David H. Koch Institute for Integrative Cancer Research, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, United States.
Yale Cancer Biology Institute, Department of Pharmacology, Yale University, West Haven, United States.
Elife. 2021 Jan 22;10:e63645. doi: 10.7554/eLife.63645.
In budding yeast, the mitotic exit network (MEN), a GTPase signaling cascade, integrates spatial and temporal cues to promote exit from mitosis. This signal integration requires transmission of a signal generated on the cytoplasmic face of spindle pole bodies (SPBs; yeast equivalent of centrosomes) to the nucleolus, where the MEN effector protein Cdc14 resides. Here, we show that the MEN activating signal at SPBs is relayed to Cdc14 in the nucleolus through the dynamic localization of its terminal kinase complex Dbf2-Mob1. Cdc15, the protein kinase that activates Dbf2-Mob1 at SPBs, also regulates its nuclear access. Once in the nucleus, priming phosphorylation of Cfi1/Net1, the nucleolar anchor of Cdc14, by the Polo-like kinase Cdc5 targets Dbf2-Mob1 to the nucleolus. Nucleolar Dbf2-Mob1 then phosphorylates Cfi1/Net1 and Cdc14, activating Cdc14. The kinase-primed transmission of the MEN signal from the cytoplasm to the nucleolus exemplifies how signaling cascades can bridge distant inputs and responses.
在芽殖酵母中，有丝分裂退出网络（MEN），即一种 GTPase 信号级联反应，整合了时空线索，以促进有丝分裂的退出。这种信号整合需要将在纺锤体极体（SPB；酵母中心体的等价物）细胞质面产生的信号传递到核仁，MEN 效应蛋白 Cdc14 就位于核仁中。在这里，我们表明通过其末端激酶复合物 Dbf2-Mob1 的动态定位，SPB 上的 MEN 激活信号通过核仁中转导到 Cdc14。Cdc15 是在 SPB 上激活 Dbf2-Mob1 的蛋白激酶，它也调节 Dbf2-Mob1 的核内进入。一旦进入细胞核，Polo 样激酶 Cdc5 对 Cfi1/Net1（Cdc14 的核仁锚定位点）的初步磷酸化，将 Dbf2-Mob1 靶向核仁。核仁中的 Dbf2-Mob1 然后磷酸化 Cfi1/Net1 和 Cdc14，激活 Cdc14。从细胞质到核仁的 MEN 信号的激酶引发传递，就是信号级联如何连接远距离输入和反应的一个例子。
