Abstract
BackgroundArchipelago (Ago) is a Drosophila homolog of mammalian F-box and WD repeat domain-containing 7 (FBW7, also known as FBXW7). In previous studies, FBW7 has been addressed as a tumor suppressor mediating ubiquitin-dependent proteolysis of several oncogenic proteins. Ubiquitination is a type of protein modification that directs protein for degradation as well as sorting. The level of beta-catenin (β-cat), an intracellular signal transducer in Wnt signaling pathway, is reduced upon overexpression of FBW7 in human cancer cell lines. Loss of function mutations in FBW7 and overactive Wnt signaling have been reported to be responsible for human cancers.ResultsWe found that Ago is important for the formation of shafts in chemosensory bristles at wing margin. This loss of shaft phenotype by knockdown of ago was rescued by knockdown of wingless (wg) whereas wing notching phenotype by knockdown of wg was rescued by knockdown of ago, establishing an antagonistic relationship between ago and wg. In line with this finding, knockdown of ago increased the level of Armadillo (Arm), a homolog of β-cat, in Drosophila tissue. Furthermore, knockdown of ago increased the level of Distal-less (Dll) and extracellular Wg in wing discs. In S2 cells, the amount of secreted Wg was increased by knockdown of Ago but decreased by Ago overexpression. Therefore, Ago plays a previously unidentified role in the inhibition of Wg secretion. Ago-overexpressing clones in wing discs exhibited accumulation of Wg in endoplasmic reticulum (ER), suggesting that Ago prevents Wg protein from moving to Golgi from ER.ConclusionsWe concluded that Ago plays dual roles in inhibiting Wg signaling. First, Ago decreases the level of Arm, by which Wg signaling is downregulated in Wg-responding cells. Second, Ago decreases the level of extracellular Wg by inhibiting movement of Wg from ER to Golgi in Wg-producing cells.
Highlights
Archipelago (Ago) is a Drosophila homolog of mammalian F-box and WD repeat domain-containing 7 (FBW7, known as FBXW7)
Ago is involved in wing growth and formation of chemosensory bristles ago was identified as a modifier of wg in a genetic screen (Nam S., in preparation), which led us to examine the loss of ago phenotypes in the adult wing, a great tool for studying Wg signaling [22]
To modulate the level of Ago in flies, we utilized two UAS-ago lines and two UAS-ago RNAi lines. These two UAS-ago RNAi lines target different regions in the ago gene (Additional file: Fig. S1A). These flies were all obtained from stock centers except for UAS-myc-ago fly that was generated with a pUAS-myc-ago construct in our laboratory (Additional file: Fig. S1B-D)
Summary
Archipelago (Ago) is a Drosophila homolog of mammalian F-box and WD repeat domain-containing 7 (FBW7, known as FBXW7). The level of beta-catenin (β-cat), an intracellular signal transducer in Wnt signaling pathway, is reduced upon overexpression of FBW7 in human cancer cell lines. Loss of function mutations in FBW7 and overactive Wnt signaling have been reported to be responsible for human cancers. Fly Ago is a component of F-box protein in E3 ubiquitin ligase complex, and it recognizes specific substrates such as Myc, Trachealess (Trh), Similar (Sima) and Cyclin E (Cyc E) for ubiquitination [3,4,5,6]. Human FBW7 as a homolog of Ago has over 60 known substrates such as Cyc E, Myc, Jun, Notch and mTOR [7,8,9,10,11]. FBW7 has been considered as a tumor suppressor and is one of the most frequently mutated genes in human cancers [12]
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