Phosphorylation of PP1 Regulator Sds22 by PLK1 Ensures Accurate Chromosome Segregation
Phosphorylation of PP1 Regulator Sds22 by PLK1 Ensures Accurate Chromosome Segregation
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PLK1 磷酸化 PP1 调节因子 Sds22 可确保准确的染色体分离
DOI：
10.1074/jbc.m116.745372
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发表时间：
2016-09-30
影响因子：
4.8
通讯作者：
Yao, Xuebiao
中科院分区：
文献类型：
--
作者：
Duan, Hequan;Wang, Chunli;Yao, Xuebiao
在细胞分裂过程中，准确的染色体分离受到 Polo 样激酶 1 (PLK1) 以及 Aurora B 激酶和蛋白磷酸酶 1 (PP1) 的相反活性的严格调节。然而，有丝分裂染色体分离期间上述分级信号级联背后的调节机制仍然难以捉摸。 Sds22是PP1活性的保守调节因子，但它如何在有丝分裂过程中在空间和时间上调节PP1活性仍然难以捉摸。在此，我们表明，Sds22 是有丝分裂中 PLK1 的新型同源底物，PLK1 对 Sds22 的磷酸化以剂量依赖性方式引发对 PP1 介导的 Aurora B 在苏氨酸 232 (Thr(232)) 去磷酸化的抑制。 Sds22 的磷酸模拟突变体的过度表达会导致有丝分裂延迟显着增加，而 Sds22 的不可磷酸化突变体的过度表达会导致有丝分裂停滞。从机制上讲，PLK1 对 Sds22 的磷酸化增强了 Sds22 与 PP1 的结合，并抑制 Aurora B Thr(232) 的去磷酸化，以确保稳健、无差错的中期-后期转变。这些发现描绘了一个保守的信号传导层次，在染色体分离过程中协调关键有丝分裂调节因子的动态蛋白质磷酸化和去磷酸化，以保护染色体稳定性。
During cell division, accurate chromosome segregation is tightly regulated by Polo-like kinase 1 (PLK1) and opposing activities of Aurora B kinase and protein phosphatase 1 (PP1). However, the regulatory mechanisms underlying the aforementioned hierarchical signaling cascade during mitotic chromosome segregation have remained elusive. Sds22 is a conserved regulator of PP1 activity, but how it regulates PP1 activity in space and time during mitosis remains elusive. Here we show that Sds22 is a novel and cognate substrate of PLK1 in mitosis, and the phosphorylation of Sds22 by PLK1 elicited an inhibition of PP1-mediated dephosphorylation of Aurora B at threonine 232 (Thr(232)) in a dose-dependent manner. Overexpression of a phosphomimetic mutant of Sds22 causes a dramatic increase in mitotic delay, whereas overexpression of a non-phosphorylatable mutant of Sds22 results in mitotic arrest. Mechanistically, the phosphorylation of Sds22 by PLK1 strengthens the binding of Sds22 to PP1 and inhibits the dephosphorylation of Thr(232) of Aurora B to ensure arobust, error-freemetaphase-anaphasetransition. Thesefindings delineate a conserved signaling hierarchy that orchestrates dynamic protein phosphorylation and dephosphorylation of critical mitotic regulators during chromosome segregation to guard chromosome stability.