Cell Cycle Control of Wnt Receptor Activation
Cell Cycle Control of Wnt Receptor Activation
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DOI：
10.1016/j.devcel.2009.11.006
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发表时间：
2009-12-15
影响因子：
11.8
通讯作者：
Niehrs, Christof
中科院分区：
文献类型：
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作者：
Davidson, Gary;Shen, Jinlong;Niehrs, Christof
低密度脂蛋白受体相关蛋白5和6（LRP5/6）是启动Wnt/β -连环蛋白信号传导的跨膜受体。LRP6胞质结构域中PPPSP基序的磷酸化对信号转导至关重要。通过全激酶组RNA干扰筛选，我们发现PPPSP磷酸化需要果蝇细胞周期蛋白依赖性激酶（CDK）L63。L63及其脊椎动物同源物PFTK受膜结合的G2/M细胞周期蛋白——细胞周期蛋白Y调控，细胞周期蛋白Y介导与LRP6的结合及对LRP6的磷酸化。因此，LRP6磷酸化和Wnt/β -连环蛋白信号传导受细胞周期控制，并在G2/M期达到峰值；有丝分裂调节因子CDC25/string的敲低会导致G2/M期阻滞，并以细胞周期蛋白Y依赖的方式增强Wnt信号传导。在非洲爪蟾胚胎中，体内LRP6磷酸化、母源Wnt信号传导以及Wnt依赖的胚胎前后轴模式形成都需要细胞周期蛋白Y。细胞周期蛋白/CDK复合物对LRP6在G2/M期的启动作用为Wnt信号传导引入了一种意想不到的新调控层面。
Low-density lipoprotein receptor related proteins 5 and 6 (LRP5/6) are transmembrane receptors that initiate Wnt/beta-catenin signaling. Phosphorylation of PPPSP motifs in the LRP6 cytoplasmic domain is crucial for signal transduction. Using a kinome-wide RNAi screen, we show that PPPSP phosphorylation requires the Drosophila Cyclin-dependent kinase (CDK) L63. L63 and its vertebrate homolog PFTK are regulated by the membrane tethered G2/M Cyclin, Cyclin Y, which mediates binding to and phosphorylation of LRP6. As a consequence, LRP6 phosphorylation and Wnt/beta-catenin signaling are under cell cycle control and peak at G2/M phase; knockdown of the mitotic regulator CDC25/string, which results in G2/M arrest, enhances Wnt signaling in a Cyclin Y-dependent manner. In Xenopus embryos, Cyclin Y is required in vivo for LRP6 phosphorylation, maternal Wnt signaling, and Wnt-dependent anteroposterior embryonic patterning. G2/M priming of LRP6 by a Cyclin/CDK complex introduces an unexpected new layer of regulation of Wnt signaling.