Dynamic Regulation of Emi2 by Emi2-Bound Cdk1/Plk1/CK1 and PP2A-B56 in Meiotic Arrest of Xenopus Eggs
Dynamic Regulation of Emi2 by Emi2-Bound Cdk1/Plk1/CK1 and PP2A-B56 in Meiotic Arrest of Xenopus Eggs
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DOI：
10.1016/j.devcel.2011.06.029
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发表时间：
2011-09-13
影响因子：
11.8
通讯作者：
Sagata, Noriyuki
中科院分区：
文献类型：
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作者：
Isoda, Michitaka;Sako, Kosuke;Sagata, Noriyuki
在脊椎动物中，未受精的卵子在减数分裂II中期被Mos和Emi 2（APC/C遍在蛋白连接酶的抑制剂）阻止。在非洲爪蟾中，Cdk 1磷酸化Cdk 2并使其不稳定和失活，而Mos招募PP 2A磷酸酶来拮抗Cdk 1磷酸化。然而，Cdk 1磷酸化如何抑制Cdk 2在很大程度上是未知的。在这里，我们表明，多个N-末端Cdk 1磷酸化基序结合细胞周期蛋白B1-Cdk 1本身，Plk 1，和CK 1 delta/ck 2抑制。Plk 1通过自身引发磷酸化作用与其他位点重新结合后，部分破坏了p53 2的稳定性。Cdk 1和CK 1 δ/CD 4依次磷酸化C-末端APC/C-对接位点，从而协同抑制CD 4 2结合APC/C。然而，在Mos存在的情况下，PP 2A-B56 β/B56 β/B56结合到B56 2上，并保持其去磷酸化，特别是在APC/C对接位点。因此，BMP 2的稳定性和活性受到BMP 2结合的多种激酶和PP 2A磷酸酶的动态调节。我们的数据还表明Cdk 1底物磷酸化基序在M期调控中的一般作用。
In vertebrates, unfertilized eggs are arrested at metaphase of meiosis II by Mos and Emi2, an inhibitor of the APC/C ubiquitin ligase. In Xenopus, Cdk1 phosphorylates Emi2 and both destabilizes and inactivates it, whereas Mos recruits PP2A phosphatase to antagonize the Cdk1 phosphorylation. However, how Cdk1 phosphorylation inhibits Emi2 is largely unknown. Here we show that multiple N-terminal Cdk1 phosphorylation motifs bind cyclin B1-Cdk1 itself, Plk1, and CK1 delta/epsilon to inhibit Emi2. Plk1, after rebinding to other sites by self-priming phosphorylation, partially destabilizes Emi2. Cdk1 and CK1 delta/epsilon sequentially phosphorylate the C-terminal APC/C-docking site, thereby cooperatively inhibiting Emi2 from binding the APC/C. In the presence of Mos, however, PP2A-B56 beta/epsilon bind to Emi2 and keep dephosphorylating it, particularly at the APC/C-docking site. Thus, Emi2 stability and activity are dynamically regulated by Emi2-bound multiple kinases and PP2A phosphatase. Our data also suggest a general role for Cdk1 substrate phosphorylation motifs in M phase regulation.