Ligand-induced signaling in the absence of furin processing of Notch1
Ligand-induced signaling in the absence of furin processing of Notch1
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DOI：
10.1006/dbio.2000.9992
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发表时间：
2001-01-15
影响因子：
2.7
通讯作者：
Weinmaster, G
中科院分区：
文献类型：
--
作者：
Bush, G;diSibio, G;Weinmaster, G
Notch是一种保守的细胞表面受体，通过与邻近的配体表达细胞直接接触而被激活。Notch 1基因（p300）的初级300-kDa翻译产物被弗林蛋白酶样转化酶切割，产生由180-（p180）和120-（p120）kDa多肽组成的异二聚体细胞表面受体。异二聚体Notch被认为是存在于细胞表面上并且能够响应于配体产生细胞内信号的受体的唯一形式。与先前的报道一致，我们发现，通过共表达弗林蛋白酶抑制剂或通过Notch 1自身内弗林蛋白酶靶序列的突变来破坏Notch 1的弗林蛋白酶加工，通过充分表征的Notch信号转导介体CSL（CBF 1、Su（H）和LAG-1）扰乱配体依赖性信号传导。然而，与这些报道相反，我们可以在细胞表面检测到全长p300 Notch 1产物。此外，这种未切割形式的Notch 1可以抑制C2 C12成肌细胞响应配体的分化。综上所述，这些数据支持我们以前的研究，其特征在于CSL独立的Notch信号通路，并将这种未切割的Notch亚型鉴定为该通路的潜在介体。我们的研究结果提示了一种新的信号转导模式，即同一细胞表面受体的两种亚型可以介导两种不同的信号通路。(C)北京：科学出版社.
Notch is a conserved cell surface receptor that is activated through direct contact with neighboring ligand-expressing cells. The primary 300-kDa translation product of the Notch1 gene (p300) is cleaved by a furin-like convertase to generate a heterodimeric, cell-surface receptor composed of 180- (p180) and 120- (p120) kDa polypeptides. Heterodimeric Notch is thought to be the only form of the receptor which is both present on the cell surface and able to generate an intracellular signal in response to ligand. Consistent with previous reports, we found that disruption of furin processing of Notch1, either by coexpression of a furin inhibitor or by mutation of furin target sequences within Notch1 itself, perturbed ligand-dependent signaling through the well-characterized mediator of Notch signal transduction, CSL (CBF1, Su(H), and LAG-1). Yet contrary to these reports, we could detect the full-length p300 Notch1 product on the cell surface. Moreover, this uncleaved form of Notch1 could suppress the differentiation of C2C12 myoblasts in response to ligand. Taken together, these data support our previous studies characterizing a CSL-independent Notch signaling pathway and identify this uncleaved isoform of Notch as a potential mediator of this pathway. Our results suggest a novel paradigm in signal transduction, one in which two isoforms of the same cell-surface receptor could mediate two distinct signaling pathways hi response to ligand. (C) 2001 Academic Press.