Complex formation of adenomatous polyposis coli gene product and Axin facilitates glycogen synthase kinase-3β-dependent phosphorylation of β-catenin and down-regulates β-catenin
Complex formation of adenomatous polyposis coli gene product and Axin facilitates glycogen synthase kinase-3β-dependent phosphorylation of β-catenin and down-regulates β-catenin
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DOI：
10.1074/jbc.m003997200
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发表时间：
2000-11-03
影响因子：
4.8
通讯作者：
Kikuchi, A
中科院分区：
文献类型：
--
作者：
Hinoi, T;Yamamoto, H;Kikuchi, A
腺瘤性息肉病大肠杆菌基因产物（APC）具有肿瘤抑制基因的功能，其在家族性腺瘤性息肉病和结直肠癌中的突变导致细胞质β-连环蛋白的积累。研究了APC调节β-连环蛋白稳定性的分子机制。 APC 的中心区域 APC-(1211-2075) 具有 β-连环蛋白和轴蛋白结合位点并下调 β-连环蛋白。糖原合成酶激酶 3 beta (GSK-3 beta) 在 APC-(1211-2075) 或 Axin(Delta beta-catenin)（其中 β-catenin 结合位点被删除）存在时轻微磷酸化 β-catenin，而在两种蛋白存在时则大大磷酸化。 Axin 的 APC 结合位点消除了 GSK-3 β 依赖性β-连环蛋白磷酸化的增强。 Axin 下调 SW480 细胞中的 β-catenin，但不下调 Axin(Delta beta-catenin)。 APC 完整的 I、L 细胞中，Axin(Delta β-catenin) 抑制 Wnt 依赖性 β-catenin 积累，但不抑制 APC 和 β-catenin 结合位点被删除的 Axin-(298-832)(Delta β-catenin)。这些结果表明，APC和Axin的复合物形成增强了GSK-3β对β-连环蛋白的磷酸化，导致β-连环蛋白的下调。
Adenomatous polyposis coli gene product (APC) functions as a tumor suppressor and its mutations in familial adenomatous polyposis and colorectal cancers lead to the accumulation of cytoplasmic beta -catenin. The molecular mechanism by which APC regulates the stability of beta -catenin was investigated. The central region of APC, APC-(1211-2075), has the beta -catenin- and Axin-binding sites and down-regulates beta -catenin. Glycogen synthase kinase-3 beta (GSK-3 beta) phosphorylated beta -catenin slightly in the presence of either APC-(1211-2075) or Axin(Delta beta -catenin) in which the beta -catenin-binding site is deleted, and greatly in the presence of both proteins. The enhancement of the GSK-3 beta -dependent phosphorylation of beta -catenin was eliminated by the APC-binding site of Axin. Axin down-regulated beta -catenin in SW480 cells, but not Axin(Delta beta -catenin). I, L cells where APC is intact, Axin(Delta beta -catenin) inhibited Wnt-dependent accumulation of beta -catenin but not Axin-(298-832)(Delta beta -catenin) in which the APC- and beta -catenin-binding sites are deleted. These results indicate that the complex formation of APC and Axin enhances the phosphorylation of beta -catenin by GSK-3 beta, leading to the down-regulation of beta -catenin.