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Negative regulation of Armadillo, a Wingless effector in Drosophila
L M Pai1, S Orsulic, A Bejsovec
1Department of Biology and Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill 27599-3280, USA.
Abstract:
Drosophila Armadillo and its vertebrate homolog beta-catenin play essential roles both in the transduction of Wingless/Wnt cell-cell signals and in the function of cell-cell adherens junctions. Wingless and Wnts direct numerous cell fate choices during development. We generated a mutant protein, Armadillo(S10), with a 54 amino acid deletion in its N-terminal domain. This mutant is constitutively active in Wingless signaling; its activity is independent of both Wingless signal and endogenous wild-type Armadillo. Armadillo's role in signal transduction is normally negatively regulated by Zeste-white 3 kinase, which modulates Armadillo protein stability. Armadillo(S10) is more stable than wild-type Armadillo, suggesting that it is less rapidly targeted for degradation. We show that Armadillo(S10) has escaped from negative regulation by Zeste white-3 kinase, and thus accumulates outside junctions even in the absence of Wingless signal. Finally, we present data implicating kinases in addition to Zeste white-3 in Armadillo phosphorylation. We discuss two models for the negative regulation of Armadillo in normal development and discuss how escape from this regulation contributes to tumorigenesis.
Insights
A study on Drosophila Armadillo (a protein crucial for cell signaling and adhesion) identified a mutant protein, Armadillo(S10), that bypasses normal regulatory processes. This discovery sheds light on Wingless/Wnt signaling pathways and potential links to tumorigenesis.
Area of Science:
- Developmental Biology
- Cell Biology
- Molecular Biology
Background:
- Armadillo and beta-catenin are key proteins in Wingless/Wnt signaling and adherens junctions.
- Wingless/Wnt pathways are critical for cell fate determination during development.
Purpose of the Study:
- To investigate the regulatory mechanisms of Armadillo protein in Wingless signaling.
- To characterize a novel mutant protein, Armadillo(S10), with altered signaling activity.
Main Methods:
- Generation of a mutant Armadillo protein (Armadillo(S10)) with an N-terminal deletion.
- Analysis of Armadillo(S10) activity, stability, and localization in Drosophila.
- Investigation of the role of Zeste-white 3 kinase in Armadillo regulation.
Main Results:
- Armadillo(S10) exhibits constitutive Wingless signaling activity, independent of Wingless signal and wild-type Armadillo.
- Armadillo(S10) is more stable than wild-type Armadillo, indicating resistance to degradation.
- Armadillo(S10) accumulates outside junctions due to escaped negative regulation by Zeste-white 3 kinase.
Conclusions:
- Wingless/Wnt signaling is negatively regulated by Zeste-white 3 kinase, affecting Armadillo stability.
- The Armadillo(S10) mutant provides insights into escape from negative regulation, potentially contributing to tumorigenesis.
- Additional kinases may be involved in Armadillo phosphorylation and regulation.