E3 ubiquitin ligase Mule targets β-catenin under conditions of hyperactive Wnt signaling
E3 ubiquitin ligase Mule targets β-catenin under conditions of hyperactive Wnt signaling
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DOI：
10.1073/pnas.1621355114
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发表时间：
2017-02-14
影响因子：
11.1
通讯作者：
Mak, Tak W.
中科院分区：
文献类型：
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作者：
Dominguez-Brauer, Carmen;Khatun, Rahima;Mak, Tak W.
Wnt信号，以与细胞表面受体结合激活该通路的分泌蛋白命名，在胚胎发育和许多成年组织的稳态维持中发挥关键作用。由Wnt信号调控的两个特别重要的细胞程序是增殖和干细胞自我更新。Wnt通路因突变或通路成分的不适当调节而导致的组成性激活有助于各种组织的癌症发展。结肠癌经常发生大肠腺瘤性息肉病（APC）基因失活突变，其产物是调节β -连环蛋白水平的破坏复合体的重要组成部分。β -连环蛋白的稳定和核定位导致一组Wnt靶基因的表达。我们之前发现Mule/ Huwe1/Arf-BP1 （Mule）通过c-Myc调节Wnt通路来控制小鼠肠干细胞和祖细胞的增殖。在这里，我们扩展了Mule对肿瘤发生影响的研究，表明Mule直接与β -连环蛋白相互作用，并在Wnt信号过度活跃的条件下靶向其降解。我们的研究结果表明，Mule使用多种机制来调节Wnt通路，并提供多种预防肿瘤发生的措施。
Wnt signaling, named after the secreted proteins that bind to cell surface receptors to activate the pathway, plays critical roles both in embryonic development and the maintenance of homeostasis in many adult tissues. Two particularly important cellular programs orchestrated by Wnt signaling are proliferation and stem cell self-renewal. Constitutive activation of the Wnt pathway resulting from mutation or improper modulation of pathway components contributes to cancer development in various tissues. Colon cancers frequently bear inactivating mutations of the adenomatous polyposis coli (APC) gene, whose product is an important component of the destruction complex that regulates beta-catenin levels. Stabilization and nuclear localization of beta-catenin result in the expression of a panel of Wnt target genes. We previously showed that Mule/ Huwe1/Arf-BP1 (Mule) controls murine intestinal stem and progenitor cell proliferation by modulating the Wnt pathway via c-Myc. Here we extend our investigation of Mule's influence on oncogenesis by showing that Mule interacts directly with beta-catenin and targets it for degradation under conditions of hyperactive Wnt signaling. Our findings suggest that Mule uses various mechanisms to finetune the Wnt pathway and provides multiple safeguards against tumorigenesis.