A ligand-induced extracellular cleavage regulates γ-secretase-like proteolytic activation of Notch1
A ligand-induced extracellular cleavage regulates γ-secretase-like proteolytic activation of Notch1
复制标题
DOI：
10.1016/s1097-2765(00)80416-5
复制
发表时间：
2000-02-01
期刊：
影响因子：
16
通讯作者：
Kopan, R
中科院分区：
文献类型：
--
作者：
Mumm, JS;Schroeter, EH;Kopan, R
跨膜结构域内位点 3 (S3) 的 γ-分泌酶样蛋白水解释放 Notch 胞内结构域 (NICD) 并激活 CSL 介导的 Notch 信号传导。 S3 处理仅在响应配体结合时发生；然而，这种调节的分子基础尚不清楚。在这里，我们证明配体结合促进了细胞外近膜区域内新位点（S2）的裂解，该位点用于释放 NICD 产生的胞外域抑制。 S2 处的切割产生称为 NEXT（Notch 细胞外截短）的瞬时中间肽。当 NICD 的产生被点突变或γ-分泌酶抑制剂或早老素 1 的缺失阻断时，NEXT 就会积累，并且抑制 NEXT 会消除 NICD 的产生。我们的数据表明，S2 裂解是导致 Notch 激活的蛋白水解级联中配体调节的步骤。
gamma-secretase-like proteolysis at site 3 (S3), within the transmembrane domain, releases the Notch intracellular domain (NICD) and activates CSL-mediated Notch signaling. S3 processing occurs only in response to ligand binding; however, the molecular basis of this regulation is unknown. Here we demonstrate that ligand binding facilitates cleavage at a novel site (S2), within the extracellular juxtamembrane region, which serves to release ectodomain repression of NICD production. Cleavage at S2 generates a transient intermediate peptide termed NEXT (Notch extracellular truncation). NEXT accumulates when NICD production is blocked by point mutations or gamma-secretase inhibitors or by loss of presenilin 1, and inhibition of NEXT eliminates NICD production. Our data demonstrate that S2 cleavage is a ligand-regulated step in the proteolytic cascade leading to Notch activation.