Syntenin mediates Delta1-induced cohesiveness of epidermal stem cells in culture
Syntenin mediates Delta1-induced cohesiveness of epidermal stem cells in culture
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DOI：
10.1242/jcs.016253
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发表时间：
2007-08-15
影响因子：
4
通讯作者：
Watt, Fiona M.
中科院分区：
文献类型：
--
作者：
Estrach, Soline;Legg, James;Watt, Fiona M.
在人滤泡间表皮中，干细胞簇表达高水平的 Notch 配体 Delta1。 Delta1 刺激邻近细胞分化并促进干细胞聚集。尽管已知 Notch 信号传导可刺激表皮分化，但人们对 Delta1 促进表皮细胞凝聚力的机制知之甚少。这是一个重要的问题，因为干细胞的位置决定了它们接收的局部微环境信号。我们现在表明，Delta1 PDZ 结合域的突变消除了 Delta1 介导的角质形成细胞的粘聚性，刺激 Notch 转录活性并促进表皮分化。酵母双杂交筛选显示 Delta1 与接头蛋白 Syntenin 结合 - 这种相互作用依赖于 Delta1 PDZ 结合域。 Syntenin 与 Delta1 一样，在人滤泡间表皮干细胞簇中表达上调。在过表达全长 Delta1 的细胞中敲低 Syntenin 对 Notch 信号传导、表皮分化和粘附具有与过表达具有突变 PDZ 结合域的 Delta1 相同的效果。此前已报道 Syntenin 调节膜运输，Delta1 PDZ 结合域的突变或 Syntenin 的敲低导致 Delta1 快速内化。我们提出，syntenin 与 Delta1 结合在促进细胞间粘附和调节 Notch 信号传导方面发挥双重作用。
In human interfollicular epidermis, stem cell clusters express high levels of the Notch ligand Delta1. Delta1 stimulates neighbouring cells to differentiate and also promotes stem cell clustering. Although Notch signalling is known to stimulate epidermal differentiation, little is known about the mechanism by which Delta1 promotes epidermal cell cohesiveness. This is an important issue, because the location of stem cells determines the local microenvironmental signals they receive. We now show that mutation of the Delta1 PDZ-binding domain abolishes Delta1-mediated keratinocyte cohesiveness, stimulates Notch transcriptional activity and promotes epidermal differentiation. A yeast two-hybrid screen revealed that Delta1 binds to the adaptor protein syntenin - an interaction dependent on the Delta1 PDZ-binding domain. Syntenin, like Delta1, is upregulated in the stem cell clusters of human interfollicular epidermis. Knockdown of syntenin in cells overexpressing full-length Delta1 had the same effects on Notch signalling, epidermal differentiation and adhesion as overexpressing Delta1 with a mutated PDZ-binding domain. Syntenin has previously been reported to regulate membrane traffic, and mutation of the Delta1 PDZ-binding domain or knockdown of syntenin led to rapid internalisation of Delta1. We propose that syntenin binding to Delta1 plays a dual role in promoting intercellular adhesion and regulating Notch signalling.