Crumbs promotes expanded recognition and degradation by the SCFSlimb/β-TrCP ubiquitin ligase
Crumbs promotes expanded recognition and degradation by the SCFSlimb/β-TrCP ubiquitin ligase
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DOI：
10.1073/pnas.1315508111
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发表时间：
2014-04
期刊：
影响因子：
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通讯作者：
Paulo S. Ribeiro;M. Holder;D. Frith;A. Snijders;N. Tapon
中科院分区：
文献类型：
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作者：
Paulo S. Ribeiro;M. Holder;D. Frith;A. Snijders;N. Tapon
意义组织生长的调节对于后生动物的发育和成体的体内平衡是必不可少的。Hippo（Hpo）通路是一种进化上保守的信号级联，其通过控制细胞增殖和细胞死亡而成为组织大小的关键调节剂。多种上皮结构输入汇聚在Hpo信号上，允许组织快速响应细胞-细胞和细胞-基质相互作用的破坏。在这里，我们表明极性蛋白Crumbs通过SCFSlmb/β-TRCP泛素连接酶促进Hpo途径蛋白Expanded的顶端定位和降解。这种泛素依赖性机制可能允许Hpo信号响应极性变化的动态调节。在上皮组织中，生长控制依赖于通过顶基极性和细胞-细胞接触维持适当的结构。Hippo信号通路通过与极性和细胞接触机制的紧密耦合来感知组织结构和细胞密度。顶端极性蛋白Crumbs（Crb）控制着Yorkie（Yki）/Yes激活蛋白的活性，Yorkie/Yes激活蛋白是果蝇和哺乳动物中Hippo途径核心激酶盒的促生长靶标。顶部定位的四点一、埃兹蛋白、根蛋白、膜突蛋白结构域蛋白扩展（Ex）通过促进激酶级联的活化和通过将Yki直接束缚到质膜来调节Yki。Crb与Ex相互作用并促进其顶端定位，从而将细胞极性与Hippo信号传导联系起来。我们发现，以及抑制Yki的招聘前顶端膜，Crb促进磷酸化依赖的泛素介导的降解前。我们鉴定了Skp/Cullin/F-boxSlimb/β-transducin repeats-containing protein（SCFSlimb/β-TrCP）作为负责Ex降解的E3泛素连接酶复合物。因此，Crb是促进Ex抑制Yki的稳态机制的一部分，但也通过诱导其降解来限制Ex活性，从而允许精确调节Yki功能。
Significance Regulation of tissue growth is essential for metazoan development and adult homeostasis. The Hippo (Hpo) pathway is an evolutionarily conserved signaling cascade that has emerged as a crucial regulator of tissue size by virtue of its control of cell proliferation and cell death. Multiple epithelial architecture inputs converge on Hpo signaling, allowing tissues to quickly respond to disruptions in cell–cell and cell–matrix interactions. Here, we show that the polarity protein Crumbs promotes the apical localization and degradation of the Hpo pathway protein Expanded, by the SCFSlmb/β-TRCP ubiquitin ligase. This ubiquitin-dependent mechanism could potentially allow the dynamic regulation of Hpo signaling in response to changes in polarity. In epithelial tissues, growth control depends on the maintenance of proper architecture through apicobasal polarity and cell–cell contacts. The Hippo signaling pathway has been proposed to sense tissue architecture and cell density via an intimate coupling with the polarity and cell contact machineries. The apical polarity protein Crumbs (Crb) controls the activity of Yorkie (Yki)/Yes-activated protein, the progrowth target of the Hippo pathway core kinase cassette, both in flies and mammals. The apically localized Four-point-one, Ezrin, Radixin, Moesin domain protein Expanded (Ex) regulates Yki by promoting activation of the kinase cascade and by directly tethering Yki to the plasma membrane. Crb interacts with Ex and promotes its apical localization, thereby linking cell polarity with Hippo signaling. We show that, as well as repressing Yki by recruiting Ex to the apical membrane, Crb promotes phosphorylation-dependent ubiquitin-mediated degradation of Ex. We identify Skp/Cullin/F-boxSlimb/β-transducin repeats-containing protein (SCFSlimb/β-TrCP) as the E3 ubiquitin ligase complex responsible for Ex degradation. Thus, Crb is part of a homeostatic mechanism that promotes Ex inhibition of Yki, but also limits Ex activity by inducing its degradation, allowing precise tuning of Yki function.