Abstract
Author SummaryThe Wg/Wnt signaling pathway, found in most animals, is essential for regulating tissue growth and the formation of different cell types during development. Defects in the Wg/Wnt signaling relay can have serious consequences, ranging from aberrant organ patterning to malignant tumor formation. A pivotal step in the transmission of the Wg/Wnt signal is the stabilization of the protein Armadillo/β-Catenin, a key component of the pathway. However, the means by which the levels of this protein are regulated remain unclear. Here, we describe a novel control point of Armadillo/β-Catenin levels. Using RNA interference, we performed a screen in the fruit fly Drosophila melanogaster and identified Armless, a protein whose biological function was previously unknown, as a novel regulator of Wg/Wnt signaling, essential for the Wg/Wnt-dependent expression of downstream target genes. Our experiments suggest that Armless interferes with the tagging of Armadillo/β-Catenin with ubiquitin, thereby sparing it from proteasomal degradation. We also show that Armless directly interacts in vivo with Ter94, a ubiquitous ATPase involved in protein turnover. Our results suggest that Armless antagonizes Ter94's function in protein turnover, thereby acting as a positive regulator of Wg/Wnt signaling by promoting the stabilization of Armadillo/β-Catenin.
Highlights
The wingless gene was found nearly forty years ago with the characterization of a Drosophila mutant without wings [1]
When Wg/Wnt binds its receptors at the cell membrane, degradation of Arm/bCatenin is prevented, presumably by protein interactions that lead to the dissociation of the E3 ubiquitin ligase from the Arm/bCatenin destruction complex [5]
Our experiments suggest that Armless interferes with the tagging of Armadillo/bCatenin with ubiquitin, thereby sparing it from proteasomal degradation
Summary
The wingless (wg) gene was found nearly forty years ago with the characterization of a Drosophila mutant without wings [1]. A multiprotein complex consisting of the scaffold proteins Axin and APC and the kinases Shaggy/GSK3b and Casein kinase I (CKI) recruits and phosphorylates Arm/bCatenin. This marks Arm/b-Catenin for ubiquitination by the SCF/Slimb/bTRCP E3 ubiquitin ligase and subsequent degradation by the ubiquitin-proteasome system (UPS). Arm/bCatenin translocates into the nucleus, where it adopts its role as a transcriptional effector of Wg/Wnt signaling. This step is crucial, and is a potential point of regulation, little is known about the players involved in the processing of Arm/b-Catenin and its ultimate degradation
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