Selective Use of ADAM10 and ADAM17 in Activation of Notch1 Signaling
Selective Use of ADAM10 and ADAM17 in Activation of Notch1 Signaling
复制标题
DOI：
10.1128/mcb.00406-09
复制
发表时间：
2009-11-01
影响因子：
5.3
通讯作者：
Weinmaster, Gerry
中科院分区：
文献类型：
--
作者：
Bozkulak, Esra Cagavi;Weinmaster, Gerry
Notch信号传导需要一系列蛋白水解切割事件以释放直接在信号转导中起作用的Notch胞内结构域（NICD）。Notch受体通过保护ADAM（去整合素和金属蛋白酶）切割位点的负调节区（NRR）锁定在蛋白酶抗性状态。与带有配体的细胞的接合诱导Notch中的全局构象运动，其展开NRR结构以暴露ADAM切割位点并启动蛋白水解活化。尽管已经报道了ADAM 10和ADAM 17都切割Notch以促进γ-分泌酶释放NICD，但相关的ADAM仍然存在争议。我们的研究为这一冲突提供了新的见解，因为我们发现，尽管Notch 1（N1）是ADAM 10和ADAM 17的底物，但受体激活所需的特定ADAM是依赖于环境的。具体而言，配体诱导的N1信号传导绝对需要ADAM 10，而不依赖于配体的信号传导需要ADAM 17。与ADAM 10和ADAM 17分别在正常和失调信号传导中的严格和有区别的使用相反，这两种蛋白酶都参与了与白血病相关的N1突变固有的信号传导。我们建议，除了暴露的ADAM切割位点，激活N1构象的变化，促进特定的蛋白酶的选择性切割。
Notch signaling requires a series of proteolytic cleavage events to release the Notch intracellular domain (NICD) that functions directly in signal transduction. The Notch receptor is locked down in a protease-resistant state by a negative regulatory region (NRR) that protects an ADAM (a disintegrin and metalloprotease) cleavage site. Engagement with ligand-bearing cells induces global conformational movements in Notch that unfold the NRR structure to expose the ADAM cleavage site and initiate proteolytic activation. Although both ADAM10 and ADAM17 have been reported to cleave Notch to facilitate NICD release by gamma-secretase, the relevant ADAM has remained controversial. Our study provides new insight into this conflict, as we find that although Notch1 (N1) is a substrate for both ADAM10 and ADAM17, the particular ADAM required for receptor activation is context dependent. Specifically, ADAM10 was absolutely required for N1 signaling induced by ligands, while signaling independent of ligands required ADAM17. In contrast to the strict and differential use of ADAM10 and ADAM17 in normal and dysregulated signaling, respectively, both proteases participated in signaling intrinsic to N1 mutations associated with leukemia. We propose that in addition to exposing the ADAM cleavage site, activating N1 conformational changes facilitate selective cleavage by specific proteases.