Inhibition of β-catenin-mediated transactivation by cadherin derivatives
Inhibition of β-catenin-mediated transactivation by cadherin derivatives
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DOI：
10.1073/pnas.95.26.15339
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发表时间：
1998-12-22
影响因子：
11.1
通讯作者：
Geiger, B
中科院分区：
文献类型：
--
作者：
Sadot, E;Simcha, I;Geiger, B
我们研究了N-钙粘蛋白及其游离或膜锚定胞质结构域对β-连环蛋白水平和定位及其诱导淋巴细胞增强子结合因子1（LEF-1）应答性转录激活的能力的影响。这些钙粘蛋白衍生物与β-连环蛋白形成复合物并保护其免于降解。N-钙粘蛋白引导β-连环蛋白进入粘附连接，嵌合蛋白诱导β-连环蛋白沿着膜弥散分布，而N-钙粘蛋白的胞质结构域与β-连环蛋白共定位于细胞核中。将β-连环蛋白和LEE-1共转染到中国仓鼠卵巢细胞中诱导了LEE-1报告基因的反式激活，该激活被N-钙粘蛋白衍生分子阻断。SW 480细胞中N-钙粘蛋白和白细胞介素2受体/钙粘蛋白嵌合体的表达将β-连环蛋白从细胞核转移到质膜并降低反式激活。N-或E-钙粘蛋白的胞质尾与β-连环蛋白在细胞核中共定位，并通过阻断β-连环蛋白-LEF-1相互作用抑制组成性LEE-1介导的反式激活。此外，N-钙粘蛋白的72个C-末端氨基酸稳定β-连环蛋白并降低其转录激活潜力。这些结果表明，β-连环蛋白结合钙粘蛋白的胞质尾，无论是在膜，或在核中，可以抑制β-连环蛋白的降解，并有效地阻断其反式激活能力。
We studied the effect of N-cadherin, and its free or membrane-anchored cytoplasmic domain, on the level and localization of beta-catenin and on its ability to induce lymphocyte enhancer-binding factor 1 (LEF-1)-responsive transactivation. These cadherin derivatives formed complexes with beta-catenin and protected it from degradation. N-cadherin directed beta-catenin into adherens junctions, and the chimeric protein induced diffuse distribution of beta-catenin along the membrane whereas the cytoplasmic domain of N-cadherin colocalized with beta-catenin in the nucleus. Cotransfection of beta-catenin and LEE-1 into Chinese hamster ovary cells induced transactivation of a LEE-1 reporter, which was blocked by the N-cadherin-derived molecules. Expression of N-cadherin and an interleukin 2 receptor/cadherin chimera in SW480 cells relocated beta-catenin from the nucleus to the plasma membrane and reduced transactivation, The cytoplasmic tails of N- or E-cadherin colocalized with beta-catenin in the nucleus, and suppressed the constitutive LEE-1-mediated transactivation, by blocking beta-catenin-LEF-1 interaction. Moreover, the 72 C-terminal amino acids of N-cadherin stabilized beta-catenin and reduced its transactivation potential. These results indicate that beta-catenin binding to the cadherin cytoplasmic tail either in the membrane, or in the nucleus, can inhibit beta-catenin degradation and efficiently block its transactivation capacity.