PP1 promotes cyclin B destruction and the metaphase-anaphase transition by dephosphorylating CDC20.
PP1 promotes cyclin B destruction and the metaphase-anaphase transition by dephosphorylating CDC20.
复制标题
DOI：
10.1091/mbc.e20-04-0252
复制
发表时间：
2020-10-01
影响因子：
3.3
通讯作者：
Gruneberg U
中科院分区：
文献类型：
--
作者：
Bancroft J;Holder J;Geraghty Z;Alfonso-Pérez T;Murphy D;Barr FA;Gruneberg U
细胞周期蛋白B和securin的泛素依赖性蛋白水解启动姐妹染色单体分离和分裂后期。后期促进复合物/环体及其共激活因子CDC 20（APC/CCDC 20）形成这两种蛋白的主要泛素E3连接酶。APC/CCDC 20受CDK 1-细胞周期蛋白B调节，并通过调节激活和抑制磷酸化来抵消PP 1和PP 2A家族磷酸酶。在这里，我们报告说，PP 1促进细胞周期蛋白B的破坏在后期的发病，通过消除特定的抑制性磷酸化的N-末端的CDC 20。PP 1的消耗或化学抑制稳定细胞周期蛋白B，并导致染色体排列后中期到后期的明显延迟。这种对PP 1的需求在表达CDK 1磷酸化缺陷型CDC 206 A突变体的细胞中丧失。这些CDC 206 A细胞表现出正常的纺锤体检查点反应，一旦所有染色体对齐并在缺乏PP 1活性的情况下进入后期，则迅速破坏细胞周期蛋白B。因此，PP 1通过促进APC/CCDC 20依赖性破坏人类细胞中的细胞周期蛋白B，促进中期到后期的转变。
Ubiquitin-dependent proteolysis of cyclin B and securin initiates sister chromatid segregation and anaphase. The anaphase-promoting complex/cyclosome and its coactivator CDC20 (APC/CCDC20) form the main ubiquitin E3 ligase for these two proteins. APC/CCDC20 is regulated by CDK1-cyclin B and counteracting PP1 and PP2A family phosphatases through modulation of both activating and inhibitory phosphorylation. Here, we report that PP1 promotes cyclin B destruction at the onset of anaphase by removing specific inhibitory phosphorylation in the N-terminus of CDC20. Depletion or chemical inhibition of PP1 stabilizes cyclin B and results in a pronounced delay at the metaphase-to-anaphase transition after chromosome alignment. This requirement for PP1 is lost in cells expressing CDK1 phosphorylation–defective CDC206A mutants. These CDC206A cells show a normal spindle checkpoint response and rapidly destroy cyclin B once all chromosomes have aligned and enter into anaphase in the absence of PP1 activity. PP1 therefore facilitates the metaphase-to-anaphase transition by promoting APC/CCDC20-dependent destruction of cyclin B in human cells.