Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA.
Department of Biological Structure, University of Washington, Seattle, Washington 98195, USA.
Mol Cell. 2018 Oct 4;72(1):37-47.e4. doi: 10.1016/j.molcel.2018.07.040. Epub 2018 Sep 6.
Adenomatous polyposis coli (APC) and Axin are core components of the β-catenin destruction complex. How APC's function is regulated and whether Wnt signaling influences the direct APC-Axin interaction to inhibit the β-catenin destruction complex is not clear. Through a CRISPR screen of β-catenin stability, we have identified ICAT, a polypeptide previously known to block β-catenin-TCF interaction, as a natural inhibitor of APC. ICAT blocks β-catenin-APC interaction and prevents β-catenin-mediated APC-Axin interaction, enhancing stabilization of β-catenin in cells harboring truncated APC or stimulated with Wnt, but not in cells deprived of a Wnt signal. Using ICAT as a tool to disengage β-catenin-mediated APC-Axin interaction, we demonstrate that Wnt quickly inhibits the direct interaction between APC and Axin. Our study highlights an important scaffolding function of β-catenin in the assembly of the destruction complex and suggests Wnt-inhibited APC-Axin interaction as a mechanism of Wnt-dependent inhibition of the destruction complex.
腺瘤性结肠息肉病基因（APC）和轴蛋白是β-连环蛋白降解复合物的核心组成部分。APC 的功能如何受到调节，以及 Wnt 信号是否影响 APC-Axin 的直接相互作用以抑制β-连环蛋白降解复合物尚不清楚。通过对β-连环蛋白稳定性的 CRISPR 筛选，我们发现了 ICAT，一种先前已知可阻断β-连环蛋白-TCF 相互作用的多肽，是 APC 的天然抑制剂。ICAT 可阻断β-连环蛋白与 APC 的相互作用，并阻止β-连环蛋白介导的 APC-Axin 相互作用，从而增强了携带 APC 截断或受到 Wnt 刺激的细胞中β-连环蛋白的稳定性，但在缺乏 Wnt 信号的细胞中则不会。我们使用 ICAT 作为工具来解除β-连环蛋白介导的 APC-Axin 相互作用，证明 Wnt 可迅速抑制 APC 和 Axin 之间的直接相互作用。我们的研究强调了β-连环蛋白在组装降解复合物中的重要支架功能，并表明 Wnt 抑制的 APC-Axin 相互作用是 Wnt 依赖性抑制降解复合物的机制之一。
