Chan Chih-Chiang, Zhang Shu, Cagatay Tolga, Wharton Keith A
Laboratory of Molecular Pathology, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9072, USA.
Dev Biol. 2007 Nov 15;311(2):538-53. doi: 10.1016/j.ydbio.2007.09.002. Epub 2007 Sep 15.
Robust animal development, tissue homeostasis, and stem cell renewal requires precise control of the Wnt/beta-catenin signaling axis. In the embryo of the fruit fly Drosophila melanogaster, the naked cuticle (nkd) gene attenuates signaling by the Wnt ligand Wingless (Wg) during segmentation. nkd mutants have been reported to exhibit abnormalities in wg transcription, Wg protein distribution and/or transport, and the intracellular response to Wg, but the relationship between each alteration and the molecular mechanism of Nkd action remains unclear. In addition, whether Nkd acts in a cell-autonomous or nonautonomous fashion in the embryo is not known. Mammalian Nkd homologs have N-terminal consensus sequences that direct the post-translational addition of a lipophilic myristoyl moiety, but fly and mosquito Nkd, while sharing N-terminal sequence homology, lack a myristoylation consensus sequence. Here we provide evidence that fly Nkd acts cell-autonomously in the embryo, with its N-terminus able to confer unique functional properties and membrane association that cannot be mimicked in vivo by heterologous myristoylation consensus sequences. In conjunction with our recent observation that Nkd requires nuclear localization for function, our data suggest that Nkd acts at more than one subcellular location within signal-receiving cells to attenuate Wg signaling.
稳健的动物发育、组织稳态和干细胞更新需要对Wnt/β-连环蛋白信号轴进行精确调控。在果蝇黑腹果蝇的胚胎中，裸表皮（nkd）基因在体节形成过程中减弱Wnt配体无翅（Wg）的信号传导。据报道，nkd突变体在wg转录、Wg蛋白分布和/或运输以及对Wg的细胞内反应方面表现出异常，但每种改变与Nkd作用的分子机制之间的关系仍不清楚。此外，Nkd在胚胎中是以细胞自主还是非自主方式发挥作用尚不清楚。哺乳动物的Nkd同源物具有N端共有序列，可指导翻译后添加亲脂性肉豆蔻酰基部分，但果蝇和蚊子的Nkd虽然具有N端序列同源性，但缺乏肉豆蔻酰化共有序列。在这里，我们提供证据表明果蝇Nkd在胚胎中以细胞自主方式发挥作用，其N端能够赋予独特的功能特性和膜结合能力，而异源肉豆蔻酰化共有序列在体内无法模拟这些特性。结合我们最近观察到的Nkd需要核定位才能发挥功能，我们的数据表明Nkd在信号接收细胞内的多个亚细胞位置发挥作用，以减弱Wg信号传导。
