Cho Eunjoo, Feng Yongqiang, Rauskolb Cordelia, Maitra Sushmita, Fehon Rick, Irvine Kenneth D
Howard Hughes Medical Institute and Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.
Nat Genet. 2006 Oct;38(10):1142-50. doi: 10.1038/ng1887. Epub 2006 Sep 17.
Recent studies in Drosophila melanogaster of the protocadherins Dachsous and Fat suggest that they act as ligand and receptor, respectively, for an intercellular signaling pathway that influences tissue polarity, growth and gene expression, but the basis for signaling downstream of Fat has remained unclear. Here, we characterize functional relationships among D. melanogaster tumor suppressors and identify the kinases Discs overgrown and Warts as components of a Fat signaling pathway. fat, discs overgrown and warts regulate a common set of downstream genes in multiple tissues. Genetic experiments position the action of discs overgrown upstream of the Fat pathway component dachs, whereas warts acts downstream of dachs. Warts protein coprecipitates with Dachs, and Warts protein levels are influenced by fat, dachs and discs overgrown in vivo, consistent with its placement as a downstream component of the pathway. The tumor suppressors Merlin, expanded, hippo, salvador and mob as tumor suppressor also share multiple Fat pathway phenotypes but regulate Warts activity independently. Our results functionally link what had been four disparate groups of D. melanogaster tumor suppressors, establish a basic framework for Fat signaling from receptor to transcription factor and implicate Warts as an integrator of multiple growth control signals.
近期对黑腹果蝇原钙黏蛋白Dachsous和Fat的研究表明，它们分别作为一种影响组织极性、生长和基因表达的细胞间信号通路的配体和受体，但Fat下游信号传导的基础仍不清楚。在此，我们描述了黑腹果蝇肿瘤抑制因子之间的功能关系，并确定了激酶“盘状过度生长”和“疣”是Fat信号通路的组成部分。fat、“盘状过度生长”和“疣”在多个组织中调节一组共同的下游基因。遗传学实验表明，“盘状过度生长”的作用位于Fat信号通路成分dachs的上游，而“疣”则作用于dachs的下游。“疣”蛋白与Dachs共沉淀，并且“疣”蛋白水平在体内受fat、dachs和“盘状过度生长”的影响，这与其作为该信号通路下游成分的定位一致。肿瘤抑制因子Merlin、expanded、河马、萨尔瓦多和“作为肿瘤抑制因子的mob”也具有多种Fat信号通路表型，但独立调节“疣”的活性。我们的研究结果在功能上联系了黑腹果蝇四组不同的肿瘤抑制因子，建立了从受体到转录因子的Fat信号传导基本框架，并表明“疣”是多种生长控制信号的整合者。
