Adenomatous polyposis coli (APC) membrane recruitment 3, a member of the APC membrane recruitment family of APC-binding proteins, is a positive regulator of Wnt-β-catenin signalling
Adenomatous polyposis coli (APC) membrane recruitment 3, a member of the APC membrane recruitment family of APC-binding proteins, is a positive regulator of Wnt-β-catenin signalling
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DOI：
10.1111/febs.12624
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发表时间：
2014-02-01
期刊：
影响因子：
5.4
通讯作者：
Behrens, Juergen
中科院分区：
文献类型：
--
作者：
Brauburger, Katharina;Akyildiz, Senem;Behrens, Juergen
大肠腺瘤性息肉病（APC）膜募集（Amer）家族蛋白Amer1/Wilms肿瘤基因位于X染色体上，Amer2是APC肿瘤抑制蛋白的结合伴侣，在Wnt信号级联中起负调控作用。到目前为止，人们对这个家族的第三个成员Amer3一无所知。这里我们发现Amer3与APC的犰狳重复结构域结合，类似于Amer1和Amer2。Amer3还与Wnt通路调节因子传导/轴蛋白2结合。此外，我们确定Amer1是Amer3的结合伙伴。Amer1和Amer2通过一个n端膜定位结构域与质膜相连，而Amer3缺乏这个结构域。Amer3定位于上皮细胞的细胞质和细胞核，这依赖于特定的核输入和输出序列。功能上，外源性Amer3增强了β -catenin/ t细胞因子依赖性报告基因的表达，内源性Amer3的敲低降低了结直肠癌细胞中Wnt靶基因的表达。因此，Amer3作为Wnt信号传导的激活剂，而Amer1和Amer2作为抑制剂，这表明Amer蛋白在这一途径的调节中具有非冗余作用。我们的数据，连同那些以前的研究，提供了一个全面的相似性和差异性在Amer蛋白家族。
The adenomatous polyposis coli (APC) membrane recruitment (Amer) family proteins Amer1/Wilms tumour gene on the X chromosome and Amer2 are binding partners of the APC tumour suppressor protein, and act as negative regulators in the Wnt signalling cascade. So far, nothing has been known about the third member of the family, Amer3. Here we show that Amer3 binds to the armadillo repeat domain of APC, similarly to Amer1 and Amer2. Amer3 also binds to the Wnt pathway regulator conductin/axin2. Furthermore, we identified Amer1 as binding partner of Amer3. Whereas Amer1 and Amer2 are linked to the plasma membrane by an N-terminal membrane localization domain, Amer3 lacks this domain. Amer3 localizes to the cytoplasm and nucleus of epithelial cells, and this is dependent on specific nuclear import and export sequences. Functionally, exogenous Amer3 enhances the expression of a beta-catenin/T-cell factor-dependent reporter gene, and knockdown of endogenous Amer3 reduces Wnt target gene expression in colorectal cancer cells. Thus, Amer3 acts as an activator of Wnt signalling, in contrast to Amer1 and Amer2, which are inhibitors, suggesting a nonredundant role of Amer proteins in the regulation of this pathway. Our data, together with those of previous studies, provide a comprehensive picture of similarities and differences within the Amer protein family.