(A) novel function of Drosophila FBW7, Archipelago, in Wnt/Wingless signaling

Abstract

Wnt/Wingless (Wg), as an important signaling molecule, elicits a series of signaling cascades for development and adult homeostasis in all animals. Malfunction of Wnt signaling results in developmental defects such as Tetra-amelia, changes in bone density and stem cell maintenance, and cancers. Wg signaling in responding cells has been extensively studied in last few decades, but the mechanism of Wg secretion and gradient formation by Wg-producing cells is still largely unknown. Here, I demonstrated that a Drosophila E3 ubiquitin ligase FBW7, Archipelago (Ago), is involved in Wg signaling by regulating the extracellular level of Wg. ago exhibited a positive genetic relationship with sol narae (sona) that is also involved in Wg signaling as a Drosophila Disintegrin and Metalloprotease with Thrombospondin motif (ADAMTS). Loss of ago increased the level of extracellular Wg and enhanced the expression level of Wg effector proteins by post-transcriptional manner. Interestingly, knockdown of ago reduced the extracellular level of active Sona that is involved in Wg processing, which may explain why the extracellular level of Wg is increased by the knock-down of ago. Knockdown of ago also caused the loss of shaft in chemosensory bristles, suggesting that ago is involved in Notch (N) signaling. Consistent with this, knockdown of ago reduced the level of Cut (Ct) at the dorso-ventral boundary of the 3rd wing imaginal disc, and overexpression of ago dramatically increased the level of Ct. Taken together, Ago regulates not only Wnt/Wg secretion and signaling but also N signaling. Further studies on Ago will help understanding the role of Ago in normal development and diseases.