Self-association of the APC tumor suppressor is required for the assembly, stability, and activity of the Wnt signaling destruction complex.
Self-association of the APC tumor suppressor is required for the assembly, stability, and activity of the Wnt signaling destruction complex.
复制标题
DOI：
10.1091/mbc.e14-04-0885
复制
发表时间：
2014-11-01
影响因子：
3.3
通讯作者：
McCartney BM
中科院分区：
文献类型：
--
作者：
Kunttas-Tatli E;Roberts DM;McCartney BM
结肠癌肿瘤抑制性腺瘤性息肉病 (APC) 通过与 β-连环蛋白结合并促进其磷酸化和降解，负向调节 β-连环蛋白破坏复合物中的 Wnt 信号传导。 APC 自缔合在破坏复合物的组装、稳定性和活性中起着不可或缺的作用。肿瘤抑制性腺瘤性息肉病大肠杆菌 (APC) 通过其与 Axin、GSK3β 和 CK1 的破坏复合物的活性，成为 Wnt 信号传导的重要负调节因子，该复合物以 β-连环蛋白/犰狳 (β-cat/Arm) 为目标进行蛋白酶体降解。破坏复合物形成大分子颗粒，我们称之为破坏体。尽管 APC 通过其结合 β-cat 和 Axin 的能力在复合物中发挥作用，但我们假设 APC 蛋白通过自缔合在破坏体组装中发挥额外作用。在这里，我们展示了在脊椎动物和无脊椎动物 APC 中发现的一种新型 N 端线圈，即 APC 自关联结构域 (ASAD)，它直接介导果蝇 APC2 的自关联，并在调节果蝇和人类细胞中 β-cat 降解的破坏体的组装和稳定性中发挥重要作用。与此一致的是，从果蝇胚胎中去除 ASAD 会导致 β-cat/Arm 积累和异常的 Wnt 通路激活。这些结果表明，APC 蛋白不仅是破坏体活性所必需的，而且也是这种大分子机器的组装和稳定性所必需的。
The colon cancer tumor suppressor adenomatous polyposis coli (APC) negatively regulates Wnt signaling in the β-catenin destruction complex by binding to β-catenin and facilitating its phosphorylation and degradation. APC self-association plays an integral role in the assembly, stability, and activity of the destruction complex. The tumor suppressor adenomatous polyposis coli (APC) is an essential negative regulator of Wnt signaling through its activity in the destruction complex with Axin, GSK3β, and CK1 that targets β-catenin/Armadillo (β-cat/Arm) for proteosomal degradation. The destruction complex forms macromolecular particles we termed the destructosome. Whereas APC functions in the complex through its ability to bind both β-cat and Axin, we hypothesize that APC proteins play an additional role in destructosome assembly through self-association. Here we show that a novel N-terminal coil, the APC self-association domain (ASAD), found in vertebrate and invertebrate APCs, directly mediates self-association of Drosophila APC2 and plays an essential role in the assembly and stability of the destructosome that regulates β-cat degradation in Drosophila and human cells. Consistent with this, removal of the ASAD from the Drosophila embryo results in β-cat/Arm accumulation and aberrant Wnt pathway activation. These results suggest that APC proteins are required not only for the activity of the destructosome, but also for the assembly and stability of this macromolecular machine.