Division of Life Science and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China.
Shenzhen Key Laboratory of Edible and Medicinal Bioresources, HKUST Shenzhen Research Institute, Shenzhen, China.
J Cell Biol. 2020 May 4;219(5). doi: 10.1083/jcb.201909094.
Centrosome disjunction occurs in late G2 to facilitate bipolar spindle formation and is mediated by the NIMA-related kinase Nek2. Here, we show that GAS2L1, a microtubule- and F-actin-binding protein required for centrosome disjunction, undergoes Nek2-mediated phosphorylation at Ser352 in G2/M. The phosphorylation is essential for centrosome disjunction in late G2 and for proper spindle assembly and faithful chromosome segregation in mitosis. GAS2L1 contains a calponin-homology (CH) domain and a GAS2-related (GAR) domain, which bind to F-actin and microtubules, respectively. Notably, the CH and GAR domains bind to each other to inhibit the functions of both domains, and Ser352 phosphorylation disrupts the interaction between the two domains and relieves the autoinhibition. We dissected the roles of the GAS2L1 phosphorylation and of centrosome-linker disassembly, which is another Nek2-mediated event, and found that these events together trigger centrosome disjunction. Therefore, our findings demonstrate the concerted Nek2 actions that split the centrosomes in late G2.
中心体分离发生在 G2 晚期，以促进两极纺锤体的形成，这一过程由 NIMA 相关激酶 Nek2 介导。在这里，我们表明，GAS2L1 是一种微管和 F-肌动蛋白结合蛋白，对于中心体分离是必需的，它在 G2/M 期经历 Nek2 介导的丝氨酸 352 磷酸化。这种磷酸化对于 G2 晚期的中心体分离以及有丝分裂中纺锤体的正确组装和染色体的正确分离是必不可少的。GAS2L1 含有钙调蛋白同源（CH）结构域和 GAS2 相关（GAR）结构域，分别与 F-肌动蛋白和微管结合。值得注意的是，CH 和 GAR 结构域相互结合，抑制两个结构域的功能，而丝氨酸 352 磷酸化破坏了两个结构域之间的相互作用，并解除了自动抑制。我们剖析了 GAS2L1 磷酸化和中心体连接体解聚的作用，这是另一个由 Nek2 介导的事件，发现这两个事件共同触发了中心体分离。因此，我们的发现表明 Nek2 在 G2 晚期协同作用分裂中心体。
