Evolutionary and Molecular Facts Link the WWC Protein Family to Hippo Signaling
Evolutionary and Molecular Facts Link the WWC Protein Family to Hippo Signaling
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DOI：
10.1093/molbev/msu115
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发表时间：
2014-07-01
影响因子：
10.7
通讯作者：
Kremerskothen, Joachim
中科院分区：
文献类型：
--
作者：
Wennmann, Dirk Oliver;Schmitz, Juergen;Kremerskothen, Joachim
支架蛋白 KIBRA（也称为 WWC1）参与重要细胞内转运过程的调节和细胞极性的建立。此外，KIBRA/WWC1 是 Hippo 信号通路的上游调节因子，控制动物的细胞增殖和器官大小。 KIBRA/WWC1 仅代表 WWC 蛋白家族的一个成员，该家族还包括高度相似的蛋白 WWC2 和 WWC3。尽管 KIBRA/WWC1 的功能在细胞和动物模型中得到了深入研究，但 WWC2 和 WWC3 的重要性尚未阐明。在这里，我们描述了 WWC 家族的进化、分子和功能方面。我们表明，WWC 基因起源于双侧动物（昆虫和脊椎动物等进化枝）的祖先，其起源于与现有果蝇 KIBRA/WWC1 样序列最相似的单个创始基因。这种情况一直维持到文昌鱼和脊椎动物的共同祖先出现。在鱼类中，哺乳动物 KIBRA/WWC1 和 WWC2 的类祖序列与 WWC3 一起表达。最后，在所有四足动物中，除了小家鼠中包括WWC3在内的大基因组缺失之外，还发现了三个家族成员KIBRA/WWC1、WWC2和WWC3。在分子水平上，高度保守的WWC蛋白具有相似的一级结构、形成同二聚体和异二聚体的能力以及与一组常见结合蛋白的相互作用。此外，由于 Hippo 途径的主要效应子 YAP 的转录活性受到抑制，所有 WWC 蛋白都会负向调节细胞增殖和器官生长。
The scaffolding protein KIBRA (also called WWC1) is involved in the regulation of important intracellular transport processes and the establishment of cell polarity. Furthermore, KIBRA/WWC1 is an upstream regulator of the Hippo signaling pathway that controls cell proliferation and organ size in animals. KIBRA/WWC1 represents only one member of the WWC protein family that also includes the highly similar proteins WWC2 and WWC3. Although the function of KIBRA/WWC1 was studied intensively in cells and animal models, the importance of WWC2 and WWC3 was not yet elucidated. Here, we describe evolutionary, molecular, and functional aspects of the WWC family. We show that the WWC genes arose in the ancestor of bilateral animals (clades such as insects and vertebrates) from a single founder gene most similar to the present KIBRA/WWC1-like sequence of Drosophila. This situation was still maintained until the common ancestor of lancelet and vertebrates. In fish, a progenitor-like sequence of mammalian KIBRA/WWC1 and WWC2 is expressed together with WWC3. Finally, in all tetrapods, the three family members, KIBRA/WWC1, WWC2, and WWC3, are found, except for a large genomic deletion including WWC3 in Mus musculus. At the molecular level, the highly conserved WWC proteins share a similar primary structure, the ability to form homo- and heterodimers and the interaction with a common set of binding proteins. Furthermore, all WWC proteins negatively regulate cell proliferation and organ growth due to a suppression of the transcriptional activity of YAP, the major effector of the Hippo pathway.