the switch that drives cells into mitosis. The generation of a critical "trigger" of active MPF promotes a positive feedback loop that employs Polo kinase to boost Cdc25 activity and inhibit Wee1, thereby ensuring that mitotic commitment is a bistable switch. Mutations in the spindle pole body (SPB) component Cut12 suppress otherwise lethal deficiencies in Cdc25.Results: Cut12 harbors a bipartite protein phosphatase 1 (PP1) docking domain. Mutation of either element alone suppressed the temperature-dependent lethality of cdc25.22, whereas simultaneous ablation of both allowed cells to divide in the complete absence of Cdc25. Late G2 phase phosphorylation between the two elements by MPF and the NIMA kinase Fin1 blocked PP1(Dis2) recruitment, thereby promoting recruitment of Polo to Cut12 and the SPB and elevating global Polo kinase activity throughout the cell.Conclusions: PP1 recruitment to Cut12 sets a threshold for Polo's feedback-loop activity that locks the cell in interphase until Cdc25 pushes MPF activity through this barrier to initiate mitosis. We propose that events on the SPB (and, by inference, the centrosome) integrate inputs from diverse signaling networks to generate a coherent decision to divide that is appropriate for the particular environmental context of each cell. PP1 recruitment sets one or more critical thresholds for single or multiple local events within this switch.