A genome-wide screen identifies conserved protein hubs required for cadherin-mediated cell–cell adhesion

作者：Christopher P. Toret, Michael V. D’Ambrosio, Ronald D. Vale, Michael A. Simon, William James Nelson · 发表于：The Journal of Cell Biology · 年份：2014 · DOI：10.1083/jcb.201306082 · 被引用次数：47 · 研究领域：Cellular Mechanics and Interactions、Wnt/β-catenin signaling in development and cancer、Hippo pathway signaling and YAP/TAZ

Cadherins and associated catenins provide an important structural interface between neighboring cells, the actin cytoskeleton, and intracellular signaling pathways in a variety of cell types throughout the Metazoa. However, the full inventory of the proteins and pathways required for cadherin-mediated adhesion has not been established. To this end, we completed a genome-wide (~14,000 genes) ribonucleic acid interference (RNAi) screen that targeted Ca(2+)-dependent adhesion in DE-cadherin-expressing Drosophila melanogaster S2 cells in suspension culture. This novel screen eliminated Ca(2+)-independent cell-cell adhesion, integrin-based adhesion, cell spreading, and cell migration. We identified 17 interconnected regulatory hubs, based on protein functions and protein-protein interactions that regulate the levels of the core cadherin-catenin complex and coordinate cadherin-mediated cell-cell adhesion. Representative proteins from these hubs were analyzed further in Drosophila oogenesis, using targeted germline RNAi, and adhesion was analyzed in Madin-Darby canine kidney mammalian epithelial cell-cell adhesion. These experiments reveal roles for a diversity of cellular pathways that are required for cadherin function in Metazoa, including cytoskeleton organization, cell-substrate interactions, and nuclear and cytoplasmic signaling.