The two SAMP repeats and their phosphorylation state in Drosophila Adenomatous polyposis coli-2 play mechanistically distinct roles in negatively regulating Wnt signaling.
The two SAMP repeats and their phosphorylation state in Drosophila Adenomatous polyposis coli-2 play mechanistically distinct roles in negatively regulating Wnt signaling.
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果蝇腺瘤性息肉病 coli-2 中的两个 SAMP 重复序列及其磷酸化状态在负调节 Wnt 信号传导中发挥着机制上不同的作用。
DOI：
10.1091/mbc.e15-07-0515
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发表时间：
2015
影响因子：
3.3
通讯作者：
McCartney,BrookeM
中科院分区：
文献类型：
--
作者：
Kunttas-Tatli,Ezgi;VonKleeck,RyanA;Greaves,BradfordD;Vinson,David;Roberts,DavidM;McCartney,BrookeM
抑癌基因大肠杆菌 (APC) 作为 β-连环蛋白破坏复合物的重要组成部分，在调节经典 Wnt 信号通路中发挥着关键作用。 APC C 末端截短与散发性和家族性结直肠癌密切相关。然而，关于这些突变如何干扰 APC 的肿瘤抑制活性，仍然存在许多问题。在这些与癌症相关的截短中经常丢失的一组基序是介导 APC 和 Axin 之间相互作用的 SAMP 重复序列。脊椎动物和果蝇中的 APC 蛋白都含有多个 SAMP 重复序列，这些重复序列在轴蛋白结合基序之外缺乏高度的序列保守性。在本研究中，我们使用果蝇 APC2 及其两个 SAMP 重复序列作为模型，测试了不同 SAMP 之间的功能冗余以及这些结构域的调节方式。与基于序列保守的预测一致，我们表明 SAMP2 在体外对 Axin 具有更强的结合活性，但 SAMP1 在体内 Wnt 破坏复合物中也发挥着重要作用。此外，我们证明 SAMP 重复序列的磷酸化是调节其活性的潜在机制。总的来说，我们的研究结果支持一个模型，其中每个 SAMP 重复序列在机制上发挥着不同的作用，但它们合作实现最大程度的破坏复杂功能。
The tumor suppressor Adenomatous polyposis coli (APC) plays a key role in regulating the canonical Wnt signaling pathway as an essential component of the β-catenin destruction complex. C-terminal truncations of APC are strongly implicated in both sporadic and familial forms of colorectal cancer. However, many questions remain as to how these mutations interfere with APC’s tumor suppressor activity. One set of motifs frequently lost in these cancer-associated truncations is the SAMP repeats that mediate interactions between APC and Axin. APC proteins in both vertebrates andDrosophilacontain multiple SAMP repeats that lack high sequence conservation outside of the Axin-binding motif. In this study, we tested the functional redundancy between different SAMPs and how these domains are regulated, usingDrosophilaAPC2 and its two SAMP repeats as our model. Consistent with sequence conservation–based predictions, we show that SAMP2 has stronger binding activity to Axin in vitro, but SAMP1 also plays an essential role in the Wnt destruction complex in vivo. In addition, we demonstrate that the phosphorylation of SAMP repeats is a potential mechanism to regulate their activity. Overall our findings support a model in which each SAMP repeat plays a mechanistically distinct role but they cooperate for maximal destruction complex function.