糖原合酶激酶3β与DF3/MUC1癌相关抗原及β-连环蛋白的相互作用。
Interaction of glycogen synthase kinase 3beta with the DF3/MUC1 carcinoma-associated antigen and beta-catenin.
作者信息
Li Y, Bharti A, Chen D, Gong J, Kufe D
机构信息
Cancer Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
出版信息
Mol Cell Biol. 1998 Dec;18(12):7216-24. doi: 10.1128/MCB.18.12.7216.
The DF3/MUC1 mucin-like glycoprotein is highly overexpressed in human carcinomas. Recent studies have demonstrated that the cytoplasmic domain of MUC1 interacts with beta-catenin. Here we show that MUC1 associates with glycogen synthase kinase 3beta (GSK3beta). GSK3beta binds directly to an STDRSPYE site in MUC1 and phosphorylates the serine adjacent to proline. Phosphorylation of MUC1 by GSK3beta decreases binding of MUC1 to beta-catenin in vitro and in vivo. GSK3beta-mediated phosphorylation of MUC1 had no apparent effect on beta-catenin levels or the transcriptional coactivation function of beta-catenin. The results, however, demonstrate that MUC1 expression decreases binding of beta-catenin to the E-cadherin cell adhesion molecule. Negative regulation of the beta-catenin-MUC1 interaction by GSK3beta is associated with restoration of the complex between beta-catenin and E-cadherin. These findings indicate that GSK3beta decreases the interaction of MUC1 with beta-catenin and that overexpression of MUC1 in the absence of GSK3beta activity inhibits formation of the E-cadherin-beta-catenin complex.
DF3/MUC1 黏蛋白样糖蛋白在人类癌症中高度过表达。最近的研究表明，MUC1 的细胞质结构域与 β-连环蛋白相互作用。在此我们发现 MUC1 与糖原合酶激酶 3β（GSK3β）相关联。GSK3β 直接结合到 MUC1 中的 STDRSPYE 位点，并使脯氨酸相邻的丝氨酸磷酸化。GSK3β 对 MUC1 的磷酸化在体外和体内均降低了 MUC1 与 β-连环蛋白的结合。GSK3β 介导的 MUC1 磷酸化对 β-连环蛋白水平或 β-连环蛋白的转录共激活功能没有明显影响。然而，结果表明 MUC1 的表达降低了 β-连环蛋白与 E-钙黏蛋白细胞黏附分子的结合。GSK3β 对 β-连环蛋白-MUC1 相互作用的负调控与 β-连环蛋白和 E-钙黏蛋白之间复合物的恢复相关。这些发现表明 GSK3β 减少了 MUC1 与 β-连环蛋白的相互作用，并且在缺乏 GSK3β 活性的情况下 MUC1 的过表达抑制了 E-钙黏蛋白-β-连环蛋白复合物的形成。
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