DSL ligand endocytosis physically dissociates Notch1 heterodimers before activating proteolysis can occur.
DSL ligand endocytosis physically dissociates Notch1 heterodimers before activating proteolysis can occur.
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DOI：
10.1083/jcb.200609014
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发表时间：
2007-02-12
期刊：
影响因子：
--
通讯作者：
Weinmaster G
中科院分区：
文献类型：
--
作者：
Nichols JT;Miyamoto A;Olsen SL;D'Souza B;Yao C;Weinmaster G
需要弗林蛋白酶切割Notch以产生成熟的细胞表面异源二聚体受体，该受体可以被蛋白水解激活以释放其在信号转导中起作用的细胞内结构域。目前的模型提出，配体与异二聚体Notch（hNotch）的结合诱导Notch胞外结构域（NECD）的解整合素和金属蛋白酶（ADAM）蛋白水解释放，其随后被DSL配体细胞脱落和/或内吞。我们提供的证据NECD释放和内化的DSL配体细胞，这令人惊讶的是，不需要ADAM活性。然而，hNotch形成或配体内吞作用的损失显著降低了NECD向DSL配体细胞的转移，以及Notch细胞中的信号传导。由于内吞缺陷配体结合hNotch，但不解离它，额外的力量以外，通过配体结合产生的功能必须破坏分子内的相互作用，保持hNotch完整和失活。基于我们的研究结果，我们提出DSL配体内吞作用过程中产生的机械力物理解离hNotch，解离是Notch激活的必要步骤。
Cleavage of Notch by furin is required to generate a mature, cell surface heterodimeric receptor that can be proteolytically activated to release its intracellular domain, which functions in signal transduction. Current models propose that ligand binding to heterodimeric Notch (hNotch) induces a disintegrin and metalloprotease (ADAM) proteolytic release of the Notch extracellular domain (NECD), which is subsequently shed and/or endocytosed by DSL ligand cells. We provide evidence for NECD release and internalization by DSL ligand cells, which, surprisingly, did not require ADAM activity. However, losses in either hNotch formation or ligand endocytosis significantly decreased NECD transfer to DSL ligand cells, as well as signaling in Notch cells. Because endocytosis-defective ligands bind hNotch, but do not dissociate it, additional forces beyond those produced through ligand binding must function to disrupt the intramolecular interactions that keep hNotch intact and inactive. Based on our findings, we propose that mechanical forces generated during DSL ligand endocytosis function to physically dissociate hNotch, and that dissociation is a necessary step in Notch activation.
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