Cell cycle regulated interaction of a yeast Hippo kinase and its activator MO25/Hym1.
Cell cycle regulated interaction of a yeast Hippo kinase and its activator MO25/Hym1.
复制标题
DOI：
10.1371/journal.pone.0078334
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Weiss EL
中科院分区：
文献类型：
--
作者：
Hsu J;Weiss EL
Hippo信号通路是一种古老的信号系统，在多种真核生物中促进细胞生长和增殖，并已成为后生动物中器官大小控制的保守调节因子。在芽殖酵母中，称为Ace 2和形态发生（RAM）网络调节的Hippo信号通路促进极化细胞生长和母细胞和子细胞分离的最终事件。细胞分离的RAM网络控制的一个关键调控输入是NDR/LATS家族激酶Cbk 1上保守疏水基序（HM）位点的磷酸化。在这里，我们提供了第一个直接的证据表明，河马样激酶Kic 1实际上磷酸化的Cbk 1的HM网站，并表明Kic 1是由Hym 1，一个高度保守的蛋白质相关的哺乳动物MO 25变构激活。利用哺乳动物MO 25的结构与Kic 1相关的假激酶STRAD的复合物，我们确定了Kic 1上的保守残基，需要与Hym 1的相互作用。我们发现Kic 1和Hym 1蛋白水平在整个细胞周期中保持恒定，但蛋白质的关联受到调节，最大相互作用与Cbk 1 HM位点磷酸化峰值一致。我们表明，这种关联是必要的，但不足以磷酸化，这表明需要另一个层次的监管，以促进复杂的作用于其底物。这项工作提出了以前未发现的Hippo激酶和广泛保守的变构激活剂之间的细胞周期调节相互作用。由于该途径在高等真核生物中的保守性，这项工作也可能提供对Hippo信号通路模块化的深入了解。
Hippo pathways are ancient signaling systems that contribute to cell growth and proliferation in a wide diversity of eukaryotes, and have emerged as a conserved regulator of organ size control in metazoans. In budding yeast, a Hippo signaling pathway called the Regulation of Ace2 and Morphogenesis (RAM) network promotes polarized cell growth and the final event in the separation of mother and daughter cells. A crucial regulatory input for RAM network control of cell separation is phosphorylation of a conserved hydrophobic motif (HM) site on the NDR/LATS family kinase Cbk1. Here we provide the first direct evidence that the Hippo-like kinase Kic1 in fact phosphorylates the HM site of Cbk1, and show that Kic1 is allosterically activated by Hym1, a highly conserved protein related to mammalian MO25. Using the structure of mammalian MO25 in complex with the Kic1-related pseudokinase STRAD, we identified conserved residues on Kic1 that are required for interaction with Hym1. We find that Kic1 and Hym1 protein levels remain constant throughout the cell cycle but the proteins’ association is regulated, with maximal interaction coinciding with peak Cbk1 HM site phosphorylation. We show that this association is necessary but not sufficient for this phosphorylation, suggesting another level of regulation is required to promote the complex to act upon its substrates. This work presents a previously undiscovered cell cycle regulated interaction between a Hippo kinase and a broadly conserved allosteric activator. Because of the conserved nature of this pathway in higher eukaryotes, this work may also provide insight into the modularity of Hippo signaling pathways.
登录
查看更多内容
影响因子：
64.5
作者：
Emoto, K;He, Y;Jan, YN
通讯作者：
Jan, YN
影响因子：
2.5
作者：
Bogomolnaya, Lydia M.;Pathak, Ritu;Polymenis, Michael
通讯作者：
Polymenis, Michael
影响因子：
2.7
作者：
Fang X;Adler PN
通讯作者：
Adler PN
影响因子：
64.5
作者：
Harvey, KF;Pfleger, CM;Hariharan, IK
通讯作者：
Hariharan, IK
影响因子：
4.8
作者：
Goshima, Tetsuya;Kume, Kazunori;Hirata, Dai
通讯作者：
Hirata, Dai