Negative regulation of Armadillo, a Wingless effector in Drosophila.
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.
Pai
L M
LM
Department of Biology and Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill 27599-3280, USA.
Orsulic
S
S
Bejsovec
A
A
Peifer
M
M
D000595:Amino Acid Sequence; D000818:Animals; D051186:Armadillo Domain Proteins; D002448:Cell Adhesion; D002462:Cell Membrane / Q000737:chemistry; D002467:Cell Nucleus / Q000737:chemistry; D003593:Cytoplasm / Q000737:chemistry; D004330:Drosophila / Q000196:embryology*; D029721:Drosophila Proteins; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D038362:Glycogen Synthase Kinase 3; D018398:Homeodomain Proteins / Q000032:analysis; D019476:Insect Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D007365:Intercellular Junctions / Q000737:chemistry; D008969:Molecular Sequence Data; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000502:physiology*; D011993:Recombinant Fusion Proteins; D017384:Sequence Deletion; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators; D014157:Transcription Factors; D051155:Wnt1 Protein
C495305:ARM protein, Drosophila; D051186:Armadillo Domain Proteins; D029721:Drosophila Proteins; D018398:Homeodomain Proteins; D019476:Insect Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051155:Wnt1 Protein; C106185:engrailed homeobox proteins; C074622:wg protein, Drosophila; D017346:Protein Serine-Threonine Kinases; C080335:Sgg protein, Drosophila; D038362:Glycogen Synthase Kinase 3