Role of conserved intracellular motifs in Serrate signalling, cis-inhibition and endocytosis
Role of conserved intracellular motifs in Serrate signalling, cis-inhibition and endocytosis
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DOI：
10.1038/sj.emboj.7601337
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发表时间：
2006-10-18
期刊：
影响因子：
11.4
通讯作者：
Bray, Sarah
中科院分区：
文献类型：
--
作者：
Glittenberg, Marcus;Pitsouli, Chrysoula;Bray, Sarah
Notch是信号通路中的受体，在多种发育过程中起作用。其配体（例如Serrate）是跨膜蛋白，其信号传导能力受促进内吞作用的E3泛素连接酶Mindbomb 1和Neuralized调节。配体还抑制同一细胞中存在的Notch（顺式抑制）。在这里，我们确定了两个保守的基序在胞内结构域的锯齿，需要有效的内吞作用。第一，一个双亮氨酸基序，是反式激活和顺式抑制，尽管内吞缺陷，表明信号可以从散装内吞分离。第二个是一个新的基序，是与Mindbomb 1/Neuralized相互作用所必需的，并且是Serrate有效地反式激活和内化所必需的，但不是为了抑制Notch信号传导。当ER滞留信号被添加到Serrate时，或者当Neuralized的水平增加时，顺式抑制受到损害，并且这些数据一起表明顺式抑制相互作用发生在细胞表面。因此，泛素化/未泛素化配体的平衡将在几个水平上影响细胞的信号传导能力。
Notch is the receptor in a signalling pathway that operates in a diverse spectrum of developmental processes. Its ligands (e.g. Serrate) are transmembrane proteins whose signalling competence is regulated by the endocytosis-promoting E3 ubiquitin ligases, Mindbomb1 and Neuralized. The ligands also inhibit Notch present in the same cell (cis-inhibition). Here, we identify two conserved motifs in the intracellular domain of Serrate that are required for efficient endocytosis. The first, a dileucine motif, is dispensable for trans-activation and cis-inhibition despite the endocytic defect, demonstrating that signalling can be separated from bulk endocytosis. The second, a novel motif, is necessary for interactions with Mindbomb1/Neuralized and is strictly required for Serrate to trans-activate and internalise efficiently but not for it to inhibit Notch signalling. Cis-inhibition is compromised when an ER retention signal is added to Serrate, or when the levels of Neuralized are increased, and together these data indicate that cis-inhibitory interactions occur at the cell surface. The balance of ubiquitinated/ unubiquitinated ligand will thus affect the signalling capacity of the cell at several levels.