Pai L M, Orsulic S, Bejsovec A, Peifer M
Department of Biology and Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill 27599-3280, USA.
Development. 1997 Jun;124(11):2255-66. doi: 10.1242/dev.124.11.2255.
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.
果蝇中的犰狳蛋白及其脊椎动物同源物β-连环蛋白，在无翅型/翼状信号通路的转导以及细胞间黏附连接的功能中都发挥着重要作用。无翅型蛋白和翼状信号通路蛋白在发育过程中指导众多细胞命运的选择。我们构建了一种突变蛋白犰狳（S10），其N端结构域缺失了54个氨基酸。这种突变体在无翅型信号通路中具有组成型活性；其活性独立于无翅型信号和内源性野生型犰狳蛋白。犰狳蛋白在信号转导中的作用通常受到Zeste-white 3激酶的负调控，该激酶调节犰狳蛋白的稳定性。犰狳（S10）比野生型犰狳蛋白更稳定，这表明它被靶向降解的速度较慢。我们发现犰狳（S10）已逃脱Zeste white-3激酶的负调控，因此即使在没有无翅型信号的情况下也会在连接点外积累。最后，我们提供的数据表明，除了Zeste white-3激酶外，还有其他激酶参与犰狳蛋白的磷酸化。我们讨论了正常发育过程中犰狳蛋白负调控的两种模型，并讨论了这种调控的逃逸如何导致肿瘤发生。
