Protection of Armadillo/β-Catenin by Armless, a Novel Positive Regulator of Wingless Signaling
| Autor: | Konrad Basler, Gerlinde Reim, Martina Hruzova, Sandra Goetze |
|---|---|
| Přispěvatelé: | University of Zurich, Basler, Konrad |
| Rok vydání: | 2014 |
| Předmět: |
Cellular differentiation
Autophagy-Related Proteins Cell Cycle Proteins 0302 clinical medicine Valosin Containing Protein 2400 General Immunology and Microbiology Drosophila Proteins Wings Animal Biology (General) beta Catenin 0303 health sciences integumentary system Receptors Notch biology General Neuroscience Intracellular Signaling Peptides and Proteins Wnt signaling pathway 2800 General Neuroscience Gene Expression Regulation Developmental 10124 Institute of Molecular Life Sciences Hedgehog signaling pathway 3. Good health Cell biology Ubiquitin ligase embryonic structures Drosophila Signal transduction General Agricultural and Biological Sciences Research Article animal structures Beta-catenin QH301-705.5 Ubiquitin-Protein Ligases Notch signaling pathway 1100 General Agricultural and Biological Sciences Wnt1 Protein General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 1300 General Biochemistry Genetics and Molecular Biology Animals Humans Hedgehog Proteins Adaptor Proteins Signal Transducing 030304 developmental biology Armadillo Domain Proteins General Immunology and Microbiology fungi Biology and Life Sciences Wnt Proteins Adaptor Proteins Vesicular Transport HEK293 Cells Catenin biology.protein 570 Life sciences Carrier Proteins 030217 neurology & neurosurgery Transcription Factors |
| Zdroj: | PLoS Biology PLoS Biology, Vol 12, Iss 11, p e1001988 (2014) |
| ISSN: | 1545-7885 |
| DOI: | 10.1371/journal.pbio.1001988 |
| Popis: | This study uses an RNAi screen in Drosophila to identify a UBX protein, Armless, as a novel positive regulator of the important Wingless/Wnt signaling pathway, acting to stabilize Armadillo/?-Catenin by antagonizing its turnover. The Wingless (Wg/Wnt) signaling pathway is essential for metazoan development, where it is central to tissue growth and cellular differentiation. Deregulated Wg pathway activation underlies severe developmental abnormalities, as well as carcinogenesis. Armadillo/β-Catenin plays a key role in the Wg transduction cascade; its cytoplasmic and nuclear levels directly determine the output activity of Wg signaling and are thus tightly controlled. In all current models, once Arm is targeted for degradation by the Arm/β-Catenin destruction complex, its fate is viewed as set. We identified a novel Wg/Wnt pathway component, Armless (Als), which is required for Wg target gene expression in a cell-autonomous manner. We found by genetic and biochemical analyses that Als functions downstream of the destruction complex, at the level of the SCF/Slimb/βTRCP E3 Ub ligase. In the absence of Als, Arm levels are severely reduced. We show by biochemical and in vivo studies that Als interacts directly with Ter94, an AAA ATPase known to associate with E3 ligases and to drive protein turnover. We suggest that Als antagonizes Ter94's positive effect on E3 ligase function and propose that Als promotes Wg signaling by rescuing Arm from proteolytic degradation, spotlighting an unexpected step where the Wg pathway signal is modulated. Author Summary The 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. |
| Databáze: | OpenAIRE |
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