The GTPase regulatory proteins Pix and Git control tissue growth via the Hippo pathway.
The GTPase regulatory proteins Pix and Git control tissue growth via the Hippo pathway.
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DOI：
10.1016/j.cub.2014.11.041
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发表时间：
2015-01-05
期刊：
影响因子：
--
通讯作者：
Harvey KF
中科院分区：
文献类型：
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作者：
Dent LG;Poon CL;Zhang X;Degoutin JL;Tipping M;Veraksa A;Harvey KF
萨尔瓦多-沃茨-河马(Hippo)途径是一种保守的器官大小调节因子，在人类癌症中被解除调控。在上皮组织中，河马途径受基本细胞生物学特性的调节，如极性和粘附性，并与组织生长相协调。尽管河马在疾病、发育和再生方面很重要，但调节河马信号的一整套蛋白质仍然不确定。为了解决这个问题，我们使用蛋白质组学来鉴定与河马(Hpo)激酶结合的蛋白质。其中最突出的是PAK相互作用交换因子(称为Pix或Rtgef)和G蛋白偶联受体激酶相互作用蛋白(Git)。PIX是哺乳动物中与β-PIX和Alpha-PIX同源的一种保守的Rho-型鸟嘌呤核苷酸交换因子。Git是哺乳动物GIT1和GIT2蛋白的单一黑腹葡萄球菌同源物，最初是在寻找与G蛋白偶联受体激酶相互作用的分子时发现的。PIX和Git形成一个寡聚的支架，促进无菌的20-样激酶的激活，也与GTP酶的调节有关。我们表明，Pix和Git调节黑腹果蝇中依赖河马途径的组织生长，并且它们与已知的上游调节因子Fat cadherin平行地调节这一过程。PIX和Git通过作为支架复合体而不是酶来影响Hpo激酶的活性，并促进Hpo激活环的Hpo二聚化和自动磷酸化。因此，我们为控制后生动物组织生长的古老信号网络提供了重要的新见解。
The Salvador-Warts-Hippo (Hippo) pathway is a conserved regulator of organ size and is deregulated in human cancers. In epithelial tissues, the Hippo pathway is regulated by fundamental cell biological properties, such as polarity and adhesion, and coordinates these with tissue growth. Despite its importance in disease, development and regeneration, the complete set of proteins that regulate Hippo signalling remain undefined. To address this, we used proteomics to identify proteins that bind to the Hippo (Hpo) kinase. Prominent among these were PAK-interacting exchange factor (known as Pix or RtGEF) and G-protein-coupled receptor kinase interacting protein (Git). Pix is a conserved Rho-type guanine nucleotide exchange factor (Rho-GEF) homologous to Beta-PIX and Alpha-PIX in mammals. Git is the single D. melanogaster homologue of the mammalian GIT1 and GIT2 proteins, which were originally identified in the search for molecules that interact with G-Protein-coupled receptor kinases. Pix and Git form an oligomeric scaffold to facilitate sterile 20-like kinase activation and have also been linked to GTPase regulation. We show that Pix and Git regulate Hippo pathway-dependent tissue growth in Drosophila melanogaster, and that they do this in parallel to the known upstream regulator Fat cadherin. Pix and Git influence activity of the Hpo kinase by acting as a scaffold complex, rather than enzymes, and promote Hpo dimerization and autophosphorylation of Hpo’s activation loop. Therefore, we provide important new insights into an ancient signalling network that controls the growth of metazoan tissues.
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