Both inhibition and activation of Notch signaling rely on a conserved Neuralized-binding motif in Bearded proteins and the Notch ligand Delta.
Both inhibition and activation of Notch signaling rely on a conserved Neuralized-binding motif in Bearded proteins and the Notch ligand Delta.
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DOI：
10.1016/j.ydbio.2009.06.039
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发表时间：
2009-09-15
影响因子：
2.7
通讯作者：
Posakony, James W.
中科院分区：
文献类型：
--
作者：
Fontana, Joseph R.;Posakony, James W.
侧抑制是Notch信号在动物发育过程中的关键功能之一。在产生果蝇机械感觉刷毛的前神经簇中，感觉器官前体（SOP）细胞中的Delta （Dl）配体被E3连接酶Neuralized （Neur）泛素化，从而激活Dl向邻近细胞上的Notch受体发出信号的能力。接收到这一信号的细胞激活了一个基因程序，该程序抑制了它们的SOP命运潜力，确保在每个集群中只有一个SOP发育。通过多种调查，我们提供了证据，证明beard家族蛋白（BFMs）的成员通过与Neur结合并阻止其与Dl相互作用来抑制非sop细胞中的Dl活化。我们发现bfm的这种活性依赖于保守的NXXN基序，并报告了意想不到的发现，一些bfm包含该基序的多个功能拷贝。我们发现Dl的胞内结构域中保守的NXXN基序负责其与Neur的相互作用，这表明Dl和BFMs之间直接竞争与Neur结合，并且我们发现Dl的神经依赖性内吞作用需要其NXXN基序的完整性。我们的研究结果阐明了Notch信号中一个重要的调控事件的机制，该事件似乎在昆虫和甲壳类动物之间是保守的。
Lateral inhibition is one of the key functions of Notch signaling during animal development. In the proneural clusters that give rise to Drosophila mechanosensory bristles, Delta (Dl) ligand in the sensory organ precursor (SOP) cell is targeted for ubiquitination by the E3 ligase Neuralized (Neur), resulting in activation of Dl’s capacity to signal to the Notch receptor on neighboring cells. The cells that receive this signal activate a genetic program that suppresses their SOP fate potential, insuring that only a single SOP develops within each cluster. Using multiple lines of investigation, we provide evidence that members of the Bearded family of proteins (BFMs) inhibit Dl activation in non-SOP cells by binding to Neur and preventing it from interacting with Dl. We show that this activity of BFMs is dependent on the conserved NXXN motif, and report the unexpected finding that several BFMs include multiple functional copies of this motif. We find that a conserved NXXN motif in the intracellular domain of Dl is responsible for its interaction with Neur, indicating direct competition between Dl and BFMs for binding to Neur, and we show that Neur-dependent endocytosis of Dl requires the integrity of its NXXN motif. Our results illuminate the mechanism of an important regulatory event in Notch signaling that appears to be conserved between insects and crustaceans.
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