Structural and Functional Characterization of the Wnt Inhibitor APC Membrane Recruitment 1 (Amer1)
Structural and Functional Characterization of the Wnt Inhibitor APC Membrane Recruitment 1 (Amer1)
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DOI：
10.1074/jbc.m111.224881
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发表时间：
2011-06-03
影响因子：
4.8
通讯作者：
Behrens, Juergen
中科院分区：
文献类型：
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作者：
Tanneberger, Kristina;Pfister, Astrid S.;Behrens, Juergen
Amer 1/WTX与肿瘤抑制基因腺瘤性息肉病大肠杆菌结合，通过诱导β-连环蛋白降解作为Wnt信号传导的抑制剂。我们在这里显示，Amer 1直接相互作用的β-连环蛋白的犰狳重复通过一个结构域组成的重复精氨酸-谷氨酸-丙氨酸（REA）的基序，Amer 1组装的β-连环蛋白破坏复合物在质膜招募β-连环蛋白，腺瘤性结肠息肉病，和轴蛋白/传导。Amer 1的膜结合结构域的缺失或特异性突变消除了其膜定位并废除了Wnt信号传导的负控制，这可以通过人工靶向Amer 1至质膜来恢复。与此同时，缺乏质膜定位结构域的Amer 1的天然剪接变体缺乏Wnt抑制。敲除Amer 1导致Wnt靶基因的激活，与稀疏细胞培养物相比，优先在密集细胞中，这表明Amer 1功能受细胞接触调节。Amer 1稳定Axin并抵消Wnt诱导的Axin降解，这需要Amer 1的膜定位。这些数据表明，Amer 1发挥其负调控作用的Wnt信号作为一个支架蛋白的β-连环蛋白破坏复合物和促进稳定的轴蛋白在质膜。
Amer1/WTX binds to the tumor suppressor adenomatous polyposis coli and acts as an inhibitor of Wnt signaling by inducing beta-catenin degradation. We show here that Amer1 directly interacts with the armadillo repeats of beta-catenin via a domain consisting of repeated arginine-glutamic acid-alanine (REA) motifs, and that Amer1 assembles the beta-catenin destruction complex at the plasma membrane by recruiting beta-catenin, adenomatous polyposis coli, and Axin/Conductin. Deletion or specific mutations of the membrane binding domain of Amer1 abolish its membrane localization and abrogate negative control of Wnt signaling, which can be restored by artificial targeting of Amer1 to the plasma membrane. In line, a natural splice variant of Amer1 lacking the plasma membrane localization domain is deficient for Wnt inhibition. Knockdown of Amer1 leads to the activation of Wnt target genes, preferentially in dense compared with sparse cell cultures, suggesting that Amer1 function is regulated by cell contacts. Amer1 stabilizes Axin and counteracts Wnt-induced degradation of Axin, which requires membrane localization of Amer1. The data suggest that Amer1 exerts its negative regulatory role in Wnt signaling by acting as a scaffold protein for the beta-catenin destruction complex and promoting stabilization of Axin at the plasma membrane.