By knocking down 14,000 Drosophila genes, Toret et al. uncover 17 control circuits that orchestrate cell–cell adhesion.
Cadherin proteins are the central component of the adherens junctions that connect epithelial cells to one another. Because the junctions are crucial for multicellular organisms, enumerating all of the proteins that organize them has been difficult.
To get around this problem, Toret et al. used Drosophila S2 cells, which are descended from macrophage-like cells and don’t normally form adherens junctions or produce DE-cadherin, the fruit fly version of E-cadherin. The researchers engineered these cells to manufacture DE-cadherin, spurring the cells to adhere to one another. To find out which proteins were essential for these linkages, the team knocked down each Drosophila gene one at a time and gauged the cells’ stickiness.
The researchers pinpointed 378 proteins whose loss dramatically reduced cells’ ability to attach to their neighbors. By comparing these proteins to their human equivalents and tracing their interactions, Toret et al. teased out 17 networks that help control the formation and function of adherens junctions. One of the networks includes proteins that partner with cadherin, such as β-catenin, and another contains proteins that control actin dynamics. To their surprise, the researchers also fingered proteins that promote cell migration, such as elmo and cyfip. One of the largest protein hubs comprised nuclear proteins, some of which alter gene expression.
The researchers confirmed the function of many of these proteins in Drosophila oocytes and in mammalian epithelial cells, indicating that these different cellular pathways have conserved roles in regulating intercellular adhesion.