Casein kinase 1γ couples Wnt receptor activation to cytoplasmic signal transduction
Casein kinase 1γ couples Wnt receptor activation to cytoplasmic signal transduction
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DOI：
10.1038/nature04170
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发表时间：
2005-12-08
期刊：
影响因子：
64.8
通讯作者：
Niehrs, C
中科院分区：
文献类型：
--
作者：
Davidson, G;Wu, W;Niehrs, C
Wnt蛋白（果蝇中的无翅蛋白）的信号传导在胚胎发育和成人中具有不同的作用，并与人类疾病（包括癌症）有关（1，2）。LDL受体相关蛋白5和6（LRP 5和LRP 6;果蝇中的Arrow）是多细胞动物中Wnt/β-连环蛋白信号传递所需的关键受体（3）。虽然这些受体在Wnt信号传导中的作用已经很好地建立，但它们与细胞质信号传导装置的偶联仍然不清楚。使用LRP 6调节蛋白修饰筛选，我们描述了爪蟾酪蛋白激酶1 γ（CK 1 γ），CK 1家族的膜结合成员的鉴定。功能获得和功能丧失实验表明，CK 1 γ是脊椎动物和果蝇细胞中抑制LRP 6信号传导所必需的，也是足够的。在非洲爪蟾胚胎中，前后图案形成期间需要CK 1 γ以促进后向Wnt/β-连环蛋白信号传导。CK 1 γ与LRP 6相关，LRP 6具有多个模块化CK 1磷酸化位点。Wnt处理诱导LRP 6内这些位点的快速CK 1 γ介导的磷酸化，这反过来又促进了支架蛋白Axin的募集。我们的研究结果揭示了一个进化上保守的机制，耦合Wnt受体激活的细胞质信号转导装置。
Signalling by Wnt proteins ( Wingless in Drosophila) has diverse roles during embryonic development and in adults, and is implicated in human diseases, including cancer(1,2). LDL-receptor-related proteins 5 and 6 (LRP5 and LRP6; Arrow in Drosophila) are key receptors required for transmission of Wnt/beta-catenin signalling in metazoa(3). Although the role of these receptors in Wnt signalling is well established, their coupling with the cytoplasmic signalling apparatus remains poorly defined. Using a protein modification screen for regulators of LRP6, we describe the identification of Xenopus Casein kinase 1 gamma (CK1 gamma), a membrane-bound member of the CK1 family. Gain-of-function and loss-of-function experiments show that CK1 gamma is both necessary and sufficient to transduce LRP6 signalling in vertebrates and Drosophila cells. In Xenopus embryos, CK1 gamma is required during anterio-posterior patterning to promote posteriorizing Wnt/beta-catenin signalling. CK1 gamma is associated with LRP6, which has multiple, modular CK1 phosphorylation sites. Wnt treatment induces the rapid CK1 gamma-mediated phosphorylation of these sites within LRP6, which, in turn, promotes the recruitment of the scaffold protein Axin. Our results reveal an evolutionarily conserved mechanism that couples Wnt receptor activation to the cytoplasmic signal transduction apparatus.