Fringe glycosyltransferases differentially modulate Notch1 proteolysis induced by Delta1 and Jagged1
Fringe glycosyltransferases differentially modulate Notch1 proteolysis induced by Delta1 and Jagged1
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DOI：
10.1091/mbc.e04-07-0614
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发表时间：
2005-02-01
影响因子：
3.3
通讯作者：
Weinmaster, G
中科院分区：
文献类型：
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作者：
Yang, LT;Nichols, JT;Weinmaster, G
Fringe 0-岩藻糖-β1,3-N-乙酰氨基葡萄糖转移酶通过增强 Delta 样配体诱导的信号传导来调节 Notch 信号传导，同时抑制 Serrate/Jagged1 配体诱导的信号传导。根据结合研究，果蝇边缘 (DFng) 对 Notch 信号传导的不同影响被认为是由于 Notch 糖基化的改变引起的，这种改变增强了 Delta 与 Notch 的结合，但减少了 Serrate 的结合。在此，我们报告哺乳动物边缘蛋白（Lunatic [LFng]、Manic [MFng] 或 Radical [RFng] Fringe）的表达增加了 293T 和 NIH 3T3 细胞中 Delta1 的结合和 Notch1 信号传导的激活。尽管Jagged1诱导的信号传导被LFng和MFng抑制，但RFng增强了Delta1或Jagged1诱导的信号传导，强调了哺乳动物边缘糖基转移酶在调节不同配体-受体组合下游信号传导方面的多样性。有趣的是，Jagged1 诱导的 Notch1 信号传导的抑制与 Delta1 中 Jagged1 结合的变化并不相关。我们的数据支持边缘糖基化增加 Delta1 结合以增强信号传导的观点，但我们提出，尽管边缘糖基化不会减少 Jagged1 与 Notch1 的结合，但由此产生的配体-受体相互作用并不能有效促进激活下游信号事件所需的 Notch1 蛋白水解。
Fringe 0-fucose-beta1,3-N-acetylglucosaminyltransferases modulate Notch signaling by potentiating signaling induced by Delta-like ligands, while inhibiting signaling induced by Serrate/Jagged1 ligands. Based on binding studies, the differential effects of Drosophila fringe (DFng) on Notch signaling are thought to result from alterations in Notch glycosylation that enhance binding of Delta to Notch but reduce Serrate binding. Here, we report that expression of mammalian fringe proteins (Lunatic [LFng], Manic [MFng], or Radical [RFng] Fringe) increased Delta1 binding and activation of Notch1 signaling in 293T and NIH 3T3 cells. Although Jagged1-induced signaling was suppressed by LFng and MFng, RFng enhanced signaling induced by either Delta1 or Jagged1, underscoring the diversity of mammalian fringe glycosyltransferases in regulating signaling downstream of different ligand-receptor combinations. Interestingly, suppression of Jagged1-induced Notch1 signaling did not correlate with changes in Jagged1 binding as found for Delta1. Our data support the idea that fringe glycosylation increases Delta1 binding to potentiate signaling, but we propose that although fringe glycosylation does not reduce Jagged1 binding to Notch1, the resultant ligand-receptor interactions do not effectively promote Notch1 proteolysis required for activation of downstream signaling events.