Identification of ICAT as an APC Inhibitor, Revealing Wnt-Dependent Inhibition of APC-Axin Interaction
Identification of ICAT as an APC Inhibitor, Revealing Wnt-Dependent Inhibition of APC-Axin Interaction
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DOI：
10.1016/j.molcel.2018.07.040
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发表时间：
2018-10-04
期刊：
影响因子：
16
通讯作者：
Cong, Feng
中科院分区：
文献类型：
--
作者：
Ji, Lei;Lu, Bo;Cong, Feng
腺瘤性结肠息肉病（APC）和Axin是β-连环蛋白破坏复合体的核心成分。APC的功能是如何调节的，Wnt信号是否影响APC-Axin的直接相互作用以抑制β-连环蛋白破坏复合物尚不清楚。通过对β-连环蛋白稳定性的CRISPR筛选，我们已经将ICAT（一种先前已知阻断β-连环蛋白-TCF相互作用的多肽）鉴定为APC的天然抑制剂。ICAT阻断β-连环蛋白-APC相互作用并阻止β-连环蛋白介导的APC-Axin相互作用，增强了携带截短的APC或用Wnt刺激的细胞中的β-连环蛋白的稳定性，但在剥夺Wnt信号的细胞中不稳定。使用ICAT作为一种工具，脱离β-连环蛋白介导的APC-Axin相互作用，我们证明，Wnt迅速抑制APC和Axin之间的直接相互作用。我们的研究突出了β-连环蛋白在破坏复合物组装中的重要支架功能，并表明Wnt抑制的APC-Axin相互作用是Wnt依赖性抑制破坏复合物的机制。
Adenomatous polyposis coli (APC) and Axin are core components of the beta-catenin destruction complex. How APC's function is regulated and whether Wnt signaling influences the direct APC-Axin interaction to inhibit the beta-catenin destruction complex is not clear. Through a CRISPR screen of beta-catenin stability, we have identified ICAT, a polypeptide previously known to block beta-catenin-TCF interaction, as a natural inhibitor of APC. ICAT blocks beta-catenin-APC interaction and prevents beta-caten in-mediated APC-Axin interaction, enhancing stabilization of beta-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 beta-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 beta-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.