Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China.
Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China.
Cell Rep. 2018 Jul 17;24(3):546-556. doi: 10.1016/j.celrep.2018.06.087.
The key mitotic regulator Polo-like kinase 1 (Plk1) is activated during G2 phase by Aurora A kinase (AurkA)-mediated phosphorylation of its activation loop, which is important for timely mitotic entry. The mechanism for Plk1 activation remains incompletely understood. Here, we report that the activation of Plk1 requires WAC, a WW domain-containing adaptor protein with a coiled-coil region that predominantly localizes to the nucleus in interphase. Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1. Knockdown of WAC compromises Plk1 activity and delays mitotic entry. These defects are rescued by exogenous expression of wild-type WAC, but not the Plk1-binding-deficient mutant. WAC also binds AurkA and can enhance Plk1 phosphorylation by AurkA in vitro. Taken together, these results indicate an important role for WAC in promoting Plk1 activation and the timely entry into mitosis.
关键的有丝分裂调控因子 Polo 样激酶 1（Plk1）在 G2 期被 Aurora A 激酶（AurkA）介导的激活环磷酸化激活，这对于及时进入有丝分裂至关重要。Plk1 的激活机制仍不完全清楚。在这里，我们报告说，Plk1 的激活需要 WAC，这是一种含有 WW 结构域的衔接蛋白，具有卷曲螺旋区，在间期主要定位于核内。细胞周期蛋白依赖性激酶 1（Cdk1）磷酸化 WAC，使其与 Plk1 的 polo 盒结构域直接相互作用。WAC 的敲低会损害 Plk1 的活性并延迟有丝分裂的进入。这些缺陷可以通过外源性表达野生型 WAC 得到挽救，但不能通过缺乏 Plk1 结合的突变体来挽救。WAC 还可以与 AurkA 结合，并可以增强 AurkA 在体外对 Plk1 的磷酸化。总之，这些结果表明 WAC 在促进 Plk1 激活和及时进入有丝分裂中起着重要作用。
