Saurin Adrian T, Durgan Joanne, Cameron Angus J, Faisal Amir, Marber Michael S, Parker Peter J
Protein Phosphorylation Laboratory, London Research Institute, Cancer Research UK, London, WC2A 3PX, UK.
Nat Cell Biol. 2008 Aug;10(8):891-901. doi: 10.1038/ncb1749. Epub 2008 Jul 6.
The cell cycle is exquisitely controlled by multiple sequential regulatory inputs to ensure fidelity. Here we demonstrate that the final step in division, the physical separation of daughter cells, is controlled by a member of the PKC gene superfamily. Specifically, we have identified three phosphorylation sites within PKCepsilon that control its association with 14-3-3. These phosphorylations are executed by p38 MAP kinase (Ser 350), GSK3 (Ser 346) and PKC itself (Ser 368). Integration of these signals is essential during mitosis because mutations that prevent phosphorylation of PKCepsilon and/or PKCepsilon binding to 14-3-3 also cause defects in the completion of cytokinesis. Using chemical genetic and dominant-negative approaches it is shown that selective inhibition of PKCepsilon halts cells at the final stages of separation. This arrest is associated with persistent RhoA activation at the midbody and a delay in actomyosin ring dissociation. This study therefore identifies a new regulatory mechanism that controls exit from cytokinesis, which has implications for carcinogenesis.
细胞周期受到多个连续调节输入的精确控制，以确保忠实性。在这里，我们证明了分裂的最后一步，即子细胞的物理分离，是由PKC基因超家族的一个成员控制的。具体而言，我们在PKCε中鉴定出三个磷酸化位点，它们控制其与14-3-3的结合。这些磷酸化由p38丝裂原活化蛋白激酶（Ser 350）、糖原合成酶激酶3（Ser 346）和PKC自身（Ser 368）执行。这些信号的整合在有丝分裂期间至关重要，因为阻止PKCε磷酸化和/或PKCε与14-3-3结合的突变也会导致胞质分裂完成缺陷。使用化学遗传学和显性负性方法表明，选择性抑制PKCε会使细胞在分离的最后阶段停滞。这种停滞与中体处RhoA的持续激活以及肌动球蛋白环解离延迟有关。因此，这项研究确定了一种控制胞质分裂退出的新调节机制，这对肿瘤发生具有重要意义。
